Table S2. ABCA4 variant categorization:
This variant was not evaluated.
270 Matching Annotations
- Last 7 days
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Table S2. ABCA4 variant categorization:
This variant was not evaluated.
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Table S2. ABCA4 variant categorization:
This variant is found in table S2A to have an OR of 0 with a CI (0-0.02). PS4 not met
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Table S2. ABCA4 variant categorization:
This variant was not evaluated.
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Table S2. ABCA4 variant categorization:
This variant is found in table S2A to have an OR of infinity with a CI (10.92-infinity).
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Table S2. ABCA4 variant categorization:
This variant is found in table S2A to have an OR of infinity with a CI (25.35-infinity), so PS4 is applicable
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Table S2. ABCA4 variant categorization:
This variant is found in table S2A to have an OR of infinity with a CI (14.02-infinity), so PS4 is applicable
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Table S2. ABCA4 variant categorization:
This variant was not evaluated.
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Table S2. ABCA4 variant categorization:
This variant was not evaluated.
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Table S2. ABCA4 variant categorization:
This variant is found in table S2A to have an OR of 47.7 with a CI (4.71-2311.43).
Tags
- automated_hgnc:34
- CA341277621
- CA202970
- ClinVarID: 1393961
- ClinGen ABCA4 Annotations
- ClinVarID: 1460063
- ClinVarID: 193579
- CA341280736
- CA341277358
- CA341277622
- CA200666
- CA341283936
- ClinVarID: 99455
- CA957117
- automated_hgnc_source:CAID
- CA227399
- PS4
- CA915941330
- ClinVarID: 99494
- ClinVarID: 2202780
- NoEvidence
- ClinVar ID: 2202779
- ClinVarID: 812202
- ClinVarID: 867010
- ClinVarID: 2114998
- SupplementalTable
Annotators
URL
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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7,554 ABCA4 ar Isolated female c.1554G>A (p.[?])a c.4254-2A>G (p.(?))a
Case#: 7,554 Female
DiseaseAssertion: Retinitis Pigmentosa
FamilyInfo: autosomal recessive
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
Genotyping Method: Previous genotyping and NGS
PreviouslyPublished:
Variant: NM_000350.3:c.1554G>A
ClinVar: 3720226
CAID: CA418825668
SupplementalData:
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www.ajo.com www.ajo.com
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STGD1 was determined according to initial symptoms of VA loss; fundus images showing orange-yellow flecks in the retina, a beaten-bronze appearance; and normal or cone-altered ffERG results
Case#: MD-0242, onset at 18yo, 24yo at report
DiseaseAssertion: STGD1
FamilyInfo: Segregation noted, but no specific details provided
CasePresentingHPOs:
CaseHPOFreeText: VA loss, BCVA=0.1/0.1, "STGD1 was determined according to initial symptoms of VA loss; fundus images showing orange-yellow flecks in the retina, a beaten-bronze appearance; and normal or cone-altered ffERG results"
CaseNotHPOs:
CaseNotHPOFreeText: VF loss, abnormal ERG
GenotypingMethod:
PreviouslyPublished: n/a
Variant: c.1715G>C p.(Arg572Pro); c.5242G>A p.(Gly1748Arg)
ClinVar: 99073
CAID: CA226919
SupplementalData: Table S1
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STGD1 was determined according to initial symptoms of VA loss; fundus images showing orange-yellow flecks in the retina, a beaten-bronze appearance; and normal or cone-altered ffERG results
Case#: MD-0790, Spanish
DiseaseAssertion: STGD1
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: "STGD1 was determined according to initial symptoms of VA loss; fundus images showing orange-yellow flecks in the retina, a beaten-bronze appearance; and normal or cone-altered ffERG results"
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Index cases were studied by different next-generation sequencing (NGS) strategies, including targeted gene panels, clinical exome, and/or whole-exome sequencing
PreviouslyPublished: n/a
Variant: c.1715G>C p.(Arg572Pro); c.4918C>T p.(Arg1640Trp)
ClinVar: 99073
CAID: CA226919
SupplementalData: Table S1
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iovs.arvojournals.org iovs.arvojournals.org
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Patients with RPE atrophy areas ≥0.05 mm2 secondary to STGD1 or AMD were included. RPE atrophy was defined as clearly demarcated definitely decreased fundus autofluorescence (FAF) under short-wavelength excitation light (488 nm) in combination with hypertransmission in optical coherence tomography (OCT).31,32 Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting visual function or image quality (e.g., significant media opacity, amblyopia or optic nerve disease) led to exclusion from the study. The diagnosis of AMD was based on soft drusen and other retinal alterations consistent with the disease,9 while the diagnosis of STGD1 was based on (1) a compatible phenotype (yellow-white flecks that correlated with hyperautofluorescent flecks on FAF imaging) and (2) the presence of at least one mutated ABCA4 allele as well as the absence of mutations in peripherin-2 (PRPH2). To avoid potential confounding, patients exhibiting “diffuse-trickling geographic atrophy” were not included, as choroidal insufficiency has been previously implicated in the pathogenesis.33–37 Genetic testing was conducted at the Institute of Human Genetics, University of Regensburg (n = 7), and at the Center for Human Genetics Bioscientia, Ingelheim (n = 6). Analysis of all coding exons of the ABCA4 and PRPH2 genes was done by either direct chain-terminating dideoxynucleotide Sanger sequencing, a custom-designed GeneChip CustomSeq Resequencing Array (RetChip; Affymetrix, Santa Clara, CA, USA), or next-generation sequencing (Regensburg, n = 5; Bioscientia, n = 6). Two patients (#1 and #3) were screened for known mutations/polymorphisms using the Asper Ophthalmics ABCR400 microarray followed by Sanger sequencing to confirm selected variants.38 Only STGD1 patients with a minimum age of onset (first reported subjective symptoms) of 45 years were included as defined previously.38,39 Healthy subjects without retinal pathology served as controls.
Case#: Patient #13
DiseaseAssertion: STGD1
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: RPE atrophy (clearly demarcated definitely decreased fundus autofluorescence (FAF) under short-wavelength excitation light (488 nm) in combination with hypertransmission in optical coherence tomography (OCT)) areas ≥0.05 mm2 secondary to STGD1 or AMD. diagnosis of STGD1 was based on (1) a compatible phenotype (yellow-white flecks that correlated with hyperautofluorescent flecks on FAF imaging) and (2) the presence of at least one mutated ABCA4 allele as well as the absence of mutations in peripherin-2 (PRPH2). Minimum age of onset (first reported subjective symptoms) of 45 years.
CaseNotHPOs:
CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting visual function or image quality (e.g., significant media opacity, amblyopia or optic nerve disease) led to exclusion from the study. “diffuse-trickling geographic atrophy”
GenotypingMethod: Analysis of all coding exons of the ABCA4 and PRPH2 genes was done by either direct chain-terminating dideoxynucleotide Sanger sequencing, a custom-designed GeneChip CustomSeq Resequencing Array, or NGS
PreviouslyPublished: possible since the study was at the same university with the same first author as PMID: 33214501
Variant: c.3468C>G/p.(Tyr1156*) and c.5059A>T/p.(Ile1687Phe)
ClinVar: n/a
CAID: CA341290648
SupplementalData: supplement 1 has the genotype for probands
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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STGD102 R572Q-2588G→C IVS35+2T→A Yes
Case#: STGD102, 10-14yo at onset, German
DiseaseAssertion: STGD
FamilyInfo: segregation in family
CasePresentingHPOs:
CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing
PreviouslyPublished: n/a
Variant: R572Q-2588G→C IVS35+2T→A in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"
ClinVar: 7900
CAID: CA226918
SupplementalData: n/a
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STGD113 L541P-A1038V 2588G→C Yes
Case#: STGD113, 20-24yo at onset, German
DiseaseAssertion: STGD
FamilyInfo: segregation in family
CasePresentingHPOs:
CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing
PreviouslyPublished: n/a
Variant: L541P-A1038V; 2588G→C in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"
ClinVar: 7879
CAID: CA119128
SupplementalData: n/a
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STGD138 IVS13+1GA 2588G→C Yes
Case#: STGD138, 15-19yo at onset, German
DiseaseAssertion: STGD
FamilyInfo: segregation in family
CasePresentingHPOs:
CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing
PreviouslyPublished: n/a
Variant: IVS13+1G→A; 2588G→C in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"
ClinVar: 7879
CAID: CA119128
SupplementalData: n/a
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STGD87 2588G→C Q1750X Yes
Case#: STGD87, 10-14yo at onset, German
DiseaseAssertion: STGD
FamilyInfo: segregation in family
CasePresentingHPOs:
CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing
PreviouslyPublished: n/a
Variant: Q1750X; 2588G→C in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"
ClinVar: 7879
CAID: CA119128
SupplementalData: n/a
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STGD47/164 IVS13+1G→A 2588G→C Yes
Case#: STGD47/164, 10-14yo at onset, German
DiseaseAssertion: STGD
FamilyInfo: segregation in family
CasePresentingHPOs:
CaseHPOFreeText: "The diagnosis of STGD was based on the demonstration of bilateral impairment of central vision and the appearance of perimacular and/or peripheral yellow-white flecks, with or without atrophy of the central retinal-pigment epithelium and a normal or only mildly abnormal flash electroretinogram when recorded in early stages of the disease."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: denaturing gradient gel electrophoresis, dHPLC, and SSCP analysis, PCR amplification of individual coding exons and flanking intron sequences, direct DNA sequencing
PreviouslyPublished: n/a
Variant: IVS13+1G→A; 2588G→C in trans "Correct segregation of disease alleles was demonstrated in all 39 cases in which family samples were available for study"
ClinVar: 7879
CAID: CA119128
SupplementalData: n/a
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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S2 File: This file contains the following sub-files: Figures A-C, Tables A-E and the references of the detected mutations in Tables A-E. Figure A shows the overall coverage of genes in the panel. Figures B and C show the genes that doesn’t reach 100% and 99%, respectively. Table A shows the variant numbers detected by NGS of 68 samples have previously tested by Sanger sequencing before. Table B shows the results of all 68 samples previously screened by Sanger sequencing. Table C shows the Z-score results for CNV detecting of family P041 and P048. Table D: Statistics of targeted NGS in 99 RP patients, shows the depth, coverage and variant numbers detected in 99 RP patients. Table E shows the mutations identified in 61 out of 99 RP patients.(RAR)pone.0185237.s002.rar (1.9M)GUID: D12AF020-8D31-4449-ACC9-879865E75832
Unable to open this type of file, but according to LOVD this paper contains this variant and it is not in the main text.
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Mutation scanning and direct DNA sequencing of all 50 exons of ABCR were completed for 150 families segregating recessive Stargardt disease (STGD1). ABCR variations were identified in 173 (57%) disease chromosomes, the majority of which represent missense amino acid substitutions. These ABCR variants were not found in 220 unaffected control individuals (440 chromosomes) but do cosegregate with the disease in these families with STGD1, and many occur in conserved functional domains. Missense amino acid substitutions located in the amino terminal one-third of the protein appear to be associated with earlier onset of the disease and may represent misfolding alleles. The two most common mutant alleles, G1961E and A1038V, each identified in 16 of 173 disease chromosomes, composed 18.5% of mutations identified. G1961E has been associated previously, at a statistically significant level in the heterozygous state, with age-related macular degeneration (AMD). Clinical evaluation of these 150 families with STGD1 revealed a high frequency of AMD in first- and second-degree relatives. These findings support the hypothesis that compound heterozygous ABCR mutations are responsible for STGD1 and that some heterozygous ABCR mutations may enhance susceptibility to AMD.
Annotating here since the full text is a PDF.
Case#: Family AR263 proband, male, US, 9yo at onset
DiseaseAssertion: Stargardt
FamilyInfo: 3 generations, no other affected members in the pedigree
CasePresentingHPOs:
CaseHPOFreeText: The essential and defining features of STGD were (1) pedigrees with at least one living affected individual compatible with autosomal recessive inheritance; (2) an ophthalmoscopically characteristic retinal disorder in families with both parents living; (3) bilateral central visual loss with both “beaten metal” elliptical foveal dystrophy and temporal pallor of the optic discs, documented by retinal color photography, with or without yellow-pigment epithelial flecks in the macular and/or retinal “near periphery”; and (4) the characteristic fluorescein angiographic feature of a dark choroid (Blacharski 1988).
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.6445C>T (p.Arg2149Ter); c.6079C>T (p.Leu2027Phe). Heteroduplex and SSCP analyses were used to screen the 50 exons of ABCA4
ClinVar: 99460
CAID: CA227404
SupplementalData: n/a
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Classification of noncanonical splice site variants according to the splice defects The percentage of correctly spliced ABCA4 RNA product for NCSS variants was calculated by using a capillary electrophoresis system (Fig. 4; Supplemental Table S3; Supplemental Fig. S5). Three variants, c.4634G>A, c.5196+3_5196+8del, and c.5585−10T>C, showed 100% correctly spliced ABCA4 mRNAs. We could rule out pathogenicity for the last two variants but not for c.4634G>A p.(Ser1545Asn), as this variant is significantly enriched in >3000 Caucasian STGD1 patients compared to the non-Finnish ExAC population (Cornelis et al. 2017). Sixteen variants showed between 4.3% and 79.6% normal RNA and were tentatively classified as severe, moderately severe, and mild, while the remaining 26 NCSS variants did not show any normal RNA and were thus deemed severe variants. For c.2382+5G>C and c.2588G>C, no quantification was performed as the wild-type BA12 clone also showed exon skipping. Based on the Sanger sequence validation, we were able to annotate all the variants at the RNA level and predict their effect at the protein level (Table 1). Figure 4. Open in a new tab Percentages of remaining normal ABCA4 transcripts due to noncanonical splice site variants based on capillary electrophoresis system analyses. The percentages of normal ABCA4 transcript for 45 noncanonical splice site variants are represented by black bars. Nineteen variants showed varying fractions (4.3%–100%) of correct ABCA4 mRNA. Four of them also result in missense changes as depicted, but only p.(Ser1545Asn) and p.(Lys2160Glu) are likely to have an effect on protein function, as significant amounts of ABCA4 protein will be produced. For the remaining 26 variants (in the square box), no residual RNA was observed. (#) For this variant, densitometric scanning was performed.Table 1. In vitro tested noncanonical splice site variants and their observed RNA and predicted protein effects Open in a new tabWe correlated the predicted effect of the NCSS variants with the phenotypes in reported cases and, when the variants were not present in a homozygous state, with the severity of the second allele. For 25 of 47 variants, sufficient clinical data were available, and in all these cases, our predicted effect of the NCSS variants correlated with the observed phenotypes (Supplemental Table S4).
RT-PCR of midigenes demonstrated that this variant impacts splicing by causing a deletion (r.5461_5714del) which is predicted to result in a frameshift (p.Thr1821Aspfs*6). This variant showed 0% correctly spliced ABCA4 mRNA. This frameshift variant introduces a premature stop codon between codons 1-2255 (PVS1(RNA); 29162642). There do appear to be alternative splice products (supplemental figure s2), where exon 39 or 40, or both 39 and 40, are skipped, but in all cases, this leads to a frameshift.
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Among 161 patients with a Stargardt-related phenotype previously assessed with the commercial ABCA4 mutation microarray, we analyzed the ABCA4 gene with High-resolution melting (HRM) in patients in whom the array analysis identified either a heterozygous mutation (n = 50) or no mutation (n = 30).
annotating here since the article is a PDF
Case#: Duno Patient D015, Danish
DiseaseAssertion: Stargardt flavimaculatus phenotype
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: The diagnosis was based on standard ophthalmological examinations including fundus photography, colour vision assessment, dark adaptometry, and full field ERG.
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: ABCA4 mutation microarray and High-resolution melting (HRM) in patients in whom the array analysis identified either a heterozygous mutation (n = 50) or no mutation (n = 30).
PreviouslyPublished: n/a
Variant: c.1654G>A p.V552I; c.6478A>G p.K2160E; c.3380G>A p.G1127E phase unknown
CAID: CA239745
SupplementalData:
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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The study included index patients with ABCA4-related retinopathy and their parents. ABCA4-related retinopathy was diagnosed based on characteristic findings on indirect ophthalmoscopy, optical coherence tomography, and conventional fundus AF imaging. The clinical diagnosis was confirmed by the presence of biallelic mutations in ABCA4, and segregation analysis was carried out with samples of the parents. All index patients and their parents underwent a complete ophthalmologic examination including best-corrected visual acuity (BCVA), slit-lamp examination, and indirect ophthalmoscopy with dilated pupils. Axial length and corneal curvature were measured using the IOL-Master 500 (Carl Zeiss Meditec, Jena, Germany). Healthy subjects without ocular disease served as controls. To minimize an influence of factors known to alter qAF measurements,22 exclusion criteria were age ≥ 65 years, ethnicity other than Caucasian, significant lens opacities, dilated pupil diameter below 7 mm, unstable fixation, refractive error > ±6 diopters (spherical equivalent), and any other additional known ocular pathology or prior intraocular surgery.
Case#: Muller Subject #8, 34yo, qAF=590
DiseaseAssertion: ABCA4-related retinopathy
FamilyInfo: mother was 59yo at report with qAF=399
CasePresentingHPOs:
CaseHPOFreeText: "ABCA4-related retinopathy was diagnosed based on characteristic findings on indirect ophthalmoscopy, optical coherence tomography, and conventional fundus AF imaging. The clinical diagnosis was confirmed by the presence of biallelic mutations in ABCA4, and segregation analysis was carried out with samples of the parents."
CaseNotHPOs:
CaseNotHPOFreeText: age ≥ 65 years, ethnicity other than Caucasian, significant lens opacities, dilated pupil diameter below 7 mm, unstable fixation, refractive error > ±6 diopters (spherical equivalent), and any other additional known ocular pathology or prior intraocular surgery.
GenotypingMethod: ABCA4 sequence analysis of all coding exons and flanking splice junctions was performed either by Sanger chain-terminating dideoxynucleotide sequencing after PCR amplification, by multiplex ligation-dependent probe amplification (MLPA) analysis (performed when only a single mutation was detected), or by next-generation sequencing (NGS) including a quantitative readout to detect large structural rearrangements using a gene panel covering 120 genes associated with inherited retinal disease as described previously.23 Validation of identified putatively pathogenic variants and segregation analysis were carried out by conventional sequencing
PreviouslyPublished: n/a
Variant: maternal allele: [c.1622T>C (p.Leu541Pro); c.3113C>T (p.Ala1038Val)]; paternal allele: c.1654G>A (p.Val552Ile); c.4771G>A (p.Gly1591Arg)
CAID: CA239745
SupplementalData:
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iovs.arvojournals.org iovs.arvojournals.org
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Thirty-Three Truncated and 98 Amino Acid–Changing Variants in the ABCA4 Gene
This variant was found on one allele of a Stargardt patient, but no additional details are provided about the patient or the other allele. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to evaluate the entire exonic and flanking intron sequence of the ABCA4 gene
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Thirty-Three Truncated and 98 Amino Acid–Changing Variants in the ABCA4 Gene
c.1989G>CA (p.Trp663Ter) variant was found on one allele of a Stargardt patient, but no additional details are provided about the patient or the other allele. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to evaluate the entire exonic and flanking intron sequence of the ABCA4 gene
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Thirty-Three Truncated and 98 Amino Acid–Changing Variants in the ABCA4 Gene
This variant was found on one allele of a Stargardt patient, but no additional details are provided about the patient or the other allele. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to evaluate the entire exonic and flanking intron sequence of the ABCA4 gene
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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-year-old girl without any detectable fundus abnormalities.
Case#: Patient 8 yo, F, Turkiye, onset at 8yo (early onset)
DiseaseAssertion:STGD1
FamilyInfo: no consanguinity between parents, neither parents are affected or show symptoms
CasePresentingHPOs: HP:0008035, HP:0011504
CaseHPOFreeText: vision of 6/10
CaseNotHPOs: HP:0000007, HP:0000608
CaseNotHPOFreeText: normal movements and mobility, unremarkable slit-lamp, no fundoscopy changes, unremarkable OCT
Genotyping Method: N/A
PreviouslyPublished: N/A
Variant: NM_000350.3a: c.3322C>T,p.(Arg1108Cys)rs61750120
CAID: CA220683
SupplementalData: N/A
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www-sciencedirect-com.libproxy.lib.unc.edu www-sciencedirect-com.libproxy.lib.unc.edu
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413; 19c.1804C>T; c.2828G>Ap.R602W (D); p.R943Q (U)16c.2453G>Ap.G818E (D)Compound heterozygous
Case#: Sporadic Case #4, Mexican
DiseaseAssertion: Stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosis based on: "onset of symptoms in childhood or early adulthood (before 20 years of age), bilateral central vision loss (central and peripheral visual field computerized testing), a retinal “beaten-bronze” foveal appearance and/or yellow-whitish flecks from the posterior pole to the mid periphery, normal caliber of the retinal vessels, no pigmented bone spicules in the retinal periphery, a normal to subnormal electroretinogram, and a typical dark choroid in fluorescein angiography."
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: allele 1: c.1804C>T (p.R602W) and c.2828G>A (p.R943Q) allele 2: c.2453G>A (p. G818E); direct sequencing of exons of ABCA4
ClinVar: 99135
CAID: CA227000
SupplementalData: n/a
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816c.2453G>Ap.G818E (D)28c.4249_4251 delTTCp.F1417del (D; N)Compound heterozygous
Case#: Familial Case #8, Mexican
DiseaseAssertion: Stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosis based on: "onset of symptoms in childhood or early adulthood (before 20 years of age), bilateral central vision loss (central and peripheral visual field computerized testing), a retinal “beaten-bronze” foveal appearance and/or yellow-whitish flecks from the posterior pole to the mid periphery, normal caliber of the retinal vessels, no pigmented bone spicules in the retinal periphery, a normal to subnormal electroretinogram, and a typical dark choroid in fluorescein angiography."
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: allele 1: c.2453G>A (p. G818E) allele 2: c.4249_4251 delTTC (p.F1417del); direct sequencing of exons of ABCA4
ClinVar: 99135
CAID: CA227000
SupplementalData: n/a
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1016c.2453G>Ap.G818E (D)16c.2453G>Ap.G818E (D)Homozygous
Case#: Sporadic Case #10, Mexican
DiseaseAssertion: Stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosis based on: "onset of symptoms in childhood or early adulthood (before 20 years of age), bilateral central vision loss (central and peripheral visual field computerized testing), a retinal “beaten-bronze” foveal appearance and/or yellow-whitish flecks from the posterior pole to the mid periphery, normal caliber of the retinal vessels, no pigmented bone spicules in the retinal periphery, a normal to subnormal electroretinogram, and a typical dark choroid in fluorescein angiography."
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.2453G>A (p. G818E) homozygous; direct sequencing of exons of ABCA4
ClinVar: 99135
CAID: CA227000
SupplementalData: n/a
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616; 41c.2453G>A; c.5824G>Cp. G818E (D); p. E1942Q (B;N)46c.6384A>Gp.H2128R (D)Compound heterozygous
Case#: Sporadic Case #16, Mexican
DiseaseAssertion: Stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosis based on: "onset of symptoms in childhood or early adulthood (before 20 years of age), bilateral central vision loss (central and peripheral visual field computerized testing), a retinal “beaten-bronze” foveal appearance and/or yellow-whitish flecks from the posterior pole to the mid periphery, normal caliber of the retinal vessels, no pigmented bone spicules in the retinal periphery, a normal to subnormal electroretinogram, and a typical dark choroid in fluorescein angiography."
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: allele 1: c.2453G>A (p. G818E); c.5824G>C (p. E1942Q) allele 2: c.6384A>G (p.H2128R) direct sequencing of exons of ABCA4
ClinVar: 867010
CAID: CA957117
SupplementalData: n/a
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1545c.6221G>Tp.G2074V (D; N)16c.2453G>Ap.G818E (D)Compound heterozygous
Case#: Sporadic Case #15, Mexican
DiseaseAssertion: Stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosis based on: "onset of symptoms in childhood or early adulthood (before 20 years of age), bilateral central vision loss (central and peripheral visual field computerized testing), a retinal “beaten-bronze” foveal appearance and/or yellow-whitish flecks from the posterior pole to the mid periphery, normal caliber of the retinal vessels, no pigmented bone spicules in the retinal periphery, a normal to subnormal electroretinogram, and a typical dark choroid in fluorescein angiography."
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: allele 1: c.6221G>T (p.G2074V) allele 2: c.2453G>A (p. G818E); direct sequencing of exons of ABCA4
ClinVar: 99135
CAID: CA227000
SupplementalData: n/a
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Local file Local file
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A 10-year-old female patient
Case#: Patient 10, female, Lithuanian, onset at 6yo
DiseaseAssertion: STGD
FamilyInfo:Both parents and older brother healthy; no clinical signs in grandparents or extended family; inheritance most likely autosomal recessive
CasePresentingHPOs: HP:0000505, HP:0012508, HP:0001105, HP:0025148, HP:0000662
CaseHPOFreeText: progressive central vision loss from age 6; visual acuity dropped from OD=0.3, OS=0.3 to OD=0.08, OS=0.1 over 4 years; fundus examination: yellow pisciform flecks at the maculae; OCT: thin atrophic neurosensory retina in foveal region, altered photoreceptor reflectivity, thinner RPE; ERG: loss of scotopic b-waves, attenuated scotopic a-wave, missing oscillatory potentials, loss of photopic a- and b-waves; “bull’s eye” maculopathy noted
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
Genotyping Method: RetChip v1.0 STGD-module array and confirmation by Sanger sequencing
PreviouslyPublished: n/a
Variant: ABCA4 NM_000350.2 c.1622T>C p.(L541P), NM_000350.2 c.3113C>T p.(A1038V)
CAID: CA226911, CA119135
SupplementalData: clinical images, OCT, ERG, and pedigree information included in supplemental data (Figs. 1–5)
Tags
- DecreasedCentralVA
- DecreasedERGResponses
- automated_hgnc:34
- Zygosity:Homozygous
- ClinGen ABCA4 Annotations
- InheritancePattern:AutosomalRecessive
- DiseaseEntity:STGD1
- AlleleOrigin:Germline
- automated_hgnc_source:CAID
- PreviousTesting
- Scotoma
- MacularFlecks
- FundusAutofluorescence
- Bull’sEyeMaculopathy
- MacularAtrophy
- SupplementalData
Annotators
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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MD-0560ABCA423c.3386G>Tp.Arg1129Leu47c.6410G>Ap.Cys2137Tyr16NPABCR400
Case#: Family MD-0560 Proband, 16yo at onset
DiseaseAssertion: AR Stargardt
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal electroretinogram (ERGs)." VA loss, VF loss, BCVA=0.1/0.1
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.6410G>A (p.Cys2137Tyr); c.3386G>T (p.Arg1129Leu) found by ABCR400
ClinVar: 2202779; 99224
CAID: CA341277358; CA227116
SupplementalData:
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MD-0170ABCA430c.4457C>Tp.Pro1486Leu9c.1222C>Tp.Arg408*14YesABCR400
Case#: MD-0170 Proband, 14yo at onset
DiseaseAssertion: STGD
FamilyInfo: Family MD-0170
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Haplotype analysis, ABCR400
PreviouslyPublished: unclear
Variant: c.4457C>T (p.Pro1486Leu); c.1222C>T (p.Arg408*)
ClinVar: 99283
CAID: CA227192
SupplementalData: n/a
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MD-0084ABCA447c.6410G>Ap.Cys2137Tyr47c.6410G>Ap.Cys2137Tyr7YesABCR400 + dHPLC + HRM + MLPAValverde et al. 2006 (6); Aguirre-Lamban et al. 2010 (16)
Case#: Family MD-0084 Proband, 7yo at onset
DiseaseAssertion: AR Stargardt
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)." VA loss, VF loss, BCVA=<0.05/<0.05
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: PMID: 16917483 (variant not found in this paper); PMID: 19959634
Variant: c.6410G>A (p.Cys2137Tyr) homozygous, found by ABCR400 + dHPLC + HRM + MLPA
ClinVar: 2202779
CAID: CA341277358
SupplementalData:
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MD-0242ABCA412c.1715G>Cp.Arg572ProNot detected18YesABCR400
Case#: Family MD-0242 Proband, 18yo at onset, Spanish
DiseaseAssertion: AR Stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Haplotype analysis, ABCR400 microarray, direct sequencing for confirmation
PreviouslyPublished: n/a
Variant: c.1715G>C p.Arg572Pro
ClinVar: 99073
CAID: CA226919
SupplementalData:
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MD-0302 ABCA4 12 c.1622T>C p.Leu541Pro 42 c.5882G>A p.Gly1961Glu 17 Yes ABCR400
another case with 541 variant potentially not in cis with 1038
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MD-0467 ABCA4 12 c.1622T>C p.Leu541Pro 43 c.5917delG p.Val1973* 7 NP ABCR400
another case with 541 variant potentially not in cis with 1038
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Sixty-six individuals representing 54 families were studied (Supplementary Material, Table S1). All individuals were found to harbor two ABCA4 variants likely to cause the retinal disease (18,20–26). In 40 families (74%), independent segregation of the two alleles was demonstrated. The ages at the time of their first visit ranged from 9 to 74 years (mean = 35.9, median = 35.2 years); in the majority of individuals (36/66=55%), data were available from a second visit that occurred on average 8.7 years (range=2–20 years, median = 6.9 years) after the first visit.
This variant was found in 6 different families (F32, F33, F40, F41, F42, and F43).
PP4: F32: Patient #37 is a 31yo male, ADI=4yo, dx of CRD F33: Patient #38 is a 32yo female, ADI=>32yo, dx of STGD, segregation in the family but no further details F40: Patient #45 is a 65yo male, ADI=26yo, dx of CRD, segregation of homozygous alleles with disease was demonstrated in 2 affected siblings in Family 40. F41: Patient #46 is a 38yo female, ADI=>38yo, dx of STGD F42: Patient #47 is a 45yo female, ADI=>53yo, dx of STGD F43: Patient #48 is a 55yo female, ADI=46yo, dx of STGD
PM3: In family 40, the proband was homozygous. In the other families, the variant was in compound heterozygosity with p.A1038V;p.L541P (F32); p.A1038V (F33); p.V1686M (F41); p.G1961E (F42); p.K2172R (F43).
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Sixty-six individuals representing 54 families were studied (Supplementary Material, Table S1). All individuals were found to harbor two ABCA4 variants likely to cause the retinal disease (18,20–26). In 40 families (74%), independent segregation of the two alleles was demonstrated. The ages at the time of their first visit ranged from 9 to 74 years (mean = 35.9, median = 35.2 years); in the majority of individuals (36/66=55%), data were available from a second visit that occurred on average 8.7 years (range=2–20 years, median = 6.9 years) after the first visit.
Case#: Patient #35, male, 35yo at report, 14yo at onset,
DiseaseAssertion: STGD
FamilyInfo: family 30, segregation was noted as "yes" but no other details provided
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod:
PreviouslyPublished: n/a
Variant: allele 1: A1038V;L541P allele 2: G818E
ClinVar: 99135
CAID: CA227000
SupplementalData: supplemental table 1
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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The latter finding suggests that loss of significance is likely due to lack of statistical power caused by the reduced number of individuals in the subsequent analyses (from n = 335 to n = 247 to n = 197 patients, Supplementary Table S5).
3 STGD patients have this variant but no specific clinical details (supplemental table s5).
Patient 79: c.1654G>A p.(V552I); c.5196+1013A>G
Patient 265: c.1654G>A p.(V552I) only
Patient 320: c.1654G>A p.(V552I); c.4254-1G>C; c.6230G>A p.(R2077Q)
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We found statistically significant association for six variations (c.1268A>G, c.4203C>A, c.5603A>T, c.5682G>C, c.5843C>T, c.6249C>T) (FDR < 0.05, Supplementary Table S4)
This paper is listed under the ClinVar citations for this variant, but only as a paper that references other variants in the initiator codon that have been observed in individuals with ABCA4-related conditions. The actual initiator variant included in this paper is c.1A>G
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www.nature.com www.nature.com
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Figure 3: Protein yield and ATP-binding capacity of 37 naturally occurring ABCR variants produced in transiently transfected 293 cells.Membranes were analysed by immunoblotting with affinity-purified anti-ABCR antibodies (top) and photoaffinity labelling with α-32P azido-ATP (bottom). We loaded 1 μg (immunoblotting) or 2.5 μg (azido-ATP labelling) of total membrane protein, as determined by Bradford assay, per track. The mutations that reside in NBD-1 and NBD-2 are indicated above the corresponding lanes. The relative levels of the different variant proteins and the extent of azido-ATP labelling were observed to be highly reproducible in multiple independent experiments. ABCR (large arrowhead); an endogenous 55-kD protein (small arrowhead) serves as an internal control for azido-ATP labelling. Molecular mass standards are shown on the left in kD.Full size imageThe combination of immunoblotting and azido-ATP labelling revealed defects in more than 75% of the variants tested. Among the variants with reduced yield and/or ATP binding are G863A and delG863, the two protein products of a guanosine2588→cytosine mutation that both generates a glycine-to-alanine substitution at codon 863 and activates a cryptic splice acceptor site in exon 17 that results in the removal of codon 863 from approximately 50% of the transcripts10. This is the most common allele among STGD patients in Northern Europe, representing roughly 20% of disease-associated alleles. It is also present at a frequency of approximately 3% in the general population in Northern Europe and approximately 1% in the United States population7,9,10. Genotype-phenotype correlations suggest that it is a mild allele and that it leads to STGD only when paired with a more severe allele10. Relative to wild type, the G863A variant is subtantially impaired and the delG863 variant is mildly impaired (Fig. 3).
This variant was transfected into HEK 293 cells and appears to show reduced expression and ATP-binding capacity, but no quantities were provided
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The two codon 863 variants, G863A and delG863, show a decrease in both basal and retinal-stimulated ATPase, with G863A showing the greater decrease (Fig. 4d).
In HEK293 cells, G863A was purified, reconstituted into membranes, and tested for basal and retinal-stimulated ATPase activities. G863A was shown to have reduced basal and retinal-stimulated ATPase (Fig 4d)
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Over 200 ABCA4 sequence variants have been reported so far in patients with STGD and other retinopathies1,5,6,7,8,9,10,11,12,13,14,15,16,17. We have examined 33 missense mutations, 3 small in-frame deletions and 1 frameshift near the carboxy terminus (Table 1 and Fig. 2), including those mutations most commonly encountered in STGD patients1,5,6,7,8,9,10,11 and several that were reported in AMD patients15. As an initial step in assessing protein folding and stability, we analysed each ABCR variant by immunoblotting and azido-ATP labelling (Fig. 3). Mutations that cause small deletions (delVVAIC1681 and delPAL1761) or introduce charged amino acids into predicted transmembrane domains (G851D and G1886E) produce greatly reduced amounts of protein. Among the ABCR variants that are expressed with normal or nearly normal yield, azido-ATP labelling revealed a subset that is defective in ATP binding. A variety of mutations that lie outside of the nucleotide-binding domains (NBDs) can impair azido-ATP labelling, including L541P, predicted to reside adjacent to a transmembrane domain, and W1408R, which resides between the homologous halves of ABCR (Fig. 2). These data suggest that ATP binding to the NBDs is allosterically coupled to conformational changes in or near the transmembrane regions. Moreover, some mutations within either of the two NBDs abolish or nearly abolish all azido-ATP labelling, as seen, for example, with variants T971N, L1971R, G1977S and E2096K, implying allosteric coupling between the two NBDs, as described for P-glycoprotein22,23.Table 1 Naturally occurring ABCR variants produced in transfected 293 cellsFull size tableFigure 2: Locations of 37 naturally occurring ABCR sequence variants and 4 synthetic mutations.The predicted transmembrane topography and domain structure of ABCR is based on the hydropathy profile and sequence alignment with other ABC transporters. The cytosolic face of the membrane is downward. NBD, nucleotide binding domain; HH, highly hydrophobic domain shared with other members of the ABC1/ABCR subfamily of ABC transporters. A, B and C indicate the sequence motifs characteristic of nucleotide binding folds. Asterisks denote the four synthetic mutations.Full size imageFigure 3: Protein yield and ATP-binding capacity of 37 naturally occurring ABCR variants produced in transiently transfected 293 cells.Membranes were analysed by immunoblotting with affinity-purified anti-ABCR antibodies (top) and photoaffinity labelling with α-32P azido-ATP (bottom). We loaded 1 μg (immunoblotting) or 2.5 μg (azido-ATP labelling) of total membrane protein, as determined by Bradford assay, per track. The mutations that reside in NBD-1 and NBD-2 are indicated above the corresponding lanes. The relative levels of the different variant proteins and the extent of azido-ATP labelling were observed to be highly reproducible in multiple independent experiments. ABCR (large arrowhead); an endogenous 55-kD protein (small arrowhead) serves as an internal control for azido-ATP labelling. Molecular mass standards are shown on the left in kD.Full size imageThe combination of immunoblotting and azido-ATP labelling revealed defects in more than 75% of the variants tested. Among the variants with reduced yield and/or ATP binding are G863A and delG863, the two protein products of a guanosine2588→cytosine mutation that both generates a glycine-to-alanine substitution at codon 863 and activates a cryptic splice acceptor site in exon 17 that results in the removal of codon 863 from approximately 50% of the transcripts10. This is the most common allele among STGD patients in Northern Europe, representing roughly 20% of disease-associated alleles. It is also present at a frequency of approximately 3% in the general population in Northern Europe and approximately 1% in the United States population7,9,10. Genotype-phenotype correlations suggest that it is a mild allele and that it leads to STGD only when paired with a more severe allele10. Relative to wild type, the G863A variant is subtantially impaired and the delG863 variant is mildly impaired (Fig. 3).
This variant was transfected into HEK 293 cells and appears to show reduced expression and ATP-binding capacity, but no quantities were provided
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Variants S206R and L541P have reduced basal ATPase and S206R shows little, and L541P shows no, stimulation by retinal (Fig. 4a).
L541P was purified, reconstituted into membranes, and tested for basal and retinal-stimulated ATPase activities. L541P was shown to have reduced basal ATPase, and no stimulation by retinal (Fig 4a)
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Figure 3: Protein yield and ATP-binding capacity of 37 naturally occurring ABCR variants produced in transiently transfected 293 cells.Membranes were analysed by immunoblotting with affinity-purified anti-ABCR antibodies (top) and photoaffinity labelling with α-32P azido-ATP (bottom). We loaded 1 μg (immunoblotting) or 2.5 μg (azido-ATP labelling) of total membrane protein, as determined by Bradford assay, per track. The mutations that reside in NBD-1 and NBD-2 are indicated above the corresponding lanes. The relative levels of the different variant proteins and the extent of azido-ATP labelling were observed to be highly reproducible in multiple independent experiments. ABCR (large arrowhead); an endogenous 55-kD protein (small arrowhead) serves as an internal control for azido-ATP labelling. Molecular mass standards are shown on the left in kD.
This variant was transfected into HEK 293 cells and appears to show reduced expression and ATP-binding capacity, but no quantities were provided
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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2 F 62 c.1222 C>T ND
Case Annotation Template
Case#: Patient 2, female, age 62
DiseaseAssertion: STGD
FamilyInfo: diagnosis of autosomal recessive STGD based on the pedigree and clinical phenotype of fleck deposits with or without genetic testing
CasePresentingHPOs: HP:0000608, HP:0000007, HP:0030610, HP:0030500
CaseHPOFreeText: Macular degeneration. autosomal recessive, Photoreceptor outer segment loss on macular OCT, Yellow/white lesions of the macula
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
Genotyping Method: n/a
PreviouslyPublished: n/a
Variant: ENST00000370225.4:c.1222C>T
ClinVar: NM_000350.3(ABCA4):c.1222C>T (p.Arg408Ter)
CAID: CA179692
SupplementalData: composite mask analysis shown in figure 3 for patient 2, "Both patient 2 and 14 show foveal preservation of IS/OS and RPE," "Patients 2, 19, and 11 show large areas of matched degeneration and isolated IS/OS loss, "
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10 F 19 c.2588G>C c.1222C>T
Case#: Patient 10, female, age 19
DiseaseAssertion: STGD
FamilyInfo: diagnosis of autosomal recessive STGD based on the pedigree and clinical phenotype of fleck deposits with or without genetic testing
CasePresentingHPOs: HP:0000608, HP:0000007, HP:0030610, HP:0030500
CaseHPOFreeText: Macular degeneration. autosomal recessive, Photoreceptor outer segment loss on macular OCT, Yellow/white lesions of the macula
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
Genotyping Method: n/a
PreviouslyPublished: n/a
Variant: Allele 1: NM_000350.3:c.2588G>C Allele 2: NM_000350.3:c.1222C>T
ClinVar: Allele 1: NM_000350.3(ABCA4):c.2588G>C (p.Gly863Ala) Allele 2: NM_000350.3(ABCA4):c.1222C>T (p.Arg408Ter)
CAID: Allele 1: CA119128 Allele 2: CA179692
SupplementalData: composite mask analysis shown in figure 3 for patient 10
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11 M 53 c.5461–10T>C ND
Case#: Patient 11, male, age 53
DiseaseAssertion: STGD
FamilyInfo: diagnosis of autosomal recessive STGD based on the pedigree and clinical phenotype of fleck deposits with or without genetic testing
CasePresentingHPOs: HP:0000608, HP:0000007, HP:0030610, HP:0030500
CaseHPOFreeText: Macular degeneration. autosomal recessive, Photoreceptor outer segment loss on macular OCT, Yellow/white lesions of the macula
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
Genotyping Method: n/a
PreviouslyPublished: n/a
Variant: NM_000350.3:c.5461-10T>C
ClinVar: NM_000350.3(ABCA4):c.5461-10T>C
CAID: CA220687
SupplementalData: composite mask analysis shown in figure 3 for patient 11, show large areas of matched degeneration and isolated IS/OS loss
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14 F 42 c.4222T >C c.4918C>T
Case#: Patient 14, female, age 42
DiseaseAssertion: STGD
FamilyInfo: diagnosis of autosomal recessive STGD based on the pedigree and clinical phenotype of fleck deposits with or without genetic testing
CasePresentingHPOs: HP:0000608, HP:0000007, HP:0030610, HP:0030500
CaseHPOFreeText: Macular degeneration. autosomal recessive, Photoreceptor outer segment loss on macular OCT, Yellow/white lesions of the macula
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
Genotyping Method: n/a
PreviouslyPublished: n/a
Variant: Allele 1: NM_000350.3:c.4222T>C Allele 2: NM_000350.3:c.4918C>T
ClinVar:Allele 1: NM_000350.3(ABCA4):c.4222T>C (p.Trp1408Arg) Allele 2: NM_000350.3(ABCA4):c.4918C>T (p.Arg1640Trp)
CAID:Allele 1: CA227166 Allele 2: CA227253
SupplementalData: composite mask analysis shown in figure 3 for patient 14, show diffusely intact IS/OS and RPE with central area of mixed types of degeneration. Both patient 2 and 14 show foveal preservation of IS/OS and RPE
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www.ajo.com www.ajo.commmc1.pdf7
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RP-0298 CRD 8 c.950del p.(Gly317Alafs*57) 33 c.4720G>T p.(Glu1574*) yes 10 10 8 36y - HM/HM This stud
This variant is found in compound heterozygosity with c.950del p.(Gly317Alafs*57) in family RP-0298 in this study. Proband is 10yo at onset of VA loss and VF loss, 8yo at night blindness, and 36yo at opthalmological exam. BCVA=HM/HM.
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MD-1146 STGD1 14 c.2023G>A p.(Val675Ile) 47 c.6410G>A p.(Cys2137Tyr) Yes 46 - - 46y Normal 1/1 This study
This variant is found in compound heterozygosity with c.2023G>A p.(Val675Ile) in family MD-1146 in this study. Proband is 46yo at onset of VA loss. 46yo at opthalmological exam. Normal ERG. BCVA=1/1. Not eligible for PP4 due to age of onset.
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MD-0740 STGD1 47 c.6410G>A p.(Cys2137Tyr) IVS28 c.4253+43G>A p.[=, Ile1377Hisfs*3] - 61 No - 62y - 0.8/0.16 This study
This variant is found in compound heterozygosity with c.4253+43G>A p.[=, Ile1377Hisfs*3] in family MD-0740 in this study. Proband is 61yo at onset of VA loss with no VF loss. 62yo at opthalmological exam. Cone pattern on ERG. BCVA=0.8/0.16. Not eligible for PP4 due to age of onset.
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MD-0560 STGD1 23 c.3386G>T p.(Arg1129Leu) 47 c.6410G>A p.(Cys2137Tyr) Yes 16 20 - 53y Normal 0.1/0.1 Riveiro-Alvarez et al.,2013
This variant is found in compound heterozygosity with c.3386G>T p.(Arg1129Leu) in family MD-0560 in a previous publication (PMID: 23755871)
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MD-1001 STGD1 44 c.6089G>A p.(Arg2030Gln) 47 c.6410G>A p.(Cys2137Tyr) - - - - - - - This study
This variant is found in compound heterozygosity with c.6089G>A p.(Arg2030Gln) in family MD-1001 in this study. No phenotype information provided. Not eligible for PP4 due to age of onset not being provided.
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MD-0247 STGD1 23 c.3386G>T p.(Arg1129Leu) 47 c.6410G>A p.(Cys2137Tyr) Yes 12 12 - 22y Cone-pattern 0.05/0.1 Riveiro-Alvarez et al.,2013
This variant is found in compound heterozygosity with c.3386G>T p.(Arg1129Leu) in family MD-0247 in a previous publication (PMID: 23755871)
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47 c.6410G>A p.(Cys2137Tyr) Aguirre-Lamban (2008) Hum Genet 123 547 8 missens
This variant is mentioned as being on 8 individual alleles in Spanish families from a previous publication (PMID: 19028736)
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iovs.arvojournals.org iovs.arvojournals.org
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ARDM-133 32T→C L11P 2888delG Frameshift Cosegregates
Case#: Family ARDM-133 Proband, Spanish Retinal Dystrophy Investigation Network (EsRetNet), 8yo at onset, 42yo at report
DiseaseAssertion: arCRD
FamilyInfo: cosegregates
CasePresentingHPOs: HP:0007663, HP:0000575, HP:0007641, HP:0000613
CaseHPOFreeText: "The diagnosis of CRD was based on the following criteria: initial complaints of blurred central vision without a history of night blindness, poor visual acuity (typically 20/100 or worse, with progressive decline from an early age), impairment of color vision, funduscopic evidence of atrophic macular degeneration, peripheral disturbances including pigment clumping and/or pigment epithelial thinning, and greater or earlier loss of cone than rod ERG amplitude."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: ABCR400 microarray, PCR amplification
PreviouslyPublished: n/a
Variant: 32T→C, L11P; 2888delG
ClinVar: 99217
CAID: CA227106
SupplementalData:
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jamanetwork-com.libproxy.lib.unc.edu jamanetwork-com.libproxy.lib.unc.edu
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Data from 244 and 645 individuals with ABCA4-AR from scanning and exon-sequencing techniques, respectively, from Lille University Hospital were included in the study, as well as data from 800 individuals from Moorfields Eye Hospital London and 271 individuals described by Corradi et al.13 In total, these data included 18 individuals with 2 mild_rp noncomplex variants. Individuals with c.2588G>C without c.5603A>T were mainly reported in the scanning dataset from Lille University Hospital and the Moorfields Eye Hospital London dataset. These datasets likely reported only a few cases with c.5603A>T in cis because the latter variant was long considered benign because of its high frequency. An overview of the data are given in the Table.
Looked through supplemental files and was unable to locate the patient from the LOVD entry for this variant for more phenotype details.
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academic-oup-com.libproxy.lib.unc.edu academic-oup-com.libproxy.lib.unc.edu
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(P5: G818E/L541P+A1038V
This variant is mentioned for patient 5 but is likely the same proband as in PMID: 19074458 since this is the same first author and same genotype
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Our case-control association study included 116 patients with atrophic AMD, 77 with RP, 86 with STGD, and 100 healthy controls. All the patients were evaluated by a standard ophthalmologic examination and OCT. ERG was performed on STGD and RP patients. All the subjects underwent a blood drawing for genetic testing and the CFHY402H polymorphism was genotyped with the TaqMan real-time polymerase chain reaction single nucleotide polymorphism assay.
annotating here since unable to annotate on PDF.
Case#: Stargardt patient 22, Italian
DiseaseAssertion: STGD
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: STGD criteria: "(1) juvenile to adult onset of symptoms; (2) bilateral central vision loss; (3) macular dystrophy and/or atrophy (beaten bronze appearance or large patch of atrophy); (4) normal caliber of retinal vessels; (5) absence of pigmented bone spicules. The presence of yellow-white flecks was not considered obligatory inclusion criteria, even though they could be found in most of the patients of our series. Similarly, the possible presence of the “dark choroid” phenomenon could be identified in the fluorescein angiography examinations carried out on some patients in previous clinical settings, but it was not considered significant for the recruitment."
CaseNotHPOs:
CaseNotHPOFreeText: "myopia >6 diopters, hyperopia and astigmatism >3 diopters, ocular disorders other than RP, STGD, or AMD, significant systemic diseases, a history of inflammation-associated diseases and media opacities preventing fundus examination"
GenotypingMethod: all coding exons, including intron-exon boundaries of the ABCA4 gene (NM 000350) were sequenced. PCR
PreviouslyPublished: n/a
Variant: c.5882G>A (p.Gly1961Glu); c.4450C>T (p.Pro1484Ser); c.203C>T (p.Pro68Leu)
ClinVar: 99113
CAID: CA226972
SupplementalData: Table S2
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Family: SG-04
MonDO: MONDO:0019353
Case: Family SG-04 Patient II:1. Indian Male, 26 years old diagnosed with Stargardt's disease DiseaseAssertion: Stargardt disease
FamilyInfo: Only child of nonconsanguineous parents. Proband's unaffected mother (I:1) harbored only one heterozygous variant (p.Gly1961Glu) in ABCA4. His father (I:2) was clinically normal and was not included for genetic testing.
CasePresentingHPOs: HP:0001129, HP:0007401 (Large central visual field defect, Macular atrophy)
CaseHPOFreeText: atrophic macular lesions
CaseNOTHPOs: HP:0011507 (macular flecks)
CasePreviousTesting: Five clinically confirmed unrelated patients with Stargardt disease and their available family members were enrolled for genetic analysis. Study subjects underwent a complete ophthalmic examination including measurement of visual acuity, intraocular pressure, slit lamp biomicroscopy, detailed fundus examination, fundus photography, fundus autofluorescence (FAF), spectral domain optical coherence tomography (SD-OCT), and full field electroretinography (ERG). Fifty normal controls without any history of eye diseases were included.
GenotypingMethod: NGS panel testing targeting 184 genes with previously known pathogenic variations associated with multiple eye disorders. Peripheral blood samples were obtained from all subjects.
MultipleGeneVariants:
(1) GeneName: ABCA4
(1) Variant: p.Gly1961Glu
(1) CAID: CA119132
(1) gnomAD: The total minor allele frequency in gnomAD v4.1.0 is 0.003406 (5498/1614012 alleles).
(2) GeneName: ABCA4
(2) Variant: p.Tyr872X
(2) CAID: CA341276149
(2) gnomAD: Not found in gnomad v. 4.1
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www.researchgate.net www.researchgate.net
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Finally, we examined whether the phenotype‐associated known/candidate pathogenic variants could explain the patient's disease, andif the MAF in population‐matched control data (8.3kJPN) was relatedto disease prevalence. Patients were classified as “Solved” if theirgenotype was consistent with their clinical phenotype. Patients wereclassified as “Partially solved” when a heterozygous known/candidatepathogenic variant was detected in a recessive allele, but without anadditional variant in trans. Patients were categorized as “Unsolved” iftheir genotypes exhibited either no candidate pathogenic variants ormultiple heterozygous pathogenic variants that did not explain thephenotype clearly. Variants annotated as causal for solved patients arelisted in Supporting Information: Table S2. Novel variants identified inthis study are listed in the second sheet of Table S2. SupportingInformation: Table S3 shows the phenotypes and genotypes of solvedpatients.2.4 | Statistical analysisBefore counting the allele frequency in our cohort, the list ofpatients was modified to contain only the proband to avoid theoverrepresentation of pedigrees with larger numbers of affectedindividuals. Inter‐pedigree comparisons of genetic diagnoses evaluat-ing proband only and proband with family members were performedby the chi‐square test. Enrichments of the pathogenic variants ingenetically solved and unsolved patients were compared by the one‐sided binominal test. Allele frequencies were compared with thehighest allele frequencies among the 8.3KJPN, HGVD, ExAC_EAS, andgnomAD_EAS databases. Statistical analyses were performed byR (ver. 4.0.3).2.5 | Detection of RP1:c.4052‐4053ins328(Alu insertion)Previously reported primers were used to amplify the expectedAlu‐inserted region (Nikopoulos et al., 2019). Genomic DNA wasamplified with Prime Star (TAKARA) following the manufacturer'sSUGA ET AL . | 310981004, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/humu.24492 by Mie University, Wiley Online Library on [07/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
This variant is listed in supplementary tables S2 and S3. Proband TM-319 is a "solved" patient, meaning the phenotype matches the genotype. Compound heterozygous (c.5318C>T p.A1773V) female with Stargardt disease- all that is provided.
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Finally, we examined whether the phenotype‐associated known/candidate pathogenic variants could explain the patient's disease, andif the MAF in population‐matched control data (8.3kJPN) was relatedto disease prevalence. Patients were classified as “Solved” if theirgenotype was consistent with their clinical phenotype. Patients wereclassified as “Partially solved” when a heterozygous known/candidatepathogenic variant was detected in a recessive allele, but without anadditional variant in trans. Patients were categorized as “Unsolved” iftheir genotypes exhibited either no candidate pathogenic variants ormultiple heterozygous pathogenic variants that did not explain thephenotype clearly. Variants annotated as causal for solved patients arelisted in Supporting Information: Table S2. Novel variants identified inthis study are listed in the second sheet of Table S2. SupportingInformation: Table S3 shows the phenotypes and genotypes of solvedpatients.2.4 | Statistical analysisBefore counting the allele frequency in our cohort, the list ofpatients was modified to contain only the proband to avoid theoverrepresentation of pedigrees with larger numbers of affectedindividuals. Inter‐pedigree comparisons of genetic diagnoses evaluat-ing proband only and proband with family members were performedby the chi‐square test. Enrichments of the pathogenic variants ingenetically solved and unsolved patients were compared by the one‐sided binominal test. Allele frequencies were compared with thehighest allele frequencies among the 8.3KJPN, HGVD, ExAC_EAS, andgnomAD_EAS databases. Statistical analyses were performed byR (ver. 4.0.3).2.5 | Detection of RP1:c.4052‐4053ins328(Alu insertion)Previously reported primers were used to amplify the expectedAlu‐inserted region (Nikopoulos et al., 2019). Genomic DNA wasamplified with Prime Star (TAKARA) following the manufacturer'sSUGA ET AL . | 310981004, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/humu.24492 by Mie University, Wiley Online Library on [07/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
This variant is listed in supplementary tables S2 and S3. Proband TI-50 is a "solved" patient, meaning the phenotype matches the genotype. Homozygous female with MD/CORD- all that is provided.
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Finally, we examined whether the phenotype‐associated known/candidate pathogenic variants could explain the patient's disease, andif the MAF in population‐matched control data (8.3kJPN) was relatedto disease prevalence. Patients were classified as “Solved” if theirgenotype was consistent with their clinical phenotype. Patients wereclassified as “Partially solved” when a heterozygous known/candidatepathogenic variant was detected in a recessive allele, but without anadditional variant in trans. Patients were categorized as “Unsolved” iftheir genotypes exhibited either no candidate pathogenic variants ormultiple heterozygous pathogenic variants that did not explain thephenotype clearly. Variants annotated as causal for solved patients arelisted in Supporting Information: Table S2. Novel variants identified inthis study are listed in the second sheet of Table S2. SupportingInformation: Table S3 shows the phenotypes and genotypes of solvedpatients.
This variant is listed in supplementary tables S2 and S3. Proband KN-187 is a "solved" patient, meaning the phenotype matches the genotype. Compound heterozygous (c.6290C>T p.P2097L; c.6445C>T p.R2149X) male with Stargardt disease- all that is provided.
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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In 20 patients (19 STGD and 1 CRD), 18 different genotypes were identified (Table 1). Except p.Arg187His and p.Tyr954Ser variants, the rest of changes were previously reported as disease-associated allele. 14 The p.Arg187His and p.Tyr954Ser variants were not found in 100 ethnically matched control chromosomes. All the mutations identified in the 20 patients except one were detected by HRM for sensitivity of 95%; however, only 16 variants were identified by dHPLC for sensitivity of 80%. Table 1. View Table Mutations AnalyzedTable 1. Mutations Analyzed Family Exon Genotype Mutation Detected by dHPLC Mutation Detected by HRM Nucleotide Change Amino Acid Change ARDM-167 5 c.560G>A p.Arg187His No Yes ARDM-257 5 c.560G>A p.Arg187His No Yes ARDM-164 6 c.700C>T p.Gln234X Yes Yes ARDM-135 8 c.1029_1030insT p.Asn344fsX Yes No ARDM-240 15 c.2285C>A p.Ala762Glu Yes Yes ARDM-248 19 c.2861A>C p.Tyr954Ser Yes Yes ARDM-90 — IVS21-2A>T — Yes Yes ARDM-40 27 c.3943C>T p.Gln1315X Yes Yes ARDM-158 30 c.4537delC p.Gln1513fsX1525 Yes Yes ARDM-38 33 c.4739delT p.Leu1580fs Yes Yes ARDM-163 36 c.5172G>T p.Trp1724Cys Not Yes ARDM-197 36 c.5172G>T p.Trp1724Cys Yes Yes ARDM-181 — IVS38+5G>A — Yes Yes ARDM-125 40 — p.KNLFA1876dup Yes Yes ARDM-183 43 c.5929G>A(False −) p.Gly1977Ser(False −) Yes Yes ARDM-146 44 c.6140T>A p.lle2047Asn Yes Yes ARDM-174 — IVS44+2T>A — Yes Yes ARDM-247 47 c.6410G>A p.Cys2137Tyr* Yes Yes ARDM-84 47 c.6410G>A p.Cys2137Tyr† No Yes ARDM-225 48 c.6559C>T p.Gln2187X Yes Yes Previously unreported mutations are shown in bold. * Mutation in heterozygous. † Mutation in homozygous. Homozygous sequence alteration (p.Cys2137Tyr) could be identified from wild-type by HRM analyses (Fig. 1). In contrast, dHPLC did not distinguish any homozygous mutation, except when we mixed it, in a 1:1 proportion, with a previously sequenced wild-type sample at the end of each PCR session and before heteroduplex formation.
Case#: Family MD-0084/ARDM-84 Proband, 7yo at onset
DiseaseAssertion: AR Stargardt
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)." VA loss, VF loss, BCVA=<0.05/<0.05
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.6410G>A (p.Cys2137Tyr) homozygous, found by ABCR400 + dHPLC + HRM + MLPA
ClinVar: 2202779
CAID: CA341277358
SupplementalData: n/a
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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V1 H1 Exon 36.1–3 G>A chr1:94,484,001 c.5196+1137G>A 4 4 0 0
Case#: Braun Family 6 Proband (from left to right, top to bottom of available pedigrees), male
DiseaseAssertion: Stargardt
FamilyInfo: Genotypes not provided for parents. No siblings
CasePresentingHPOs:
CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer
PreviouslyPublished: n/a
Variant: c.5196+1137G>A; c.454C>T (p.R152X)
ClinVar: 438100
CAID: CA26843511
SupplementalData: pedigree in fig s2
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V1 H1 Exon 36.1–3 G>A chr1:94,484,001 c.5196+1137G>A 4 4 0
Case#: Braun Family 8 Proband (from left to right, top to bottom of available pedigrees), female
DiseaseAssertion: Stargardt
FamilyInfo: Unaffected carrier parents. c.5196+1137G>A maternally inherited; c.4577C>T (p.T1526M) paternally inherited
CasePresentingHPOs:
CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer
PreviouslyPublished: n/a
Variant: c.5196+1137G>A; c.4577C>T (p.T1526M)
ClinVar: 438100
CAID: CA26843511
SupplementalData: pedigree in fig s2
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V1 H1 Exon 36.1–3 G>A chr1:94,484,001 c.5196+1137G>A 4 4 0 0
Eight families that are not labelled all have this variant and pedigrees to show family information in supplemental figure s2.
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V1 H1 Exon 36.1–3 G>A chr1:94,484,001 c.5196+1137G>A 4 4 0 0
Case#: Braun Family 5 Proband (from left to right, top to bottom of available pedigrees), male
DiseaseAssertion: Stargardt
FamilyInfo: Proband has 1 affected sister with the same genotype and 1 unaffected, heterozygous brother. Genotypes not provided for parents.
CasePresentingHPOs:
CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer
PreviouslyPublished: n/a
Variant: c.5196+1137G>A; c.4363T>C (p.C1455R)
ClinVar: 438100
CAID: CA26843511
SupplementalData: pedigree in fig s2
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V1 H1 Exon 36.1–3 G>A chr1:94,484,001 c.5196+1137G>A 4 4 0 0
Case#: Braun Family 1 Proband (from left to right, top to bottom of available pedigrees), female
DiseaseAssertion: Stargardt
FamilyInfo: Both parents are unaffected heterozygotes. c.4139C>T (p.P1380L) paternally inherited, c.5196+1137G>A maternally inherited. Proband has 2 unaffected, heterozygous children.
CasePresentingHPOs:
CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer
PreviouslyPublished: n/a
Variant: c.5196+1137G>A; c.4139C>T (p.P1380L)
ClinVar: 438100
CAID: CA26843511
SupplementalData: pedigree in fig s2
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V1 H1 Exon 36.1–3 G>A chr1:94,484,001 c.5196+1137G>A 4 4 0 0
Case#: Braun Family 7 Proband (from left to right, top to bottom of available pedigrees), female
DiseaseAssertion: Stargardt
FamilyInfo: Unaffected carrier parents. c.5196+1137G>A maternally inherited; c.4561-10T>C paternally inherited
CasePresentingHPOs:
CaseHPOFreeText: "five or more of the following features of ABCA4-associated retinal disease: decreased visual acuity before age 20, decreased visual acuity as the first visual symptom, symmetrical fundus findings, pisciform flecks, beaten metal macular atrophy, bulls-eye maculopathy, peripapillary sparing, vermillion fundus, masked choroid on fluorescein angiography, nummular pigment overlying extensive macular atrophy, central outer retinal atrophy on optical coherence tomography and central scotomas on Goldmann perimetry."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: one plausible disease-causing mutation detected in ABCA4 after assessing the entire coding sequence and canonical retinal splice junctions with automated bidirectional Sanger sequencing using an ABI 3730 sequencer
PreviouslyPublished: n/a
Variant: c.5196+1137G>A; c.4561-10T>C
ClinVar: 438100
CAID: CA26843511
SupplementalData: pedigree in fig s2
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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5 4514 S 12 1/10 / 1/10 c.32T>C(1) / c.[1A>G(1)]+[6089G>A(44)] p.Leu11Pro [12]/p.(Met1Val [6])+(Arg2030Gln [9])
Case#: Maia-Lopes Family 5 Proband 4514, Portuguese, 12yo at onset
DiseaseAssertion: STGD
FamilyInfo: Family 5
CasePresentingHPOs:
CaseHPOFreeText: severe central fundus changes, vision: 1/10 / 1/10
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: ABCR400 microarray, dHPLC
PreviouslyPublished: n/a
Variant: c.32T>C(1) / c.[1A>G(1)]+[6089G>A(44)]; p.Leu11Pro/p.(Met1Val)+(Arg2030Gln)
ClinVar: 99217
CAID: CA227106
SupplementalData: n/a
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11 4613 S 9 FC / FC c.[4926C>G(35)]+[5041_5055del(36)] / c.32T>C(1) p.(Ser1642Arg [10])+(Val1681_Cys1685del [10])/p.Leu11Pro
Case#: Maia-Lopes Family 11 Proband 4613, Portuguese, 9yo at onset
DiseaseAssertion: STGD
FamilyInfo: Family 11
CasePresentingHPOs:
CaseHPOFreeText: severe central fundus changes, vision: FC/FC
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: ABCR400 microarray, dHPLC
PreviouslyPublished: n/a
Variant: c.[4926C>G(35)]+[5041_5055del(36)] / c.32T>C(1); p.(Ser1642Arg [10])+(Val1681_Cys1685del [10])/p.Leu11Pro
ClinVar: 99217
CAID: CA227106
SupplementalData: n/a
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18 5709 Mi 9 2/10 / 2/10 c.32T>C(1) / c.1804C<T(13) p.Leu11Pro/p.Arg602Thr
Case#: Maia-Lopes Family 18 Proband 5709, Portuguese, 9yo at onset
DiseaseAssertion: STGD
FamilyInfo: Family 18
CasePresentingHPOs:
CaseHPOFreeText: mild central fundus changes, vision: 2/10 / 2/10
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: ABCR400 microarray, dHPLC
PreviouslyPublished: n/a
Variant: c.1804C<T/ c.32T>C(1); p.Arg602Thr/p.Leu11Pro
ClinVar: 99217
CAID: CA227106
SupplementalData: n/a
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www.jmdjournal.org www.jmdjournal.org
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Thirty-eight sporadic cases (60%) were resolved, of which 34 presented mutations in AR inheritance genes, three in AD inheritance genes, and one in XL inheritance. According to the genetic results, five initially AD retinitis pigmentosa (adRP) cases were reclassified to AR retinitis pigmentosa (arRP; fRPN-110) and to XL RP (fRPN-GB, fRPN-45, fRPN-97, fRPN-174), two arRP families to adRP (fRPN-AP, fRPN-168), one autosomal dominant MD family to late-onset retinal degeneration (LORD; fRPN-100), one Best MD case to CRD (fRPN-125), and one STGD case to Best MD (fRPN-39) (Supplemental Table S5).
Case#: Proband RPN-290, Male, 43yo at genetic testing, 27yo at dx, onset in 30s, Spanish
DiseaseAssertion: Nonsyndromic Inherited Retinal Dystrophies. Stargardt
FamilyInfo: Family RPN-133
CasePresentingHPOs:
CaseHPOFreeText: decreased visual acuity, photophobia, BCVA (logMAR) 28y: 0,0/0,0 35y: 0,4/0,1 43y: 1,0/1,0, central scotoma (56/ 63), yellow-white deposits around the macula, central and peripheral neuroepithelium thinning; 43y: without significant changes, 27y: normal visual evoked potentials, normal : full field electroretinography, abnormal electrooculogram (Arden index); 36y: delayed latency right eye visual evoked potentials, decreased cone and rod ffERG.
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: NGS; MLPA and array CGH
PreviouslyPublished: n/a
Variant: c.4457C>T; p.(Pro1486Leu) homozygous
ClinVar: 99283
CAID: CA227192
SupplementalData: supplemental table S2 has phenotype, S4 and S5 have genotype information
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Natural History of Stargardt Disease: The Longest Follow-Up Cohort Study
PMID: 37510299 Gene: ABCA4 CAID: CA119132
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Through a meta-analysis of published literature38,39, we also found that individuals with inherited retinal disease caused by recessive ABCA4 deficiency (Stargardt disease or cone rod dystrophy) are likely to have ASO-amenable variants in similar proportions (Supplementary Note 7 and Supplementary Tables 15 and 16), leading us to suggest that around 15% is a reasonable first estimate for other recessive genetic conditions.
This variant is found in supplemental table 16, but is referencing the cases from PMID 32619608
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Flow of individuals. A schematic representation showing the outcome of the 677 individuals with IRD participating in the study. *Supplementary Table 4. Indiv: individuals.
Case#: Patient #330
DiseaseAssertion: Stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: "Patients clinically suspected of having a retinal dystrophy were selected for the targeted analysis based on evaluation of available clinical records (clinical diagnosis, clinical history, fundus changes, OCT imaging, ERG, visual acuity, visual fields, family history)."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: NGS panel of 125 genes known to be associated with: retinitis pigmentosa, Bardet-Biedl syndrome, cone-rod dystrophy, Leber congenital amaurosis, Usher syndrome and congenital stationary night blindness (some genes cause more than one eye disorder).
PreviouslyPublished: n/a
Variant: 2453G>A (p.Gly818Glu)
ClinVar: 99135
CAID: CA227000
SupplementalData: supplemental table s4
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Seven hundred and fifty-six patients (98%) had inherited retinal diseases (IRD), and the remaining 17 (2%) had other etiologies, such as optic atrophy (6) and coloboma (4). Four hundred and eighty-three patients (62%) had a diagnosis of non-syndromic retinitis pigmentosa (RP), 41 (5%) of early-onset severe retinal dystrophy (EOSRD), 40 (5%) of Stargardt disease, 39 (5%) of Usher syndrome, 38 (5%) of macular dystrophy (MD), 19 (2%) of cone-rod dystrophy (CORD), 19 (2%) of choroideremia (CHM), and the remaining patients had less frequent conditions (Fig. (Fig.22 and Supplementary Table 1).
Case#: Patient 339, Argentinian
DiseaseAssertion: macular dystrophy
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.6383A>G (p.His2128Arg); c.4457C>T (p.Pro1486Leu) NGS
ClinVar: 99455
CAID: CA227399
SupplementalData: supplemental table 1 contains phenotype info
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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The 1,000 probands in this study came to our clinic from 40 different states, the District of Columbia and seven foreign countries (Supplemental Figure 1). Four hundred eighty-nine were female and 511 were male. The average age at entry into the study was 37.3 years (36.3 years for males and 38.5 years for females); the range was 8 months to 88 years. Plausible disease-causing genotypes were identified in 760 of these probands, 393 males and 367 females (Supplemental Table 1). The average age at entry into the study was very slightly younger for those in whom a disease-causing genotype was identified (34.9 years for males and 37.7 years for females).
Case#: Patient 817, female, 33yo at entry
DiseaseAssertion: Stargardt disease
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: category IIA (autosomal recessive stargardt disease)
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: one or more of the following approaches: automated Sanger sequencing with an ABI 3730xl sequencer, allele-specific genotyping with a Fluidigm EP1, amplification refractory mutation system (ARMS 17), chromosomal microarray analysis, and/or plasmid cloning of PCR products followed by Sanger sequencing. WES, WGS
PreviouslyPublished: n/a
Variant: c.1654G>A (p.Val552Ile); second variant not identified
CAID: CA239745
SupplementalData: supplemental table 1
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Four hundred eighty-nine were female and 511 were male. The average age at entry into the study was 37.3 years (36.3 years for males and 38.5 years for females); the range was 8 months to 88 years. Plausible disease-causing genotypes were identified in 760 of these probands, 393 males and 367 females (Supplemental Table 1). The average age at entry into the study was very slightly younger for those in whom a disease-causing genotype was identified (34.9 years for males and 37.7 years for females).
Case#: Patient 721, male, 41yo at entry
DiseaseAssertion: Stargardt disease
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: category IIA (autosomal recessive stargardt disease)
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: one or more of the following approaches: automated Sanger sequencing with an ABI 3730xl sequencer, allele-specific genotyping with a Fluidigm EP1, amplification refractory mutation system (ARMS 17), chromosomal microarray analysis, and/or plasmid cloning of PCR products followed by Sanger sequencing. WES, WGS
PreviouslyPublished: n/a
Variant: c.6416G>C p.Arg2139Pro; c.2588G>C p.Gly863Ala. confirmed in trans
CAID: CA10611614
SupplementalData: supplemental table 1
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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Filename Description aos14218-sup-0001-TableS1.xlsxMS Excel, 27.1 KB Table S1. List of genetic variants found in IRD patients, Norway, 2018. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
This variant is supposed to be listed in this paper per the LOVD entry; however, the protein change actually says it is Glu1228* instead
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ilename Description aos14218-sup-0001-TableS1.xlsxMS Excel, 27.1 KB Table S1. List of genetic variants found in IRD patients, Norway, 2018. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
This variant is reported to be found in 1 individual in heterozygous or compound heterozygous form, but there is no patient identifier, so impossible to know whether they have a second variant
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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The patients’ demographic and genetic characteristics are provided in eTable 1 in Supplement 1.
Proband can genotype and some phenotype information can be found in eTable 1.
Case#: Patient 601691#46, male, Italian, 32yo
DiseaseAssertion: ABCA4-Associated Retinopathy
GenotypingMethod: sequencing with Illumina NexSeq500 platform, confirmation with Sanger sequencing
PreviouslyPublished: n/a
Variant: c.5018+2T>C; c.6415C>T (p.Arg2139Trp)
CAID: CA227402
SupplementalData: eTable 1
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onlinelibrary-wiley-com.libproxy.lib.unc.edu onlinelibrary-wiley-com.libproxy.lib.unc.edu
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In the German cohort of 46 patients with single heterozygous ABCA4 variants, none of the known or any novel variant was found in the regions analyzed (Supp. Table S3).
Case#: Bauwens Case ID #20864, German
DiseaseAssertion: Simplex Retinitis Pigmentosa
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Screening for V1-V7 (deep intronic variants) negative, sequencing of the coding exons and intron–exon boundaries of ABCA4, Sanger sequencing
PreviouslyPublished:
Variant: c.1654G>A p.(Val552Ile), no second allele
CAID: CA239745
SupplementalData: supplemental table s3
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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We performed diagnostic NGS testing for 537 patients (287 males and 250 females) referred with clinical indications of IRD. All of the 537 individuals were initially referred on a singleton basis.Phenotype classification IRDs have a diverse spectrum of overlapping clinical presentation, which can vary by age of onset, extent of visual impairment, nature of disease progression and involvement of additional clinical features. We grouped all referred patients into 10 distinct clinical classifications (see online supplementary table S3). The most common referral was non-syndromic RCD/RP (n=250). The most common referral of syndromic disease was Usher syndrome (n=38), a disorder characterised by neurosensory hearing loss and visual impairment. There were eight cases of suspected syndromic ciliopathies referred, including seven cases of BBS.
Case#: Case #82863
DiseaseAssertion: CRD
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: n/a
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
GenotypingMethod: NGS panel of 105 genes
PreviouslyPublished: possible since this is an international cohort
Variant: c.3098delA; c.4139C>T p.(Pro1380Leu)
ClinVar: 236516
CAID: CA10581650
SupplementalData: supplemental table S3 has genotype info and phenotype
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Only one pathogenic change was detected in proband 2; c.1988G>A, p.(Trp663*) in exon 14. A second change, anticipated because of the recessive status of the disease, was not identified.
Variant detected in one allele (heterozygous) in Czech patient with Stargardt disease. No other ABCA4 variants detected.
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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STGD in 48 patients (55%) was explained by recessive ABCA4 mutations (supplemental table S2). Only 22 patients could be solved using previously known STGD causing mutations. However, we identified 35 novel mutations in ABCA4 contributing to the diagnosis of 25 STGD patients. This contained 10 novel mutations leading to amino acid substitutions already known to cause disease and mutations known to cause diseases other than STGD. In addition, we identified 13 novel nonsense mutations. The remaining 12 novel mutations are well justified, and novel mutations were either completely absent or extremely rare in controls.
Case#: Patient #126, Chinese
DiseaseAssertion: Stargardt
FamilyInfo: n/a
CasePresentingHPOs: "Clinical diagnosis of STGD was made when the patient, usually a child, developed central visual acuity loss with an atrophic maculopathy with or without flecks." No individual details
CaseHPOFreeText: n/a
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
GenotypingMethod: shotgun sequencing; Sanger sequencing; CNV analysis using CGH microarray
PreviouslyPublished: n/a
Variant: c.6119G>A p.(R2040Q); c.5776C>T p.(Q1926X)
CAID: CA232815
SupplementalData: info found in table S2
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STGD in 48 patients (55%) was explained by recessive ABCA4 mutations (supplemental table S2). Only 22 patients could be solved using previously known STGD causing mutations. However, we identified 35 novel mutations in ABCA4 contributing to the diagnosis of 25 STGD patients. This contained 10 novel mutations leading to amino acid substitutions already known to cause disease and mutations known to cause diseases other than STGD. In addition, we identified 13 novel nonsense mutations. The remaining 12 novel mutations are well justified, and novel mutations were either completely absent or extremely rare in controls.
Case#: Patient #133, Chinese
DiseaseAssertion: Stargardt
FamilyInfo: n/a
CasePresentingHPOs: n/a "Diagnosis of STGD was based on the clinical manifestations" is all that is stated
CaseHPOFreeText: n/a
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
PreviouslyPublished: n/a
Variant: c.6289 C>T p.(P2097S); c.4605_4606insT p.(V1535fs)
ClinVar: 2202780
CAID: CA341277622
SupplementalData: info found in table S2
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STGD in 48 patients (55%) was explained by recessive ABCA4 mutations (supplemental table S2). Only 22 patients could be solved using previously known STGD causing mutations. However, we identified 35 novel mutations in ABCA4 contributing to the diagnosis of 25 STGD patients. This contained 10 novel mutations leading to amino acid substitutions already known to cause disease and mutations known to cause diseases other than STGD. In addition, we identified 13 novel nonsense mutations. The remaining 12 novel mutations are well justified, and novel mutations were either completely absent or extremely rare in controls.
Case#: Patient #9, Canadian
DiseaseAssertion: Stargardt
FamilyInfo: n/a
CasePresentingHPOs: "Clinical diagnosis of STGD was made when the patient, usually a child, developed central visual acuity loss with an atrophic maculopathy with or without flecks." No individual details
CaseHPOFreeText: n/a
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
PreviouslyPublished: n/a
Variant: c.6383 A>G p.(H2128R); c.785 G>A p.(G1961E)
ClinVar: 99455
CAID: CA227399
SupplementalData: info found in table S2
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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p.Cys2137Tyr (c.6410G>A)0.63±0.090.45±0.03 0.32±0.120Severe 17(Riveiro-Alvarez et al., 2013)
The relative expression level (0.63) and relative substrate-stimulated ATPase activity (0.45-0.32) as compared to WT were assessed in transfected HEK293T cells. F-Index= 0, which is said to be "indicative of a severe phenotype" or categorized as Class 1 (F-index <0.05). Three or more independent experiments were carried out and unpaired T-test was used to analyze differences between WT and several variants
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The locations of ABCA4 homozygous and hypomorphic missense mutations characterized in the present study are shown in Fig 1. These mutations are distributed throughout ABCA4 with 4 in ECD1 (p.Asn96Asp, p.Asn96His, p.Arg212Cys, p.Arg602Trp), 4 in ECD2 (p.Leu1430Pro, p.Gly1439Asp, p.Pro1486Leu, p.Ala1598Asp), 6 within or close to NBD1 (p.Gly863Ala, p.Asn965Ser, p.Thr1019Met, p.Glu1087Lys, p.Arg1108Cys, p.Arg1129Leu), and 6 within NBD2 (p.Leu1940Pro, p.Gly1977Ser, p.Leu2027Phe, p.Arg2030Gln, p.Arg2107His, p.Cys2137Tyr). The p.Asn1868Ile mutation is present in a loop connecting the V-shaped α-helical hairpin with membrane spanning segment 12 (TM12). Several mutations occur in well-defined motifs crucial for the binding and hydrolysis of ATP. The p.Asn965Ser and p.Glu1087Lys mutations occur in the Walker A (Gly-His-Asn-Gly-Ala-Gly-Lys-Thr) and Walker B (Val-Ile-Leu-Asp-Glu) motifs of NBD1, respectively, and the p.Gly1977Ser mutation is present in the Walker A (Gly-Val-Asn-Gly-Ala-Gly-Lys-Thr) motif of NBD2. The p.Arg2030Gln variant reported to display a mild disease phenotype in compound heterozygous STGD1 patients has been included in our analysis although this variant has yet to be found in a homozygous state.
A ClinVar entry claimed this variant showed "impaired substrate binding capacity and limited substrate release after ATP binding," but it is not found in the text or figures and there is no supplementary data.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Screening of reported pathogenic variants in ABCA4 for Stargardt (STGD) The disease prevalence of STGD is estimated as 1 in 10000 individuals4. It has been estimated that about 70% of STGD patients carry variants in ABCA45. Therefore, this represents the scenario of a recessive disease with a relatively homogeneous genetic cause. We screened 945 reported pathogenic variants in ABCA4 genes collected in HGMD. Among them, 11 variants are likely benign, as their population AF in is higher than 0.7% (1/20000‾‾‾‾‾‾‾‾√)<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="M11"><mrow><mrow><mo>(</mo><mrow><msqrt><mrow><mn>1</mn><mo>/</mo><mn>20000</mn></mrow></msqrt></mrow><mo>)</mo></mrow></mrow></math>, the cutoff based on STGD disease prevalence, therefore were excluded from further analysis. The remaining 934 variants were subjected to our test model. As a result, 26 variants with the AF in the range of 0.46% to 0.03% were identified as likely benign (Binomial test1, Bonferroni correction p-value ≤ 0.05/934 and test2 Bonferroni correction p-value > 0.05/934) (Figure 3A).
This variant is reported in Table S6, but only location, predictions, frequencies, etc are reported for it, not cases.
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Screening of reported pathogenic variants in ABCA4 for Stargardt (STGD) The disease prevalence of STGD is estimated as 1 in 10000 individuals4. It has been estimated that about 70% of STGD patients carry variants in ABCA45. Therefore, this represents the scenario of a recessive disease with a relatively homogeneous genetic cause. We screened 945 reported pathogenic variants in ABCA4 genes collected in HGMD. Among them, 11 variants are likely benign, as their population AF in is higher than 0.7% (1/20000‾‾‾‾‾‾‾‾√)<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="M11"><mrow><mrow><mo>(</mo><mrow><msqrt><mrow><mn>1</mn><mo>/</mo><mn>20000</mn></mrow></msqrt></mrow><mo>)</mo></mrow></mrow></math>, the cutoff based on STGD disease prevalence, therefore were excluded from further analysis. The remaining 934 variants were subjected to our test model. As a result, 26 variants with the AF in the range of 0.46% to 0.03% were identified as likely benign (Binomial test1, Bonferroni correction p-value ≤ 0.05/934 and test2 Bonferroni correction p-value > 0.05/934) (Figure 3A).
This variant is reported in Table S6, but only location, predictions, frequencies, etc are reported for it, not cases.
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Screening of reported pathogenic variants in ABCA4 for Stargardt (STGD) The disease prevalence of STGD is estimated as 1 in 10000 individuals4. It has been estimated that about 70% of STGD patients carry variants in ABCA45. Therefore, this represents the scenario of a recessive disease with a relatively homogeneous genetic cause. We screened 945 reported pathogenic variants in ABCA4 genes collected in HGMD. Among them, 11 variants are likely benign, as their population AF in is higher than 0.7% (1/20000‾‾‾‾‾‾‾‾√)<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="M11"><mrow><mrow><mo>(</mo><mrow><msqrt><mrow><mn>1</mn><mo>/</mo><mn>20000</mn></mrow></msqrt></mrow><mo>)</mo></mrow></mrow></math>, the cutoff based on STGD disease prevalence, therefore were excluded from further analysis. The remaining 934 variants were subjected to our test model. As a result, 26 variants with the AF in the range of 0.46% to 0.03% were identified as likely benign (Binomial test1, Bonferroni correction p-value ≤ 0.05/934 and test2 Bonferroni correction p-value > 0.05/934) (Figure 3A).
This variant is reported in Table S6, but only location, predictions, frequencies, etc are reported for it, not cases.
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Screening of reported pathogenic variants in ABCA4 for Stargardt (STGD) The disease prevalence of STGD is estimated as 1 in 10000 individuals4. It has been estimated that about 70% of STGD patients carry variants in ABCA45. Therefore, this represents the scenario of a recessive disease with a relatively homogeneous genetic cause. We screened 945 reported pathogenic variants in ABCA4 genes collected in HGMD. Among them, 11 variants are likely benign, as their population AF in is higher than 0.7% (1/20000‾‾‾‾‾‾‾‾√)<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="M11"><mrow><mrow><mo>(</mo><mrow><msqrt><mrow><mn>1</mn><mo>/</mo><mn>20000</mn></mrow></msqrt></mrow><mo>)</mo></mrow></mrow></math>, the cutoff based on STGD disease prevalence, therefore were excluded from further analysis. The remaining 934 variants were subjected to our test model. As a result, 26 variants with the AF in the range of 0.46% to 0.03% were identified as likely benign (Binomial test1, Bonferroni correction p-value ≤ 0.05/934 and test2 Bonferroni correction p-value > 0.05/934) (Figure 3A).
This variant is reported in Table S6, but only location, predictions, frequencies, etc are reported for it, not cases.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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TABLE S2 Description and classification of variants observed to change classifications over time or between laboratories depicted in Figure 4. Separate tabs are present for different types of variant classifications changes: (a) changes from uncertain to pathogenic or benign, (b) changes from pathogenic to uncertain or benign, (c) changes from benign to pathogenic, (d) changes without clear trend.
This variant is listed in table S2 to show the change in classification over time, but no additional details are provided.
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Summary genetic testing data is available on the eyeGENE website (eyeGENE.nih.gov/data), including the number of participants for each of the 38 diagnostic categories, variants detected per gene, and variant classification by gene. As of the time of this writing, 3,448 eyeGENE participants have been reported to have at least one pathogenic or likely pathogenic genetic variant. The 10 most frequently reported genes were ABCA4 (1799, 37%), USH2A (316, 7%), RPGR (283, 6%), CHM (219, 5%), PRPH2 (161, 3%), RS1 (142, 3%), RHO (130, 3%), BEST1 (114, 2%), EYS (67, 1%), and PRPF31 (62, 1%). These 10 genes represent 68% of all pathogenic and likely pathogenic variants in eyeGENE. Two thousand one hundred and four participants have genetic results where no pathogenic or likely pathogenic variant was found. Variants of uncertain significance were identified in 1,712 individuals.
This paper was listed under this variant in LOVD, but I cannot find it in the main text or supplemental documents.
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Table.
MonDO: MONDO_0800406
GenotypingMethod: combined SSCP and heteroduplex analyses of all 50 exons of ABCA4, Sanger sequencing
For PP4: Patients harbored heterozygous or homozygous ABCA4 variants in addition to G1961E.
Case 7-1: Male, Jordanian, born to consanguineous parents, disease onset at 4 years (PP4 +0.5 pts), Stage 3 STGD, Compound Hmz G1961E and H1838D. PP4: 2.5 points.
Phenotype: central macular atrophy (PP4 +0.5 pts) with parafoveal or perifoveal flecks, severe fundus abnormalities, complete resorption of flecks with choriocapillaris atrophy also within the macula
Patient was previously reported in review article by Iannaccone A. The genetics of hereditary retinopathies and optic neuropathies. Compr. Ophthalmol Update. 2005;6:39–62. (No PMID). Fig 1C: "View of the right macula of a 10-year-old Jordanian male with autosomal recessive cone-rod dystrophy. There are atrophic changes, a beaten-bronze appearance (PP4 +0.5pts), and abnormal vitreoretinal interface reflexes. The central lesion is surrounded by a halo of coarse deep mottling (PP4 +0.5pts) and there were pigmentary deposits in the retinal midperiphery (not shown). Electroretinogram testing revealed a cone-rod pattern of severe retinal dysfunction. This patient was homozygous for a previously reported ABCA4 mutation resulting in a glycine-to-glutamate amino acid substitution at codon 1961 (G1961E), as well as a previously unreported change at codon 1838, predicting a histidine-to-aspartate amino acid change (H1838D) and seven additional polymorphisms. (PP4 +0.5pts)"
CasePresentingHPOs: HP:0007401, HP:0011507, HP:0001098, HP:0000548, HP:0025147, HP:0007793, HP:0001098 (Macular atrophy, Macular flecks, Abnormal fundus morphology, Cone/cone-rod dystrophy, Beaten bronze macular sheen, Granular macular appearance, Abnormal fundus morphology)
CaseHPOFreeText: abnormal vitreoretinal interface reflexes, chroiocapillaris atrophy
Case 7-2: Female, sibling of 7-1, Jordanian, born to consanguineous parents, disease onset at 7 years (PP4 +0.5 pts), Stage 4 STGD, Compound Hmz G1961E and H1838D (PP4 +0.5pts)
Phenotype: severe central macular atrophy (PP4 +0.5 pts), peripheral intraretinal pigmentation on fundus photography, extensive atrophy of the RPE, Central scotomata (PP4 +0.5pts) with reduced visual sensitivity more peripherally, severe fundus abnormalities, central macular atrophy with parafoveal or perifoveal flecks (PP4 +0.5pts), Widespread RPE and chorioretinal atrophy throughout the fundus
Case 8-1: Female, Italian, disease onset at 7 years (PP4 +0.5pts), Stage 3 STGD, Compound G1961E Hmz and N96K Het (PP4 +0.5 pts); PP4 = 3.5 pts
Phenotype: severe central macular atrophy (PP4 +0.5pts), peripheral intraretinal pigmentation on fundus photography, extensive atrophy of the RPE, Central scotomata (PP4 +0.5pts) with reduced visual sensitivity more peripherally, severe fundus abnormalities, central macular atrophy with parafoveal or perifoveal flecks (+PP4 0.5pts), complete resorption of flecks with choriocapillaris atrophy also within the macula, Decreased central acuity (VA score of 20/2000 in both eyes) (PP4 +1 pts)
CasePresentingHPOs: HP:0007401, HP:0000603, HP:0001098, HP:0011507, HP:0001141, HP:0030491 (Macular atrophy, Central scotoma, Abnormal fundus morphology, Macular flecks, Severely reduced visual acuity, chroiocapillaris atrophy)
CaseHPOFreeText: peripheral intraretinal pigmentation on fundus photography, atrophy of RPE
Case 8-2: Male, Italian, sibling of 8-1, disease onset at 10 years, Stage 4 STGD, N96K Het Central scotomata with reduced visual sensitivity more peripherally, severe fundus abnormalities, central macular atrophy with parafoveal or perifoveal flecks, Widespread RPE and chorioretinal atrophy throughout the fundus
Case 9: Female, Italian, disease onset set 12 years (PP4 +0.5pts), Stage 4 STGD, G1961E Hmz and N96K Hmz (PP4 +0.5pts); PP4 = 3 points history of early central vision loss (PP4 +1 pts), severe fundus abnormalities, central macular atrophy (PP4 +0.5pts) with parafoveal or perifoveal flecks (PP4 +0.5 pts), Widespread RPE and chorioretinal atrophy throughout the fundus.
Family members (parents and siblings) were available in all cases except for patients 6 and 10. The phase and true homozygosity of the G1961E mutation were determined by segregation analyses. Hemizygosity, that is the homozygous appearance due to the deletion on the other chromosome, was ruled out in all cases.
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Table S9. List of unique causative variants detected in 858 STGD probands mmc8.xlsx (19.3KB, xlsx) Table S11. STGD1 cases with at least two (likely) causal ABCA4 variants mmc9.xlsx (39.6KB, xlsx)
Case#: DNAID 071549/Pat23, male
DiseaseAssertion: STGD1
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: "In classic STGD1, loss of central vision starts around the second decade of life, but both early- and late-onset subtypes have been extensively described." No patient-specific details provided
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: smMIPs sequencing of the complete ABCA4 locus
PreviouslyPublished: n/a
Variant: c.6416G>C (p.Arg2139Pro); c.1648G>A (p.Gly550Arg)
CAID: CA10611614
SupplementalData: tables s9 and s11
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able S9. List of unique causative variants detected in 858 STGD probands mmc8.xlsx (19.3KB, xlsx) Table S11. STGD1 cases with at least two (likely) causal ABCA4 variants
Case#: DNAID 072884/Pat255, female
DiseaseAssertion: STGD1
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: "In classic STGD1, loss of central vision starts around the second decade of life, but both early- and late-onset subtypes have been extensively described." No patient-specific details provided
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: smMIPs sequencing of the complete ABCA4 locus
PreviouslyPublished: n/a
Variant: c.1519G>T (p.Asp507Tyr); c.5312+3A>T (p.Asn1734Glyfs*14) phase not confirmed
CAID: CA958508
SupplementalData: tables s9 and s11
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Table S9. List of unique causative variants detected in 858 STGD probands mmc8.xlsx (19.3KB, xlsx) Table S11. STGD1 cases with at least two (likely) causal ABCA4 variants mmc9.xlsx (39.6KB, xlsx)
Case#: DNAID 072888/Pat258, female
DiseaseAssertion: STGD1
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: "In classic STGD1, loss of central vision starts around the second decade of life, but both early- and late-onset subtypes have been extensively described." No patient-specific details provided
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: smMIPs sequencing of the complete ABCA4 locus
PreviouslyPublished: n/a
Variant: c.6416G>C (p.Arg2139Pro); c.3323G>A (p.Arg1108His)
CAID: CA10611614
SupplementalData: tables s9 and s11
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www.aaojournal.org www.aaojournal.org
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Among the 390 probands and 16 pseudodominant relatives in the cohort, 736 instances of 241 different alleles of the ABCA4 gene were observed (Table S2, available at www.aaojournal.org). A total of 10% of these alleles harbored terminating variants, 22% harbored splice-altering variants, and 61% harbored missense variants. No disease-causing variants could be found on 7% of the probands' alleles.
Case#: Proband P399, Family F345, male, 8yo at onset, US
DiseaseAssertion:
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: phenotypically focused tiered testing strategy beginning with allele-specific testing of the most common disease alleles and progressing through Sanger sequencing of candidate genes and, in many cases, to next generation sequencing of whole exomes and whole genomes
PreviouslyPublished: n/a
Variant: Pro1380Leu (c.4139C>T); Glu2031Lys (c.6091G>A) phase unconfirmed
ClinVar: 866538
CAID: CA341279017
SupplementalData: table s2 (listed as table 1 when you open it)
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jamanetwork.com jamanetwork.com
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Table 1shows the age, sex, vision at the most recent visit, fluorescein angiographic findings, and clinical phenotype for 29 patients with a possible disease-causing mutation in the ABCRgene. Each of the 29 patients were from different pedigrees. However, the mother of patient 12 and the father of patient 29 were also found to have compound heterozygous sequence variations in the ABCRgene.
Case#: Fishman Patient #22, male, 28yo
DiseaseAssertion: Stargardt dystrophy or fundus flavimaculatus
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: dark choroid, diffuse yellowish white flecks in the fundus, 20/400 OU, central scotoma
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: only one variant found: c.6383A>G (p.His2128Arg) Single-strand conformation polymorphism analysis and DNA sequencing were used to identify variations in coding sequences of the ABCRgene.
ClinVar: 99455
CAID: CA227399
SupplementalData:
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iovs.arvojournals.org iovs.arvojournals.org
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Eighty-four unrelated STGD1 patients were found to carry two or more disease-causing ABCA4 mutations, and cosegregation analyses were performed in 54 (64.3%). (See Supplementary Table S3 for a summary of clinical phenotype of STGD1 patients). The mean disease onset age of the patients was 13.1 years (range, 2–44 years), and half of these patients experienced their symptoms of visual impairment in their first decade. We classified the patients into three groups by their disease onset age. For the patients in the first group, whose disease onset ages were between 1 and 10 years, the fraction (45.3%, 19/42) of patients carrying compound heterozygous or homozygous deleterious mutations (nonsense, frameshift insertion or deletion, or splicing mutations) or complex alleles was much higher than those observed for the patients in the group 2 (24.1%, 7/29) and group 3 (15.4%, 2/13), whose disease onset ages were from 11 to 20 years or older than 20 years, respectively. In contrast, the percentage of patients carrying compound heterozygous or homozygous missense mutations was higher in group 3 than in group 1 or group 2 (Table 2). The most common mutation (p.Y808X) was detected in 12 patients, and all were heterozygous compound with missense (6 patients), splicing (1 patient), and insertion or deletion (5 patients) mutations. The two most frequent missense mutations (p.F2188S and p.N965S) were identified as heterozygous. In 84 patients, 9 patients carried complex mutations, and 4 of those 9 patients carried a common complex allele p.E328V/p.E1036K. All these patients had early onset age and relatively severe visual acuity defects. One patient (010222) also carried three heterozygous mutations (p.E328, p.E1036K, and p.R1843W); however, he did not harbor the common complex allele p.E328V/p.E1036K, as only p.E1036K was detected in his son in the subsequent cosegregation analysis. Compared to the four patients carrying the common complex alleles (p.E328V/p.E1036K), patient 010221 had a late onset age (44 years old).
Case#: Patient#010046, Chinese, 28yo at onset
DiseaseAssertion: stargardt
FamilyInfo: n/a
CasePresentingHPOs: STGD1 diagnosis based on the following criteria: "a bilateral central vision defect; fundus displaying a beaten-bronze appearance and/or orange-yellow flecks in the retina from the macula to the midperiphery; fluorescein angiography presenting with a typical dark choroid; and normal to subnormal ERG results." stage 2( numerous yellow-whitish flecks throughout the posterior pole) BCVA=0.05/ 0.05
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: p.P2097S; p.A1773V phase unknown
ClinVar: 2202780
CAID: CA341277622
SupplementalData: supplementary table S3 has phenotype information
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Eighty-four unrelated STGD1 patients were found to carry two or more disease-causing ABCA4 mutations, and cosegregation analyses were performed in 54 (64.3%). (See Supplementary Table S3 for a summary of clinical phenotype of STGD1 patients). The mean disease onset age of the patients was 13.1 years (range, 2–44 years), and half of these patients experienced their symptoms of visual impairment in their first decade. We classified the patients into three groups by their disease onset age. For the patients in the first group, whose disease onset ages were between 1 and 10 years, the fraction (45.3%, 19/42) of patients carrying compound heterozygous or homozygous deleterious mutations (nonsense, frameshift insertion or deletion, or splicing mutations) or complex alleles was much higher than those observed for the patients in the group 2 (24.1%, 7/29) and group 3 (15.4%, 2/13), whose disease onset ages were from 11 to 20 years or older than 20 years, respectively. In contrast, the percentage of patients carrying compound heterozygous or homozygous missense mutations was higher in group 3 than in group 1 or group 2 (Table 2). The most common mutation (p.Y808X) was detected in 12 patients, and all were heterozygous compound with missense (6 patients), splicing (1 patient), and insertion or deletion (5 patients) mutations. The two most frequent missense mutations (p.F2188S and p.N965S) were identified as heterozygous. In 84 patients, 9 patients carried complex mutations, and 4 of those 9 patients carried a common complex allele p.E328V/p.E1036K. All these patients had early onset age and relatively severe visual acuity defects. One patient (010222) also carried three heterozygous mutations (p.E328, p.E1036K, and p.R1843W); however, he did not harbor the common complex allele p.E328V/p.E1036K, as only p.E1036K was detected in his son in the subsequent cosegregation analysis. Compared to the four patients carrying the common complex alleles (p.E328V/p.E1036K), patient 010221 had a late onset age (44 years old). Table 2 View Table Correlations Between Onset Age of STGD Patients and Their Carrying Mutations
Per ClinVar entry, this variant was associated with this paper. however, after reading through the genotypes, this variant was not found. Likely this paper was mentioned to support the statement that "Loss-of-function variants in ABCA4 are known to be pathogenic"
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academic-oup-com.libproxy.lib.unc.edu academic-oup-com.libproxy.lib.unc.edu
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Functional studies of the arRP-associated complex allele [L541P; A1038V] also showed abnormal localization to rod IS although the IF studies revealed a different staining pattern than R602W, because the mutant protein forms fine aggregates in the IS (Fig. 2E and F). The aggregate formation suggests a mechanism distinct from that observed for R602W may be responsible for the retention of [L541P; A1038V] in the IS. To determine which mutation prevents translocation of [L541P; A1038V] to ROS, we examined functionally the L541P and A1038V mutants independently. We observed retention of L541P in the IS (Fig. 2G and H) and correct localization of A1038V to ROS (Fig. 2I and J). These results suggest that L541P is a disease-causing mutation that affects ABCA4 processing.
ABCA4 localization in transgenic tadpoles showed retention of L541P in the IS (Fig. 2G and H). However, this assay does not meet the requirements for use of PS3 by the ClinGen ABCA4 VCEP.
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AR197197–057CF 3 feet OD; CF 2 feet OSRP[L541P; A1038V][L541P; A1038V]197–069CF 5 feet OD; HM OSRP[L541P; A1038V][L541P; A1038V]
Case#: Family AR197 Proband 05, male, 7yo at onset
DiseaseAssertion: arRP
FamilyInfo: parents are het carriers, sibling (06) is affected and has the same genotype
CasePresentingHPOs:
CaseHPOFreeText: "diagnosed by clinical criteria (44) consistent with international standards and confirmed by review of ophthalmic records and retinal photographs. The clinical criteria included visual impairment at early age, progressive loss of peripheral visual functions and typical retinal changes of vascular attenuation, disc pallor and bone spicule accumulation." CF 3 feet OD; CF 2 feet OS
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: microarray chip, ABCR-400, PCR
PreviouslyPublished: n/a
Variant: [L541P; A1038V] and[L541P; A1038V]
ClinVar: 99067
CAID: CA226911
SupplementalData: n/a
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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93RECRDrecessive ABCA4 c.3988G>Tp.E1330XHet[a]c.6410G>Ap.C2137YHet[a]
Case#: 93RE proband, Spanish
DiseaseAssertion: cone rod dystrophy
FamilyInfo: 1 affected sibling with the same genotype. het, carrier parents
CasePresentingHPOs: n/a
CaseHPOFreeText:
CaseNotHPOs: n/a
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.6410G>A (p.C2137Y); c.3988G>T (p.E1330X) found on WES. Cosegregation with GNAT2, ZNF513, OPA1, RP1L1
ClinVar: 2202779
CAID: CA341277358
SupplementalData: pedigree with genotype in supplemental file
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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A total of 244 candidate variants were detected by exome sequencing
Per ClinVar entry, this variant was associated with this paper. however, after reading through the genotypes, this variant was not found. Likely this paper was mentioned to support the statement that "Loss-of-function variants in ABCA4 are known to be pathogenic"
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Patient 1 (P1
Case#: 12, Somali, onset 5 years old
DiseaseAssertion: STGD
FamilyInfo: Parents were heterozygous for Arg212Cys, no family history of IRD
CasePresentingHPOs: HP:0011504, ORPHA:827, HP:0000608
CaseHPOFreeText: Bull's eye maculopathy, macular degredation, red-green color defecit, reduced cone function
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
Genotyping Method: Whole exome sequencing
PreviouslyPublished: N/a
Variant:
ClinVar: NM_000350.3:c.5882G>A p.(Gly1961Glu) ; NM_000350.3:c.634C>T p.(Arg212Cys)
ClinVar: 7888; 7898
CAID: CA119132, CA203216
SupplementalData: N/a
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Patient 2 (P2)
Case#: Somali origin, 11 years of age, onset age 8
DiseaseAssertion: STGD
FamilyInfo: Parents were heterozygous for Arg212Cys, asymptoamtic 32 year old father was found to be homozygous for Gly1961Glu
CasePresentingHPOs: HP:0011504, ORPHA:827, HP:0000608
CaseHPOFreeText: BCVA 20/70 and 20/80, atrophic zone of outer retinal and RPE atrophy, Bull's Eye Maculopathy, Macular atrophy
CaseNotHPOs: N/a
CaseNotHPOFreeText: N/a
Genotyping Method: Whole genome sequencing
PreviouslyPublished: N/a
Variant: NM_000350.3:c.5882G>A p.(Gly1961Glu) ; NM_000350.3:c.634C>T p.(Arg212Cys)
ClinVar: 7888; 7898
CAID: CA119132, CA203216
SupplementalData: N/a
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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46-year-old male
Case#: a 46-year-old male
DiseaseAssertion: Pseudoxanthoma elasticum (PXE)
FamilyInfo: NR
CasePresentingHPOs: HP:0200034, HP:0011506, HP:0001102, HP:0025533, HP:0007401, HP:0200056, HP:0007754, HP:0031526, HP:0007663
CaseHPOFreeText: skin papules, CNV in right eye, angioid steaks, peau d'orange, peripheral comet lesions and macular atrophy at the poseterior pole (more severe in left eye). Juxtafoveal pigmented scar in right eye and fibrotic tissue at the interpapillomacular region in left eye. Pattern dystrophy-like changes were evident at posterior pole. OCT scan showed subretinal fluid with ellipsoid zone abnormalities at the fovea with juxtafoveal hyperreflective alteration corresponding to the fundus scar in the right eye. At the interpapillomacular region, the atrophy of the outer retinal layer and RPE was evident (hypertransmission phenomenon). In left eye, OCT scan showed widespread RPE atrophy with atrophy of the outer retinal layers. 6/10 visual acuity in right eye and 1/20 in left eye.
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
Genotyping Method: Whole exome sequencing analysis focusing on 340 genes associated with the calcification process or inherited retinal diseases
PreviouslyPublished: NR
Variant: c.6647C>T, p.Ala2216Val, NM_000350.3
ClinVar: 236149
CAID: CA10602405
SupplementalData: NR
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Case 3A 15-year-old female presented with complaints of difficulty reading materials held greater than 6 inches from her eyes. She was clinically diagnosed with STGD 4 years prior and noted decreased visual acuity since age seven, which stabilized over the past few years. Family history was not significant for ocular disease. Best-corrected visual acuity was 20/150 OU. Anterior segment exam was unremarkable with applanation tonometry measuring 16 mmHg OU. Posterior segment exam and autofluorescence was significant for bilateral central atrophy and pisciform fleck atrophy involving the peripapillary, macular, and peripheral regions OU (Figure 3, A and B). Genotyping was significant for ABCA4 mutations P1380L and R2030Q.Open in a separate windowFig. 3A and B, Case 3. STGD mutations P1380L and R2030Q. Autofluorescence OD and OS demonstrate atrophic fleck lesions involving the macula and periphery with an area of confluent atrophy superotemporal to the fovea OD. Hyperautofluorescent flecks are also present in the periphery OU. The peripapillary regions reveal atrophic flecks OU without areas of confluent atrophy.
Case#: Hwang Case 3, female, 15yo at report, 7yo at onset
DiseaseAssertion: Stargardt
FamilyInfo: Family history was not significant for ocular disease.
CasePresentingHPOs: HP:0500087, HP:0011507
CaseHPOFreeText: difficulty reading materials held greater than 6 inches from her eyes, decreased visual acuity since age seven. BCVA was 20/150 OU. Posterior segment exam and autofluorescence was significant for bilateral central atrophy and pisciform fleck atrophy involving the peripapillary, macular, and peripheral regions OU (Figure 3, A and B).
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Genotyping was performed by the ABCR400 microarray followed by direct sequencing to confirm identified variants.
PreviouslyPublished: n/a
Variant: P1380L and R2030Q
ClinVar: 7904
CAID: CA129033
SupplementalData: n/a
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Case 1
Case#: 55 year old female
DiseaseAssertion: Stargardt
FamilyInfo: no significant ocular disease shown.
CasePresentingHPOs: difficulty reading materials 6 inches from her eyes, decreased visual acuity from age seven. BCVA was 20/150 OU. Posterior segment exam and autofluorescence was significant for bilateral central atrophy and pisciform fleck atrophy involving the peripapillary, macular, and peripheral regions.
CaseHPOFreeText: NR
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
Genotyping Method: ABCR400 microarray
PreviouslyPublished: NR
Variant: NM_000350.3:c.4139C>T, NM_000350.3(ABCA4):c.6089G>A
ClinVar: 7904, 99428
CAID: CA129033
SupplementalData: NR
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Case 2A 19-year-old female referred for consultation for difficulty reading, particularly in dim light. She was clinically diagnosed with STGD 3 month prior, after complaining of gradual difficulty in focusing. Family history was not significant for ocular disease. Visual acuity measured 20/40 OD and 20/150 OS. Slit-lamp examination was unremarkable with normal anterior segments and applanation tensions of 14 mmHg OU. Funduscopic exam revealed bilateral central atrophy, multiple fleck lesions, multiple clumps of yellowish deposits at the level of the retinal pigment epithelium in the posterior pole surrounded with some pigment clumping, and no evidence of atrophy of the retinal pigment epithelium. Autofluorescence imaging revealed multifocal atrophic lesions involving the central macula and peripheral hyperautofluorescent flecks OU. The peripapillary regions demonstrated atrophic flecks OU without confluent atrophy (Figure 2, A and B). Genotyping revealed homozygous ABCA4 mutations, P1380L and P1380L.Open in a separate windowFig. 2Case 2. STGD mutations P1380L and P1380L. A, Autofluorescence OD. B, Autofluorescence OS show multifocal hypoautofluorescent (atrophic) lesions involving the central macula OU and peripheral hyperautofluorescent flecks OU. The peripapillary regions have atrophic flecks OU but there is not confluent peripapillary atrophy.
Case#: Hwang Case 2, female, 19yo at report, 18yo at onset
DiseaseAssertion: Stargardt
FamilyInfo: Family history was not significant for ocular disease
CasePresentingHPOs: HP:0007663, HP:0500087, HP:0011507
CaseHPOFreeText: difficulty reading, particularly in dim light; gradual difficulty in focusing. Visual acuity measured 20/40 OD and 20/150 OS. bilateral central atrophy, multiple fleck lesions, multiple clumps of yellowish deposits at the level of the retinal pigment epithelium in the posterior pole surrounded with some pigment clumping, and no evidence of atrophy of the retinal pigment epithelium. Autofluorescence imaging revealed multifocal atrophic lesions involving the central macula and peripheral hyperautofluorescent flecks OU. The peripapillary regions demonstrated atrophic flecks OU without confluent atrophy (Figure 2, A and B).
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Genotyping was performed by the ABCR400 microarray followed by direct sequencing to confirm identified variants.
PreviouslyPublished: n/a
Variant: P1380L homozygous
ClinVar: 7904
CAID: CA129033
SupplementalData: n/a
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Case 4A 52-year-old male was examined for declining vision OS over the past few months. He was previously clinically diagnosed with STGD 7 years before presentation. Family history was not significant for ocular disease. Best-corrected visual acuity measured 20/100 OD and 20/70 OS. Spherical refractive error measured −3.00 OD and −3.25 OS. Anterior segment examination was unremarkable and applanation tonometry measured 17 mmHg OD and 14 mmHg OS. Posterior segment examination was significant for central atrophy and classic peripheral pisciform flecks sparing the peripapillary regions OU (Figure 4, A and B). Autofluorescence imaging demonstrated inner atrophic flecks and outer hyperautofluorescent flecks. Moderate peripapillary hypoautofluorescence, but not atrophy, was present, likely secondary to the patient’s myopia (Figure 4, C and D). Genotyping revealed two heterozygous ABCA4 mutations, P1380L and S1696N.Open in a separate windowFig. 4Case 4. STGD mutation IVS40 + 5G>A. A, Color Photo OU. B, Red-Free Photo OU reveal central atrophy and classic peripheral pisciform flecks sparing the peripapillary regions OU. C, Autofluorescence OD. D, Autofluorescence OS show that the innermost flecks are hypoautofluorescent, consistent with atrophy, whereas the outermost flecks are hyperautofluorescent, demonstrating excess lipofuscin. There is moderate peripapillary hypoautofluorescence that is not as dark as this patient’s central atrophy or the peripapillary atrophy of Case 1. This finding may thus be due to the patient’s myopia.
Case#: Hwang Case 4, male, 52yo at report, 45yo at onset
DiseaseAssertion: Stargardt
FamilyInfo: Family history was not significant for ocular disease.
CasePresentingHPOs: HP:0000545
CaseHPOFreeText: declining vision OS, BCVA was 20/100 OD and 20/70 OS. Spherical refractive error measured −3.00 OD and −3.25 OS. Posterior segment examination was significant for central atrophy and classic peripheral pisciform flecks sparing the peripapillary regions OU (Figure 4, A and B). Autofluorescence imaging demonstrated inner atrophic flecks and outer hyperautofluorescent flecks. Moderate peripapillary hypoautofluorescence, but not atrophy, was present (Figure 4, C and D).
CaseNotHPOs: HP:0500087
CaseNotHPOFreeText:
GenotypingMethod: Genotyping was performed by the ABCR400 microarray followed by direct sequencing to confirm identified variants.
PreviouslyPublished: n/a
Variant: P1380L and S1696N
ClinVar: 7904
CAID: CA129033
SupplementalData: n/a
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Case 5
Case#: a 46-year-old male
DiseaseAssertion: Stargardt Disease
FamilyInfo:visual acuity loss by his brother and father
CasePresentingHPOs: HP:0007663
CaseHPOFreeText: visual acuity measured 20/400 bilaterally
CaseNotHPOs: NR
CaseNotHPOFreeText:NR
Genotyping Method: ABCA4 microarray (ABCR5000 chip)
PreviouslyPublished: NR
Variant: c.5714+5G>A
ClinVar: 99403
CAID: CA227338
SupplementalData:NR
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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P12‡20MG1961EG1961E/P68L
previously reported in PMID: 26377081
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Patient 8, a 13-year-old individual carrying two mutations, the p.Leu541Pro and p.Ala1038Val, most likely as a complex allele, had an early disease onset with 20/200 VA and stage 4 FC (Table 1). Previous reports have documented the severity and early age of onset associated with the p.[Leu541Pro;Ala1038Val] complex variant.36,38 Our screening studies failed to detect an additional mutation in ABCA4 in patients 6, 8, or 12.
Case#: Patient 8, 13yo at report, British Columbia, Canada
DiseaseAssertion: Stargardt disease
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: stage 4 Fishman classification (extensive choroid and RPE atrophy throughout the fundus, decreased ERG cone and rod amplitudes, and moderate to severe peripheral field restriction). Visual acuity= 20/200
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: exons and exon-intron boundaries of ABCA4, CNGB3, and ELOVL4 were sequenced
PreviouslyPublished: n/a
Variant: L541P; A1038V phase unknown, but likely a complex allele
ClinVar:
CAID: CA226911
SupplementalData: n/a
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Patient 4 with an early frameshift mutation in one allele and a downstream p.Val552Ile mutation in the second allele has a mild form of STGD1. Because the frameshift mutation is likely to result in a null allele, any residual functional activity of ABCA4 would arise from ABCA4 harboring the p.Val552Ile missense mutation. Our in vitro studies showing that the p.Val552Ile variant expresses at close to WT levels, exhibits normal N-Ret-PE binding properties, and has only a modest reduction in ATPase activity (Table 2) are consistent with the mild disease phenotype of patient 4. Another study has also reported that the p.Val552Ile mutation is associated with a STGD1 disease phenotype.50 However, in silico predictions on the pathological relevance of this mutation have been variable.20,13 On the basis of allele frequencies in controls versus patients, it has been argued that the p.Val552Ile is most likely benign.20 At a protein level, a hydrophobic amino acid residue valine is replaced with another hydrophobic residue isoleucine. Accordingly, this substitution would be predicted to have only a marginal impact on ABCA4 protein structure and function. However, valine at position 552 of ABCA4 is invariable among vertebrate species, including other mammals, chicken, Xenopus, and Japanese puffer fish (Takifugu rubripes), attesting to the likely importance of valine at this position. Collectively, these studies suggest that the p.Val552Ile is a mild mutation in which the pathogenicity may only be displayed in selected cases. More specifically, the p.Val522Ile would display a mild STGD1 phenotype when combined with a null allele as in the case of patient 4 or a missense mutation with little or no activity such as the p.Asn965Ser mutation,37,51 but would not display a disease phenotype in a patient homozygous for this mutation or patients in which this mutation is combined with a mutation that shows significant ABCA4 function because under these circumstances sufficient ABCA4 activity would be realized to prevent the accumulation of toxic retinoids.
In HEK293T cells, p.Val552Ile expresses at close to WT levels, exhibits normal N-Ret-PE binding properties, and has only a modest reduction in ATPase activity. Consistent with mild disease phenotype
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Next, we measured the effect of disease-associated mutations on the ATPase activity of ABCA4. WT and ABCA4 variants were solubilized in CHAPS, purified by immunoaffinity chromatography, and subsequently reconstituted into PE-containing liposomes at similar protein concentrations. The ATPase activity of the mutants in the presence and absence of N-Ret-PE substrate is shown in Figure 6A, A,6B.6B. As previously reported,25,47 addition of 40 μM all-trans retinal to WT ABCA4 resulted in a 1.8- to 2.5-fold increase in ATPase activity (Fig. 6). The ATPase activity of the mutants was measured at the same protein concentration as WT ABCA4 to determine the effect of the mutation on the functional activity of ABCA4. Five mutants (p.Val552Ile, p.Ala1038Val, p.Ala1357Thr, p.Ala1794Pro, and p.Leu2027Phe) showed reduced basal ATPase activity relative to WT ABCA4 (∼40%–85%), but this activity was stimulated 1.6- to 3.0-fold by the addition of all-trans retinal. On the other hand, p.Gly72Arg, p.Met448Lys, p.Leu541Pro, p.Gly1091Glu, p.Gly1961Glu, and p.Arg2077Trp variants showed drastically reduced basal activity with little or no substrate stimulation.Open in a separate windowFigure 6ATPase activity of ABCA4 variants. The ATPase activity of immunopurified and reconstituted ABCA4 variants was measured in the presence or absence of all-trans retinal. (A) Quantification of the basal and retinal-stimulated ATPase activity of ABCA4 variants normalized to WT basal ATPase activity. ATPase assays were carried out using similar concentrations of purified ABCA4. Data expressed as an average ± SD for n ≥ 3 independent experiments. (B) Representative curves of specific ATPase activity as a function of all-trans retinal concentration for WT and ABCA4 variants. (C) Relative basal ATPase activity of WT and A1794P using equal amounts of transfected HEK293T cells. Data expressed as an average ± SD. Measurements were done in triplicate.To more directly evaluate the expression and function of the p.Ala1794Pro variant, we transfected HEK293T cells separately with WT ABCA4 and the p.Ala1794Pro mutant cDNAs at similar levels. After solubilization in CHAPS buffer, the samples were subjected to high-speed centrifugation and the supernatant was reconstituted into liposomes for analysis of its basal and substrate activated ATPase activity. As shown in Figure 6C, the p.Ala1794Pro had a significantly reduced activity due largely to the low expression of this variant. These studies indicate that only a small fraction of the p.Ala1794Pro mutant folds into a functionally active protein and correlates well with the phenotype of patient 5.
As shown in other publications, the ATPase activity of this variant appears to be drastically reduced compared to WT when transfected into HEK293 cells, but expression is comparable to WT.
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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5-year-old girl
Case#:5-year-old girl
DiseaseAssertion: Asymptomatic
FamilyInfo: Mother was diagnosed with STGD1 and She was homozygous for a (severe) splice site mutation, IVS 35+2 T>C, Maternal uncle was diagnosed with STGD1. Father passed down the G1961E variant.
CasePresentingHPOs: HP:0030630, HP:0011504
CaseHPOFreeText: The ELM in the central macula appeared thickened with indistinct borders, particularly along its inner border (Fig. 2C), horizontal diameter for the region of thickened ELM was 1113 μm, FAF revealed Bull’s Eye Maculopathy (BEM) (Fig. 2B),
CaseNotHPOs:
CaseNotHPOFreeText: No retinal, vasculature, pigmentary or optic nerve head abnormalities were detected on clinical examination, no focal abnormality observed in the outer nuclear layer (ONL) or RPE (Fig. 2C), There was no FAF evidence of flecks or GA
Genotyping Method:
PreviouslyPublished: No
Variant:NM_000350.3:c.5882G>,
ClinVar:7888
CAID:CA119132
SupplementalData:
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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6Mc.4720G>Tp.Glu1574*not detected 20/15020/2006/38/32
Case#: Patient #16, male, 6yo at onset, Brazilian
DiseaseAssertion: stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: type II (an area of foveal hypofluorescence surrounded by an area with a heterogeneous appearance and hyperautofluorescent and hypoautofluorescent points that extend to the temporal arcades, giving the retina a reticulate appearance). visual acuity: OD=20/150, OS=20/200
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.4720G>T p.(Glu1574*), no second variant. NGS and conclusive molecular testing regarding other Stargardt genes were excluded
ClinVar: 1460063
CAID: CA341283936
SupplementalData: n/a
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www-sciencedirect-com.libproxy.lib.unc.edu www-sciencedirect-com.libproxy.lib.unc.edu
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We identified 255 patients (87.9 %) harboring biallelic ABCA4 variants, 27 probands (9.3 %) with two or three variants but lacking familial segregation analysis, and eight patients (2.8 %) with monoallelic ABCA4 variants (Supplemental Table S4). We detected 268 distinct ABCA4 variants, consisting of 114 missense, 35 nonsense, 34 frameshift deletion or insertion, 31 canonical splice variants, 13 noncanonical splice site variants, 9 in-frame deletion or insertion, 9 DIVs, 4 structural variations, and 19 complex variants (Fig. 2).
Case#: Patient#010477, Chinese, male, 18yo at onset
DiseaseAssertion: stargardt
FamilyInfo: n/a
CasePresentingHPOs: STGD1 diagnosis based on the following criteria: "a bilateral central vision defect; fundus displaying a beaten-bronze appearance and/or orange-yellow flecks in the retina from the macula to the midperiphery; fluorescein angiography presenting with a typical dark choroid; and normal to subnormal ERG results." BCVA=0.4/ 0.5
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: p.P2097S; c.2255G>T p.(Ser752Ile) phase unknown
ClinVar: 2202780;
CAID: CA341277622;
SupplementalData: supplementary table S4 has phenotype information
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We identified 255 patients (87.9 %) harboring biallelic ABCA4 variants, 27 probands (9.3 %) with two or three variants but lacking familial segregation analysis, and eight patients (2.8 %) with monoallelic ABCA4 variants (Supplemental Table S4). We detected 268 distinct ABCA4 variants, consisting of 114 missense, 35 nonsense, 34 frameshift deletion or insertion, 31 canonical splice variants, 13 noncanonical splice site variants, 9 in-frame deletion or insertion, 9 DIVs, 4 structural variations, and 19 complex variants (Fig. 2).
Case#: Patient#010382, Chinese, male, 29yo at onset
DiseaseAssertion: stargardt
FamilyInfo: n/a
CasePresentingHPOs: STGD1 diagnosis based on the following criteria: "a bilateral central vision defect; fundus displaying a beaten-bronze appearance and/or orange-yellow flecks in the retina from the macula to the midperiphery; fluorescein angiography presenting with a typical dark choroid; and normal to subnormal ERG results." BCVA=0.4/ 0.6
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: p.P2097S; c.6050G>A p.(Cys2017Tyr) phase unknown
ClinVar: 2202780;
CAID: CA341277622;
SupplementalData: supplementary table S4 has phenotype information
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We identified 255 patients (87.9 %) harboring biallelic ABCA4 variants, 27 probands (9.3 %) with two or three variants but lacking familial segregation analysis, and eight patients (2.8 %) with monoallelic ABCA4 variants (Supplemental Table S4). We detected 268 distinct ABCA4 variants, consisting of 114 missense, 35 nonsense, 34 frameshift deletion or insertion, 31 canonical splice variants, 13 noncanonical splice site variants, 9 in-frame deletion or insertion, 9 DIVs, 4 structural variations, and 19 complex variants (Fig. 2).
Case#: Patient#010455, Chinese, male, 18yo at onset
DiseaseAssertion: stargardt
FamilyInfo: n/a
CasePresentingHPOs: STGD1 diagnosis based on the following criteria: "a bilateral central vision defect; fundus displaying a beaten-bronze appearance and/or orange-yellow flecks in the retina from the macula to the midperiphery; fluorescein angiography presenting with a typical dark choroid; and normal to subnormal ERG results." BCVA=0.01/ 0.01
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: p.P2097S; c.4906_4908del p.(Asn1636del) phase unknown
ClinVar: 2202780;
CAID: CA341277622;
SupplementalData: supplementary table S4 has phenotype information
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Of the 266 arSTGD chromosomes studied, mutations were identified in 161, resulting in a detection rate for the genotyping microarray of 60.5%: two mutant alleles were found in 64/133 patients (48.1%), whereas in 33/133 cases (24.8%) only one allele could be identified. A total of 56 different sequence variants related to the disease were identified, including missense (42), nonsense (four) frameshift (five) and splicing (five) mutations. Furthermore, combinations of variants acting in cis (complex alleles; six double alleles, one triple allele) were also found. Of this spectrum of substitutions, the p.Arg1129Leu (c.3386G>T) allele accounted for 26% of the disease-associated alleles (fig 2). Considering the percentage represented by this variant in patients (26%) and the obtained mutation detection rate (60.5%), this change would represent the 15.7% of all the potential arSTGD associated alleles.
This variant is in Figure 2 as an ABCA4 disease-associated allele identified in Spanish Stargardt disease (STGD) patients with a frequency below 5%. No additional information about phenotype or genotype is provided and a future paper focusing on those details, by the same first author (PMID: 23755871), so they are likely the same patient in the same cohort
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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56-year-old female
Case#: a 56-year-old female
DiseaseAssertion: Pseudoxanthoma elasticum (PXE)
FamilyInfo: NR
CasePresentingHPOs: HP:0200034, HP:0001102, HP:0025533, HP:0011506, HP:0500087
CaseHPOFreeText: Papules on neck and axillae, marked skin laxity and redundance in neck, axillae, periumbilican area, groyne, and inner thighs, angioid streaks, peau d'orange. In right eye, a CNV, a large peripapillary atrophy, a small iuxafoveal scar, and RPE-Bruch's membrane complex normalities nasally to the fovea.
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
Genotyping Method: Next generation sequencing focusing on 362 genes associated with calcification-related diseases and inherited retinal diseases
PreviouslyPublished: NR
Variant: c.1928T>G, p.Val643Gly, NM_000350.3
ClinVar: 99102
CAID: CA226958
SupplementalData: This variant has been reported likely pathogenic in VarSome and literature.
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jamanetwork.com jamanetwork.com
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Leu541Pro
This variant is found without ala1038val in patient 5. Patient 5 is a 36yo white female. Visual acuity= OD:10/120, OS:10/60-1. Central scotome. Type 1 fundus=diffuse pigmentary degenerative changes. Cone responses more reduced than rod amplitudes on ERG. Second variant: Asp600Tyr. Phase not confirmed
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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To overcome these limitations, we designed a genotyping microarray (gene chip) for ABCR that includes all approximately 400 disease-associated and other variants currently described, enabling simultaneous detection of all known ABCR variants.
Article is a PDF, so annotating here. In the supplemental file (table S1), this variant was listed as being included on the microarray, but that is all the information provided.
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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92 RHO c.180C>A p.Tyr60* – [a] ROM1: f 31 RP ad no Ger c.178C>A p.Pro60Thr; – [42], [43] c.323C>T p.Thr108Met rs146358003 [42], [43] ABCA4: c.1654G>A p.Val552Ile rs145525174 [44] c.5714+5G>A RP2: splice rs61751407 [45] c.844C>T RPGRIP1: c.2510C>G p.Arg282Trp rs1805147 [17], [18] p.Ala837Gly – [22]
Case#: Eisenberger Patient 92, female, 31yo, German
DiseaseAssertion: Autosomal dominant RP
FamilyInfo: non-consanguineous
CasePresentingHPOs:
CaseHPOFreeText: "The diagnoses of all patients were established by medical history, family history and detailed clinical evaluation of vision. Ophthalmological examination included stereoscopic funduscopy, standard ERG, perimetry, measurement of dark adaptation, and determination of best-corrected visual acuity in most patients."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: NGS for the exons of 55 RP and LCA genes, Sanger for confirmation
PreviouslyPublished: n/a
Variant: Allele 1: RHO c.180C>A p.Tyr60; Allele 2*: ROM1: c.178C>A p.Pro60Thr; c.323C>T p.Thr108Met;
ABCA4: c.1654G>A p.Val552Ile; c.5714+5G>A; <br /> RP2: c.844C>T p.Arg282Trp; <br /> RPGRIP1: c.2510C>G p.Ala837Gly
ClinVar:
CAID: CA239745
SupplementalData: n/a
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Case 3 showed a p.Ala643Gly variant in the PROM1 gene and a single variation in the ABCA4 gene, but molecular testing results were inconclusive.
Annotating here since unable on the PDF.
Case 3 is a 6yo male. VA: OD: 20/150, OS: 20/200. Proband had macular atrophy and flecks at the posterior pole. In the autofluorescence exam, there was peripapillary sparing of the hyper-autofluorescent flecks. On OCT images the atrophic areas at the macula correlated to disruption of the elipsoid layer and decrease in the foveal thickness. OCT showed loss of the photoreceptor layer and EPR layer. Proband has only 1 ABCA4 variant, so not eligible for PP4. Also has a variant in PROM1 (p.Ala643Gly). ABCA4, PROM1, and ELOVL4 genes sequenced by next-generation sequencing (NGS) test.
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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ABCA4 whole-gene sequencing, subsequent WGS, and segregation analysis identified a complex deep-intronic allele (NM_000350.2(ABCA4):c.[1555-5882C>A;1555-5784C>G]) in trans to the missense variant.
PMID: 39421326 (PMCID: PMC11675205)
Gene: ABCA4
HGNC ID: 34
Case#: Patient 24 (male)
DiseaseAssertion: STGD (Stargardt disease)
FamilyInfo: Caucasian family from Germany. Patient has two siblings carrying the variant but they are not clinically affected according to pedigree information.
CasePresentingHPOs: Decreased central visual acuity (HP:0000545) Macular atrophy (HP:0007754) Retinal flecks (HP:0030638) Abnormal fundus autofluorescence (HP:0030647) Macular degeneration (HP:0007754) Abnormal electroretinogram (HP:0000763)
CaseHPOFreeText: Male patient diagnosed before age 50 with Stargardt disease. Best corrected visual acuity (BCVA) approximately 0.05–0.2. Fundus imaging shows paracentral scotoma, macular atrophy, and hyperfluorescent flecks with sparing of the fovea. Autofluorescence demonstrates hyperreflective spots and patchy lesions with parafoveal involvement.
CaseNotHPOs: None explicitly reported.
CaseNotHPOFreeText: Pattern-like distribution of lesions noted on clinical examination.
Genotyping Method: Whole-exome sequencing (WES) with an in-house RD-associated gene panel including 619 candidate and disease-associated genes.
PreviouslyPublished: No (novel complex deep-intronic allele described in this study).
Variant: c.[1555-5882C>A;1555-5784C>G]
ClinVar: Not reported in ClinVar in the provided information.
CAID: CA272741; CA227172
SupplementalData: Segregation data and functional splicing analysis available in the supplemental data (Table S1, Figure S1) of the article.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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D023{"type":"entrez-protein","attrs":{"text":"STG00205","term_id":"1440289030"}}STG00205FPlano9January 21, 1985May 5, 201328.3
Case#: Bertelsen Patient D023, female, 9yo at onset
DiseaseAssertion: generalized choriocapillaris dystrophy
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: end-stage generalized choriocapillaris dystrophy characterized by semiconfluent multifocal areolar outer retinal atrophy, the severity of which decreases with increasing eccentricity. Central patches of visible sclera are surrounded by coarse confluent hyperpigmentation. The periphery shows isolated or clustered hyperpigmentation. In and around the fovea there is pronounced atrophy of the retinal pigment epithelium, the photoreceptor layer, and the outer nuclear layer and intraretinal hyperreflective material corresponding to the hyperpigmentation
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: microarray
PreviouslyPublished: n/a
Variant: c.203C>T p.P68L; c.3329-2A>G
ClinVar: 99113
CAID: CA226972
SupplementalData: n/a
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Disease-causing or likely disease-causing mutations were identified in 185 out of 251 patients (74%) with MD/CCRD (Supplementary Table 1).
Case#: Patient #43, male, 9yo at onset, 16yo at report, German
DiseaseAssertion: macular dystrophy or cone-rod dystrophy
FamilyInfo: inheritance= sporadic. phase not confirmed, but no other affected family members and no parental consanguinity
CasePresentingHPOs:
CaseHPOFreeText: reduced visual acuity, erg scotopic= reduced, erg-photopic=reduced
CaseNotHPOs:
CaseNotHPOFreeText: syndromic retinal disease, age-related macular degeneration, central serous retinopathy, autoimmune retinopathy, retinal vascular disease, achromatopsia, X-linked retinoschisis, North Carolina macular dystrophy
CasePreviousTesting: n/a
GenotypingMethod: Sanger sequencing of ABCA4
PreviouslyPublished: n/a
Variant: c.3098del (p.Lys1033Serfs*51); c.3243G>T (p.Lys1081Asn)
ClinVar: 236516
CAID: CA10581650
SupplementalData: Supplementary table 1
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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ABCA4STGD1H2128R
This paper is evaluating potential hotspots of ABC genes. The variant is mentioned as being in the C-loop2 motif, but no further information is provided on the variant.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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A six-year-old girl with vision loss and prominent behavioral changes and overlooking was presumptively diagnosed as having the Batten disease form of neuronal ceroid lipofuscinosis.
MonDO: MOND:08000406
Case: Female, onset 6 years VA 20/200 OU identify 1 ouf 15 Ishiara cards and overlooking symptom. Presumably diagnosed with Batten disease but found to harbor genetic variant for Stargardt disease.
DiseaseAssertion: Stargardt disease
FamilyInfo: No family history of visual loss in childhood.
"CasePresentingHPOs: HP:0007663, HP:0007988, HP:0030584, HP:0008043, HP:0008001, HP:0030609 (Reduced visual acuity, Macular hypopigmentation, Color vision test abnormality, Retinal arteriolar constriction, Foveal hyperpigmentation, Photoreceptor layer loss on macular OCT"
CaseHPOFreeText: bull's eye lesions, prominent overlooking, hyperreflective granular deposits
CaseNOTHPOFreeText: HP:0001336, HP:0001250, HP:0000648, HP:0000707
CasePreviousTesting: (Myoclonus, Seizure, Optic atrophy, Abnormality of the nervous system
GenotypingMethod: Genetic testing was negative for all mutations known to cause neuronal ceroid lipofuscinosis, but whole exome sequencing showed compound heterozygosity for 2 pathogenic variants in the ABCA4 gene
MultipleGeneVariants:
(1) GeneName: ABCA4
(1) Variant: c.3007C>T, p.Q1003X
(1) ClinVarID or CAID: CA119132
(1) gnomAD: 0.003406 total AF in gnomAD v4.1 (https://gnomad.broadinstitute.org/variant/1-94008251-C-T?dataset=gnomad_r4)
(2) GeneName: ABCA4
(2) Variant: c.768G>T
(2) ClinVarID or CAID: CA227458
(2) gnomAD: 0.00007930 total AF in gnomAD v4.1 (https://gnomad.broadinstitute.org/variant/1-94098794-C-A?dataset=gnomad_r4)
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Table_5.xls (35K)GUID: F0FBE3EF-4607-46DE-9804-35E6F0FB6695
This variant is found in Table S5. "Five probands with one ABCA4 disease-associated allele" Proband #89. Since this proband has only one variant they are not eligible for PP4
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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We found two variants or more in ABCA4 in 69/95 (73%) probands (Supplementary Tables 2, 3); a single ABCA4 variant was found in 9/95 (9.5%) probands with STGD1 phenotype. A second variant could be found in four of these nine patients by Khan et al. (2020) (Figure 1 and Supplementary Tables 2, 4). Therefore, a total of 73/95 (77%) probands of our cohort ended up having two or more ABCA4 variants. In 17/95 (18%) probands, no variant was found in any of the sequenced genes.
Case#: Patient STG-16, 13yo at onset, Argentina
DiseaseAssertion: STGD1
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: BCVA=0.7/0.7, FA=3B, AF pattern=2, OCT showed decreased retinal thickness with disruption of external layers
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: NGS of ABCA4 (NM_000350.2), ELOVL4 (NM_022726.3), PROM1 (NM_006017.2), and CNGB3 (NM_019098.4)
PreviouslyPublished: n/a
Variant: c.4457C>T (p.Pro1486Leu); c.1804C>T (p.Arg602Trp)
ClinVar: 99283
CAID: CA227192
SupplementalData: supplementary table 2 has genotype/phenotype info
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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RP-029895-0103 ABCA4 c.4720G>Tp.E1574*known [44]
Case#: Proband 95-0103, Spanish, onset at 8yo
DiseaseAssertion: cone-rod dystrophy
FamilyInfo: Family RP-0298. Affected sister, 95-0101, with same genotype
CasePresentingHPOs: HP:0001133, HP:0000529, HP:0000662, HP:0000512, HP:0000543, HP:0007737, HP:0007641, HP:0007787
CaseHPOFreeText: BCVA=0.1/0.1; ERG: scotopic-Low amplitude, normal latency, photopic-abolished, mixed-diminished a and b waves; dense pigment accumulation at macular region;, bilateral posterior subcapsular cataract.
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: 19365591
Variant: c.4720G>T p.E1574; c.950delG p.G317Afs57. WES, All patients were previously tested and all resulted to be negative for known autosomal recessive retinitis pigmentosa (ARRP) or Leber Congenital Amaurosis (LCA) mutations by microarray screening
ClinVar: 1460063
CAID: 341283936
SupplementalData: Table S2 has phenotype details
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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A 25‐year‐old male presented to our hospital with a chief complaint of blurred vision in the right eye and significant night vision difficulties (nyctalopia) for 5 years.
Case#:patient, 25, male
DiseaseAssertion:Retinitis Pigmentosa
FamilyInfo:Unaffected brother with no variants, parents each heterozygous for one pathogenic variant in ABCA4
CasePresentingHPOs: HP:0000007, HP:0011462, HP:0007703, HP:0000662, HP:0007641
CaseHPOFreeText: Onset 20 year old. Gradual onset of blurred vision OD, dyschromatopsia. BCVA 1/20 OD 20/20 OS. Optic disc pale, retinal arteries and foveal reflex attenuated. Yellow deposits in perofoveal area and mid-peripheral retina, which showed mottled appearance OU. OCT - thinning of outer nuclear layer and disruption of ellipsoid zone with hyper-reflective flecks. Severe bilateral constriction in visual field. Hypofluorescence of optic disc OU
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
Genotyping Method: whole exome (Sanger segregation test)
PreviouslyPublished: n/a
Variant: NM_000350.3:c.4793C>A; NM_000350.3:c.1769A>G
ClinVar: 99321
CAID: CA341279788
SupplementalData: n/a
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Case 1
Case#:1, 44-year-old man
DiseaseAssertion: Stargardt disease
FamilyInfo: no known family history of an ocular disease
CasePresentingHPOs: HP:0007663, HP:0007793, HP:0012045, HP:0000603
CaseHPOFreeText: gradual, relatively recent decreased visual acuity in the right eye, some pigment mottling in both maculae and ‘fish-tail'-like retinal flecks, central relative scotoma
CaseNotHPOs:
CaseNotHPOFreeText:
Genotyping Method: “Analysis of the entire coding region of the ABCA4 gene”
PreviouslyPublished: NR
Variant: NM_000350.3:c.191C>T
ClinVar:2733951
CAID:CA341285580
SupplementalData:
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Case 3
Case#:3, 34–year-old woman
DiseaseAssertion:NR
FamilyInfo: no family history of an ocular disease
CasePresentingHPOs: HP:0007663, HP:0030506, HP:0030528, HP:0000603
CaseHPOFreeText:bilateral markedly decreased vision (logMar BCVA OD:0.93, OS:0.95), bilateral atrophic lesions of the macula accompanied by yellow-white stellate flecks at the level of the retinal pigment epithelium, Atrophic lesions and flecks were also extending to the mid-periphery of both retinae, bilateral absolute central scotoma and relative paracentral scotomas as well in both eyes, PERG was significantly reduced, while scotopic and photopic amplitudes were also lower than normal.
CaseNotHPOs:
CaseNotHPOFreeText:NR
Genotyping Method: “Analysis of the ABCA4 gene”
PreviouslyPublished: No
Variant: NM_000350.3:c.5882G>A, NM_000350.3:c.6709dup
ClinVar: 7888, 99485
CAID: CA119132, CA227437
SupplementalData:
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www.sciencedirect.com www.sciencedirect.com
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534-05STGD2461 T→AW821RMissense4139 C→TP1380LMissense5682 G→CNoneSilent5814 A→GNoneSilent
Case#: Family AR534 Proband 05
DiseaseAssertion: Stargardt
FamilyInfo: Three paternal cousins are affected with STGD, with onset between the ages of 8 and 10 (unaffected het parents). The proband’s parents reported no visual impairment (father has P1380L/wt, mother has W821R/wt), but the paternal grandmother had been diagnosed previously with age-related macular degeneration at age 68 (het for P1380L). Subsequently, she developed hemorrhagic detachment of the macula, and a diagnosis of exudative AMD was made at age 74
CasePresentingHPOs:
CaseHPOFreeText: central visual impairment at age 11, retinal atrophy of the macula and a few peripheral flecks, A dark choroid was observed on fluorescein angiography,
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Direct DNA sequencing of the 50 exons and flanking intronic regions of ABCR. Heteroduplex analysis
PreviouslyPublished: n/a
Variant: c.2461T>A (p.W821R); c.4139C>T (p.P1380L). Phase confirmed. Also has 2 synonymous variants (c.5682G>C and c.5814A>G)
ClinVar: 7904
CAID: CA129033
SupplementalData: n//a
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illiad.lib.unc.edu illiad.lib.unc.edu
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P023 ABCA4 20 c.3035_3037delACA p.Asn1012Ile ATP-binding domain novel deletion – DCABCA4 24 c.3547G>T p.Gly1183Cys – reported – – –ABCA4 46 c.6289C>T p.Pro2097Ser ATP-binding domain novel missense probablydamagingDC
Case#: Patient #P023, Korean
DiseaseAssertion: stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: no individual phenotype information, group only
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: exome sequencing: c.6289C>T p.Pro2097Ser; c.3547G>T p.Gly1183Cys; c.3035_3037delACA p.Asn1012Ile
ClinVar: CA341277622
CAID: 2202780
SupplementalData: n/a
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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In this study, we summarized the phenotypic and genotypic characteristics of 129 Chinese patients with ABCA4-RD.
paper not publicly available, but is said to contain this variant based on LOVD entry. requested from library.
Update: Received paper from library. 1 proband in Figure 1 has this variant, but cannot access the supplementary info to see the individual phenotype information. Affected maternal aunt with homozygous c.4605_4606ins-non-segregation.
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In this study, we summarized the phenotypic and genotypic characteristics of 129 Chinese patients with ABCA4-RD.
Case#: Patient 8541, male, 10yo at presentation, 9yo at onset
DiseaseAssertion: Stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: The inclusion criteria for patients were as follows: (1) clinical phenotypes were consistent with retinal dystrophy, and two or more ABCA4 gene mutations were identified by genetic analysis; or (2) clinical phenotypes were consistent with Stargardt disease, and one ABCA4 gene mutation was identified. The diagnosis of STGD was based on visual acuity loss with an atrophic maculopathy with or without yellowish-white flecks. BCVA= 0.92 OU. FAF type 1 ( a localized low FAF signal at fovea surrounded by a homogeneous background with or without perifoveal foci of high or low signal)
CaseNotHPOs:
CaseNotHPOFreeText: Yellowish-white flecks
GenotypingMethod: Analysis by targeted panel sequencing of 256 known retinal disease genes or by clinical exome sequencing of 1651 inherited eye disease-related genes
PreviouslyPublished: n/a
Variant: c.2587_2587+6delGG TAAGC; c.3468C>G p.(Tyr1156*)
ClinVar: n/a
CAID: CA341290648
SupplementalData: supplemental table S2
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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In case 71674, diagnosed with arRD, along with a recurrent nonsense mutation (p.Trp663*, HGMD Accession = {"type":"entrez-nucleotide","attrs":{"text":"CM003370","term_id":"909078994","term_text":"CM003370"}}CM003370), a novel splice-site variant was identified (c.2160 + 1 G > T) (Fig. 3a). This variant is predicted to lead to skipping of exon 14 in the ABCA4 transcript. The patient inherited one mutant allele from each parent.
Patient 71674: Female, Swiss, 13 years old. bi-allelic variants in ABCA4, diagnosed with Retinal dystrophy DD: Retinitis pigmentosa
Figure 3: Segregation analysis performed on family samples GenotypingMethod: Whole exome sequencing performed on HiSeq2000 and NextSeq500 (252 genes)
Multiple Variants: VPS13B NM_017890.4:c.897 8A>G:p.Asn2993Ser Heterozygous CM041280
PCDH15 NM_001142763.1:c. 4329_4337del:p.Pro 1446_Pro1448del Heterozygous
DHX38 NM_014003.3:c.366 2C>T:p.Thr1221Met Heterozygous
USH1G NM_173477.4:c.310 A>G:p.Met104Val Heterozygous
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Additionally, one novel change in exon 12 (p.Val552Ile) was found in one STGD patient by means of the dHPLC technique. This variant was detected in two alleles out of 200, suggesting a polymorphism.
Case#: Aguirre-Lamban Unlabeled Proband, Spanish
DiseaseAssertion: STGD
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: "Diagnosis of STGD was determined according to a bilateral central vision loss with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; typical dark choroid observed by fluorescein angiography; and normal to subnormal electroretinograms (ERGs)."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: ABCR400 microarray, direct sequencing, dHPLC, haplotype analysis
PreviouslyPublished: n/a
Variant: c.1654G>A p.Val552Ile, interpreted as non-pathogenic, suggested to be a polymorphism
CAID: CA239745
SupplementalData: n/a
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Interestingly, we identified one 30-year-old patient (ARDM-247), double heterozygous for the p.Arg1129Leu and p.Cys2137Tyr alleles, who presented a CRD phenotype. This p.Cys2137Tyr change was located more towards the amino terminus. Moreover, in other study, the results showed that the changes located in this zone appear to result in altered processing of the protein and to be associated with an earlier onset of disease.16 The p.Cys2137Tyr change in combination with the p.Arg1129Leu allele produced a CRD phenotype. Therefore, we speculate that the novel p.Cys2137Tyr variant could be a severe allele which is modifying the patient’s phenotype.
Case#: Family MD-0247/ARDM-247 Proband, 12yo at onset
DiseaseAssertion: AR cone rod dystrophy
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)." VA loss, VF loss, BCVA=0.05/0.1, cone-pattern on ERG
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.6410G>A (p.Cys2137Tyr); c.3386G>T (p.Arg1129Leu) found by ABCR400 + dHPLC + HRM
ClinVar: 2202779
CAID: CA341277358
SupplementalData: n/a
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www.aaojournal.org www.aaojournal.org
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16P36M198426217–50.300.10 P37F198913817–40.22
Case#: Family 16, P37, female, Netherlands 13yo at onset
DiseaseAssertion: Stargardt
FamilyInfo: 1 affected sibling with same genotype
CasePresentingHPOs:
CaseHPOFreeText: visual acuity: OD=0.22, FAF images consistent with STGD1
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Sanger
PreviouslyPublished: n/a
Variant: c.5196+1137G>A; c.859-506G>C
ClinVar: 438100
CAID: CA26843511
SupplementalData:
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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ABCA4
In supplemental table S2, Case LL345 is listed as "likely solved" with a clnical diagnosis of Stargardt disease. Proband is compound heterozygous for c.4139C>T p.(Pro1380Leu) and c.4918C>T p.(Arg1640Trp).
In Supplemental table S1, this proband is a female, 25yo at report, 11yo at onset. Decreased VA: 0.08/0.05, emmetropia OU
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ABCA4
In supplemental table S2, Case LL291 is a female listed as "likely solved" with a clinical diagnosis of CRD. Proband is compound heterozygous for c.32T>C p.(Leu11Pro) and c.5196+1137G>A.
In Supplemental table S1, this proband is a female, 54yo at report, 50yo at onset. Nyctalopia, visual acuity=0.05/0.6, OD: extremely high myopia OS: high myopia, no family information
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ABCA4
Supplementary table 2 lists this variant as previously reported in 3 individuals from PMID: 19365591
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Supplementary TableS10
This variant is listed for Stargardt DNAID#071103 in trans with c.1927G>A p.(Val643Met). No phenotype information provided.
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Supplementary TableS5
This variant is included in a table that lists all ABCA4 variants
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Supplementary TableS10
This variant is listed for Stargardt DNAID#070949 in trans with c.3682G>A p.(Glu1228Lys). No phenotype information provided.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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RP-087M30c.6397T>Cp.C2133RD1D2D322.80Y
Case#: Sporadic RP Patient 087, male, Chinese, 30yo at report
DiseaseAssertion: RP
FamilyInfo: n/a, sporadic case
CasePresentingHPOs:
CaseHPOFreeText: "The sporadic RP patients generally showed pubertal night blindness, restricted peripheral vision, progressive vision loss, overall bone-spicule pigmentation of the retina, attenuation of retinal vessels, and the flattening of the rod and cone ERG responses."
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: WES with Sanger sequencing confirmation
PreviouslyPublished: no
Variant: c.6397T>C p.(C2133R)
ClinVar: 2021273
CAID: CA341277387
SupplementalData:
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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At least 1 disease-causing ABCA4 variant was identified in 38 patients (90%), including 13 novel variants; ≥2 variants were identified in 34 patients (81%). Patients with childhood-onset STGD more frequently harbored 2 deleterious variants (18% vs 5%) compared with patients with adult-onset STGD.
Per ClinVar entry, this variant was associated with this paper. however, after reading through the genotypes, this variant was not found. Likely this paper was mentioned to support the statement that "Loss-of-function variants in ABCA4 are known to be pathogenic"
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Carrier frequency analysis of mutations causing autosomal-recessive-inherited retinal diseases in the Israeli population
PMID: 29706639
Gene: ABCA4
HGNCID: HGNC:34
MonDO: MONDO:0019353
Bioinformatic analyses of an SQL-based database containing 12272 variants that appear in 178 IRD genes in 5706 individuals of Ashkenazi Jewish origin based on the gnomAD database (version 2) and variants that were published in the scientific literature that was extracted from HGMD. Authors extracted information regarding IRD variants from various sources (including data of 5706 Ashkenazi Jewish (AJ) samples and a large cohort of Israeli patients with IRDs) to estimate carrier frequency of IRD mutations in different subpopulations in Israel. Two major databases aiming to estimate carrier frequency of IRD mutations in the Israeli population (Fig. 1): “gnomAD-AJ-IRD DB” containing data of 5706 AJ controls extracted from gnomAD and “HW-IRD DB” containing data extracted from our cohort of Israeli patients with IRDs.
See Fig 2 for breakdown of variants analyzed.
The final DB (IRDB) (Fig. 1 and Table S7) includes all 399 variants from “gnomAD-AJ-IRD DB” and “HW-IRD DB” that were considered here as pathogenic mutations in 111 known IRD genes.
To establish the “HW-IRD DB” (Fig. 1), we collected data on Israeli IRD patients with a known cause of disease (a cohort of >2000 IRD families). The HW-IRD DB includes 289 pathogenic mutations (Fig. 1) that were identified in IRD patients who have biallelic variants.
SupplementalData: S7, carrier frequency data for each mutation in all nine studied subpopulations. Carrier frequency was calculated as 2pq where p = 1 − q and q was calculated as the root square of the number of homozygous patients plus half the number of compound heterozygous patients divided by the population size
Variant: NM_000350.2:c.4895dup,p.Asn1632fs
CAID: CA915941330
Case: Ashkenazi Jewish patient with inherited retinal disease, STGD, CRD
CasePresentingHPOs: HP:0000548 (Cone/cone-rod dystrophy, CRD)
CaseHPOFreeText: Stargardt disease (STGD)
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone- or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees. The first and second most frequently mutated genes were EYS and RP1, associated primarily with autosomal recessive (ar) RP, and RP and arMD/CORD, respectively. Examinations of variant frequency in total and by phenotype showed high accountability of a frequent EYS missense variant (c.2528G>A). In addition to the two known EYS founder mutations (c.4957dupA and c.8805C>G) of arRP, we observed a frequent RP1 variant (c.5797C>T) in patients with arMD/CORD.
This paper is not publicly available. Requested from library since it is said to contain this variant.
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jamanetwork.com jamanetwork.com
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We identified 44 novel sequence changes (Table 3). Of these changes, 30 were potentially pathogenic and 14were classified as potentially neutral polymorphisms or changes of unknown significance.
This variant is in table 3 as a "potentially neutral polymorphism or change of unknown significance" but it is unclear which patient this is associated with, what their phenotype is, what their genotype is
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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15 MEH c.5196+1137G>A p.[=,M1733Efs∗78] c.[1715G>A;2588G>C] p.[(R572Q;G863A,G863del] Y U 20546
Case#: Patient #15, Moorfields Eye Hospital, London, UK, female, 39yo at onset, 51yo at report,
DiseaseAssertion: ABCA4-Associated Retinopathy, clinical diagnosis of STG
FamilyInfo: no additional family-member WGS data available
CasePresentingHPOs:
CaseHPOFreeText: BCVA= OD: 6/9, OS: 6/9, Fishmann Classification=2 (fleck-like lesions anterior to the vascular arcades and/or nasal to the optic disc), early changes to foveal photoreceptors, Extent of FAF abnormalities with Regard to Vascular Arcades: beyond. ffERG Group: 1(normal). PERG: Abnormal. FAF in Fig. 1B. characteristic yellow-white pisciform flecks in the RPE of the posterior pole that were hyperautofluorescent on FAF imaging or progressive atrophy of the macular RPE
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Haplotype analysis, ABCA4 mutation screening was performed by next-generation sequencing, sequenced as part of the retinal panel at the Molecular Vision Lab
PreviouslyPublished:
Variant: c.5196+1137G>A p.[=,M1733Efs∗78] c.[1715G>A;2588G>C] p.[(R572Q;G863A,G863del]
ClinVar: 7900
CAID: CA226918
SupplementalData:
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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c.1A>G, p.Met1Val
This paper is listed under the ClinVar citations for this variant, but only as a paper that references other variants in the initiator codon that have been observed in individuals with ABCA4-related conditions
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Supplementary data. bjophthalmol-2018-312064supp004.pdf
This variant is found on pg 16 in proband 14075. Compound heterozygous for c.6817-2A>C. MEH institute (UK). Said to have Stargardt based on the following criteria: "(1) patients (at least 6 years old) with at least two ABCA4 variants or one ABCA4 variant associated with a typical STGD1 phenotype and (2) presence of a well-defined atrophic lesion with/without flecks at the most recent visit of at least 300 µm in diameter (the total area of all lesions <12 mm2)." No additional details provided
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Supplementary data. bjophthalmol-2018-312064supp004.pdf
This variant is found on pg 11 in proband 18034. Compound heterozygous for c.2588G>C p.Gly863Ala. Said to have Stargardt based on the following criteria: "(1) patients (at least 6 years old) with at least two ABCA4 variants or one ABCA4 variant associated with a typical STGD1 phenotype and (2) presence of a well-defined atrophic lesion with/without flecks at the most recent visit of at least 300 µm in diameter (the total area of all lesions <12 mm2)." No additional details provided
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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29-year-old man
Case#: a 29-year-old man
DiseaseAssertion: Stargardt Disease
FamilyInfo: NR
CasePresentingHPOs: HP:0007663
CaseHPOFreeText: 20/70 visual acuity in both eyes
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
Genotyping Method: ABCA4 microarray (ABCR5000 chip)
PreviouslyPublished: NR
Variant: NM_000350.3:c.5882G>A, p.G1961E and c.5018+2C>T (rare splice variant)
ClinVar: 7888, NR
CAID: CA119132, NR
SupplementalData: No CAID or ClinVar ID were found for the rare splice variant c.5018+2C>T
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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In contrast, we found that the expression levels of the WT and all three mutant proteins were equivalent as determined by western blotting (Fig. 3B).
ABCA4 expression in HEK293 cells showed equivalent expression of wild type and this variant, indicating that this variant does not impact protein function (BS3_Supporting; PMIDs).
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Stargardt disease (STGD) and fundus flavimaculatus are infrequent autosomal recessive conditions characterized by a juvenile macular dystrophy and variable degrees of peripheral retinal changes. Linkage analysis performed in 47 STGD/fundus flavimaculatus families demonstrated significant linkage to 13 polymorphic DNA markers on chromosome 1p. The maximum combined two-point lod score was 32.7 (maximum recombination fraction [phi max] = .006) with the polymorphic marker D1S188. Our data demonstrate that STGD and fundus flavimaculatus are the same disorder clinically and genetically and provide further evidence for genetic homogeneity of this phenotype. Analysis of recombination events on disease chromosomes placed the STGD gene within a 4-cM interval between markers D1S435 and D1S236. A physical map was constructed of a YAC contig flanking STGD, from markers D1S500 to D1S495, and includes the critical interval delineated by historical recombinants. This contig spans approximately 31 cM, with one gap (3-5 cM) that is outside the 4-cM critical region. Localization of STGD to a single YAC contig will facilitate its positional cloning.
Text is a PDF, but this paper is the previously published paper referenced in PMID: 9973280. Pedigree is found here
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Introducing a comprehensive genetic testing strategy by combining single gene Sanger sequencing, next-generation sequencing (NGS) including whole exome sequencing (WES), and a specific hereditary eye disease enrichment panel (HEDEP) sequencing, to identify the disease-causing variants of 800 Chinese probands affected with non-syndromic IRDs.
This paper is listed in LOVD as containing this variant. Unable to find the variant in the main text and unable to locate the supplemental info. At the end of the paper, it says supplemental info can be found online, so used the DOI linked at the end of the article but it just leads to a PDF again with no supplemental
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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This work reported presence of 22 alterations, including two changes not found in other populations, c.2T>C (p.Met1Thr) and c.4036_4037delAC (p.Thr1346fs), and two novel disease associated variants, c.400C>T (p.Gln134X) and c.4720G>T (p.Glu1574X).
This variant was mentioned only as a previously published report.
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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A total of 42 unrelated patients (28 men and 14 women) were included in this study. Two patients (A002 and A035) were from consanguineous families (Figure 1). The detailed clinical findings are presented in Data S1.
Case#: Liu Proband A034, Chinese, female
DiseaseAssertion: Stargardt
FamilyInfo: Mother has the Pro68Leu variant, but the father was not genotyped to know the phase of the second variant. Proband's daughter also has the Pro68Leu variant, but is unaffected.
CasePresentingHPOs:
CaseHPOFreeText: no individual details provided
CaseNotHPOs:
CaseNotHPOFreeText: patients with other ocular diseases, such as choroidal neovascularization, glaucoma, and diabetic retinopathy, or were undergoing treatments/therapeutic trials were excluded.
GenotypingMethod: Either eye gene-enriched (from 36 to 450 target genes) panel-based next-generation sequencing (NGS). Sanger bi-directional sequencing was conducted to confirm the rare candidate variants (allele frequency: less than 1.0% of the general population) and to perform the co-segregation analysis
PreviouslyPublished: n/a
Variant: c.203C>T p.(Pro68Leu); c.3883_3884del p.(Glu1295Lysfs*126)
ClinVar: 99113
CAID: CA226972
SupplementalData: S1 only provides group demographics for the different clinical classifications (fundus grade, FAF type, etc)
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Pt-75Mc.4539 + 2028C > Tp.[= ,Arg1514Leufs*36]c.2453G > Ap.(Gly818Glu)
Case#: Pt 7, male, 60yo at report, onset between 6-49yo, Irish
DiseaseAssertion: Stargardt
FamilyInfo: family 5
CasePresentingHPOs:
CaseHPOFreeText: VA: OD=6/36 OS=6/120, FAF and OCT in figure 2, FAF WRT vascular arcades=beyond, beaten bronze appearance, yellow flecks centrally, peripapillary sparing, central retinal thickness: OD=100 microns OS=117 microns, optical coherence tomography (OCT) atrophy horizontal width: OD=6000 microns OS=5446 microns
CaseNotHPOs:
CaseNotHPOFreeText: bulls eye pattern, flecks peripherally
GenotypingMethod: Target capture NGS of the exons and known pathogenic intronic regions of ABCA4, whole-gene single molecule molecular inversion probe (smMIP) based sequencing of ABCA4 as well as 40 kb of flanking sequence, direct Sanger sequencing, or WGS
PreviouslyPublished: n/a
Variant: c.4539 + 2028C > T p.[= ,Arg1514Leufs*36]; c.2453G> A p.(Gly818Glu)
ClinVar: 99135; 236116
CAID: CA227000; CA10576057
SupplementalData: n/a
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iovs.arvojournals.org iovs.arvojournals.org
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Patients and Methods The protocol of the study adhered to the provisions of the Declaration of Helsinki. After informed consent was obtained, blood samples were taken and molecular analysis on the ABCA4 gene was performed as described by Maugeri et al. 14 The charts of patients with ABCA4 mutations who originally had received diagnoses of isolated or autosomal recessive CRD were reviewed. All patients originated from the University Medical Centre Nijmegen (Nijmegen, The Netherlands) and the University of Heidelberg (Heidelberg, Germany). In this study the diagnosis of CRD was based on the following criteria: initial symptoms of blurred central vision without a history of night blindness, impairment of color vision, and fundoscopic evidence of maculopathy without or with mild peripheral retinopathy. 3 4 5 7 8 In patients with recordable ERGs a cone–rod pattern of degeneration had to be present (i.e., the photopic b-wave impairment had to be greater than or equal to the scotopic b-wave amplitude impairment). Patients 9250 and 13163, who had nonrecordable ERGs, were included because their histories and clinical features were similar to those of other patients with cone–rod degeneration and they were believed to represent advanced cases of CRD. In addition to an ophthalmic examination, Goldmann kinetic perimetry routinely was performed using III-4-e and I-4-e isopters. Color vision was tested with the Ishihara and Panel D15 tests, except in patients 9369, 9378, and 10125, who were tested under conditions described earlier. 18 Because these patients were examined in two different clinics and ERGs were recorded over a long period, the methods, instrumentation, and analysis techniques of the electroretinography varied. The ERGs in patients 9369, 9378, 10125, and 11872 were performed as described by Thijssen et al. 19 The ERG method used in patients 9370, 9553, 9633, and 13163 was described by Alexandridis and Krastel. 20 The ERGs of the remaining patients (9250, 9371, and 9650) are of a more recent date and were performed according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards. 21 Fundus photographs were taken in most patients and some of the patients (9650, 9369, 9378, and 10125) also underwent fluorescein angiography. Results The characteristics of 12 patients with ABCA4-associated retinal dystrophy resembling CRD are summarized in Table 1 . Most did not have affected family members, and therefore their retinal dystrophies could not be classified as autosomal dominant, autosomal recessive or X-linked. Four patients reported a brother or sister with subnormal vision. In view of the reputedly normal visual acuity of the parents and the molecular defects, the inheritance pattern of the gene defects in these patients (individuals 9303, 9369, 9553, and 13163) was classified as autosomal recessive. The visual acuity of the patients did not exceed 20/200 and, on average, was much lower. With the exception of patient 9553, the age of onset was at or before the age of 12, and in each of the patients, blurred vision was the initial symptom. Night blindness did not occur except in patients 9378 and 10125, in the final stages of retinal degeneration. Evidence of maculopathy in the form of bull’s eye maculopathy or pigmentary changes was present in all the patients reported in this study (Fig. 1A) . The functional equivalent of the mainly centrally located retinal disease was a central scotoma, varying from 8° to more than 40°. In all but one patient, the scotoma was absolute. Only in patient 9378 was the central scotoma relative and surrounded by absolute scotomas. Fundoscopic evidence of early peripheral involvement of the retina was mild, and only in the later stages of the disease did peripheral changes characteristic of RP, such as narrowing of retinal vessels and bone spicula, occur in patients 9369 (Fig. 1B) and 10125. Similarly, mild constriction of the visual fields occurred only in two patients (9650 and 10125) and only in the advanced state. Color vision was tested in 10 patients. Six demonstrated a red–green defect, and in two of these (patients 11872 and 10125), it was accompanied by a blue-yellow defect. In the remaining four patients, color vision was so severely disturbed that the exact type of impairment could not be assessed. The ERG recordings demonstrated degeneration of both rods and cones. When ERG responses could be elicited, the cones appeared to be affected as much as the rod photoreceptors and, in most of the patients, even more severely. The ERG responses in five patients progressively deteriorated until no photopic and scotopic responses could be recorded. In these patients, with exception of patients 9250 and 13163, ERG recordings of an earlier date were used in Table 1 . This applies to patient 9369, in whom an ERG was recorded at age 12 (all ERG responses had been nondetectable since the age of 21), patient 9378 at age 33 (all ERG responses at age 46 were nondetectable), and patient 10125 at age 8 (in 1998, at age 28, the ERG responses were no longer detectable). Recent ERG findings were not available for patients 9650 and 9371. Their ERGs were recorded in 1989 and 1985, respectively. The remaining ERG data were derived from ERG recordings performed in the past 4 years. Of patient 9371 only the ERG data in the left eye were available. Two patients warrant a more detailed description, due to the unusual course of their retinal dystrophies. Patient 9378, at the age of 12, had blurred vision with fundoscopic evidence of irregular chorioretinal atrophy in the posterior pole. At that time, there were no peripheral abnormalities on ophthalmoscopy, and there was no history of night blindness. The ERG demonstrated an equal reduction of both cone- and rod-mediated responses. Later in life, however, fundoscopic changes developed that were characteristic of RP, and the patient reported a decrease in night vision. With fluorescein angiography partly confluent patches of chorioretinal atrophy were visible (Fig. 1C) . The clinical picture of patient 10125 differed from that of the other patients, despite the mutation in the ABCA4 gene. Initially, disease in this patient was diagnosed as STGD because of the bull’s eye maculopathy, the granular pigment alterations in the macular area, and the pisciform flecks surrounding the posterior pole. At age 8 his visual acuity had decreased to 20/200 in both eyes. When he was referred to our clinic in 1998 at the age of 28, peripheral degeneration in the form of narrow retinal vessels and deposition of peripheral bone spicula had developed, in addition to the earlier described disease of the central retina. A fluorescein angiogram showed typical findings: a central small hypofluorescent spot enclosed by an ellipsoid—a markedly hyperfluorescent area that in turn was surrounded by hyperfluorescent dots against a dark background, most likely caused by obscuration of choroidal background fluorescence (Fig. 1D) . Early ERG recordings were not available, and the ERG tracings recorded at age 28 represent the final stage of the degenerative process, with absence of both cone and rod responses. This retinal dystrophy seemed to have evolved from STGD into more widespread retinal degeneration, resulting in loss of function of both rods and cones. Discussion Progressive CRD is a clinically heterogeneous retinal disorder, but typical findings include reduced visual acuity, impairment of the central visual field, color vision deficits, and fundoscopic evidence of maculopathy, with no or few midperipheral retinal pigment deposits. 3 4 7 8 There is some dispute about typical ERG findings in CRD. Some state that the diagnosis of CRD must be based on the reduction or absence of cone responses in the presence of quantitatively less reduction in rod responses, whereas others state that an equal impairment of both photoreceptor systems, if accompanied by the characteristic features, suffices to justify the diagnosis of CRD. 3 7 8 22 Several propositions have been made in the past to classify cone–rod disorders. Some classification systems have focused on individual case reports and were based on nosologic aspects; others have made a distinction according to the various patterns of inheritance. 3 6 23 24 In recent studies, Szlyk et al. 7 and Yagasaki et al. 8 made use of full-field ERGs, dark adaptometry, and modified perimetric techniques to identify functionally distinct subtypes of CRD. Finally, over the past few years, a molecular genetic classification of CRD has emerged. At the moment, four genes and three loci have been implicated in autosomal dominant CRD, whereas one X-linked locus has been described. 25 26 27 28 29 30 31 32 Thus far, two loci and one gene (ABCA4) have been associated with autosomal recessive CRD. 12 33 34 The genetic heterogeneity seen in CRD is matched by the range of the clinical findings attributed by various investigators to this type of retinal dystrophy. Whatever the classification system used, some patients display retinal disorders that cannot be classified satisfactorily. Often, these retinal degenerations involve overlapping features. Krill et al. 5 reported that 9 of 45 patients with cone degenerations showed typical features associated with fundus flavimaculatus. Heckenlively 2 described 76 patients with cone–rod patterns on the ERG in whom retinal disease otherwise met the standard definition of RP (progressive peripheral visual field loss with ring scotoma). Alternatively, as seen in patient 10125 in this study, patients with STGD have been described who had progressive peripheral retinal degeneration with severe abnormalities in the ERG and electro-oculogram (EOG) later in life—a condition that has been described by Fishman 4 as secondary progressive cone–rod dysfunction. The association of CRD and a dark choroid has also been described previously. 35 36 The atypical pattern of retinal degeneration with confluent patches of chorioretinal atrophy in patient 9378 resembles that in another previously described unrelated patient with CRD-like disease caused by mutations in ABCA4. 37 In the molecular genetic study by Maugeri et al., 14 in which 11 of the 12 patients with autosomal recessive CRD described in this study were analyzed, ABCA4 mutations were found in 13 of 20 unrelated patients, strongly suggesting that ABCA4 mutations are the major cause of this disorder. If this is true, the genetic heterogeneity in autosomal recessive CRD, compared with, for example, classic RP, is surprisingly low. Because autosomal recessive inheritance is believed to be the most frequent mode of inheritance of monogenic chorioretinal disorders, it is very possible that a large fraction of the patients with CRD who have been clinically studied previously carry ABCA4 mutations. In that case, the explanation for the high variability of the clinical findings in autosomal recessive CRD would not be genetic heterogeneity but rather the genotype–phenotype model for ABCA4. According to this model, there is an inverse relationship between the presumed residual ABCA4 function as an N-retinylidene-PE flippase and the severity of the disorder. 12 37 38 As a consequence, a continuum of phenotypes is to be expected, ranging from STGD to CRD to RP. Although this is probably a simplified representation of reality and needs corroboration by detailed biochemical studies of individual mutations, as described previously, this model explains why mutations in the ABCA4 gene could give rise to phenotypes that do not satisfy the standard classification of retinal dystrophies. 39 Two patients in this study may reflect borderline CRD phenotypes. Patient 9553 carries a combination of a mild (2588G>C) and severe ABCA4 mutation, which, according to the genotype–phenotype model described earlier, should be associated with STGD. We have previously discussed that most likely, one of the pathologic mutations has not yet been identified in this patient. 14 However, the age of onset in this patient (25 years) is relatively high, and although other features such as visual acuity, perimetry, and ERG findings are typical of CRD, this may indicate a relatively mild subtype. Another more convincing example of blending of ABCA4-associated phenotypes is patient 10125. The molecular findings in this patient have not yet been described elsewhere. He carries a severe splice site mutation (IVS30+1G→T) in combination with a nucleotide change leading to a stop codon at Gln1029. A patient with RP who was homozygous for the IVS30+1G→T mutation has been described, 12 whereas the Q1029X mutation has not been described. Both mutations can be considered to be null alleles. According to the proposed ABCA4 model, the clinical phenotype in patient 10125 should be RP. Instead, this patient exhibits a typical retinal dystrophy, which gradually progresses from STGD to a more widespread degeneration of photoreceptors in a cone–rod pattern later in life. At present, both rod and cone ERG responses are not detectable, indicative of a final stage similar to that in many patients with RP. Functional studies are necessary to clarify whether these specific ABCA4 mutations are responsible for the particular progression of the retinal degeneration in this patient, or whether other as yet unknown modifying factors play a role. In this study we have described 12 unrelated patients with retinal dystrophy resembling CRD caused by mutations in the ABCA4 gene. In a previous study we described the ophthalmic features in five siblings with CRD-like retinal dystrophy who were carrying ABCA4 mutations. 37 From the clinical data of these patients and previous molecular studies in patients with autosomal recessive CRD, two important conclusions can be drawn. 12 14 First, the genetic basis of autosomal recessive CRD is less heterogeneous than was thought, based on the variability in clinical features, because mutations in the ABCA4 gene seems to be the major pathologic cause. Second, given the wide clinical spectrum of CRD-like phenotypes associated with ABCA4 mutations, detailed clinical subclassifications are difficult and may not be very useful. Supported by the British Retinitis Pigmentosa Society, the Rotterdamse Vereniging Blindenbelangen, the Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, the Stichting Blindenhulp, the Stichting de Drie Lichten, the Gelderse Blindenvereniging and the Landelijke Stichting voor Blinden en Slechtzienden and the Stichting voor Ooglijders. Submitted for publication June 15, 2001; revised December 21, 2001; accepted January 2, 2002. Commercial relationships policy: N. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Corresponding author: B. Jeroen Klevering, Department of Ophthalmology, University Medical Centre Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands; b.klevering@ohk.azn.nl. Table 1. View Table Patients with Cone–Rod Degeneration and ABCA4 MutationsTable 1. Patients with Cone–Rod Degeneration and ABCA4 Mutations Patient Sex Current Age (ys) ABCA4 Mutations* Visual Acuity Age of Onset (ys) Fundoscopy Color Vision Perimetry ERG Cone (μV), † ERG Rod (μV), † OD OS OD OS OD OS 9250 M 30 1622T→C; 3113C→T 194G→A CF CF 6 Pigment clumping in the macula NP Large central scotoma over 40° ND, ‡ ND, ‡ 9303 M 21 1622T→C; 3113C→T 20/400 20/400 7 Granular pigmentary changes in the macula Diffusely disturbed Central scotoma of 20° Severely decreased, § Severely decreased, § 9369 F 40 6601-6602deIAG LP LP 8 Irregular hypopigmentation, mainly in the posterior pole. In later stages: attenuated vessels and bone spicula temporal to the macula Red-green defect Central scotoma varying from 10–30° 65 (65%) 80 (80%), ∥ 140 (90%) 160 (nl), ∥ 9370 M 15 1622T→C; 3113C→T 20/200 20/200 7 Granular aspect of the macula NP Concentric central scotoma of 8° 10 (13%) 9 (13%), ¶ 29 (29%) 29 (23%), ¶ 9371 M 38 1622T→C; 3113C→T 1622T→C;3113C→T 20/400 20/400 10 Bull’s eye maculopathy Red-green defect Concentric central scotoma of 20° NP 29 (16%), ‡ NP 54 (30%), ‡ 9378 F 50 768G→T CF CF 12 Bull’s eye maculopathy, narrow vessels in periphery with mild granular changes of the pigment epithelium and confluent patches of chorioretinal atrophy Severely disturbed Large, absolute, paracentral scotomas, relative scotoma centrally 20 (20%) 30 (30%), ∥ 70 (47%) 90 (60%), ∥ 9553 F 45 2588G→C IVS35del-2→+2del4 20/400 20/400 25 Bull’s eye maculopathy. Peripheral diffuse motting of RPE Severely disturbed Large central scotoma over 40° 14 (14%) 19 (19%), ¶ 41 (41%) 24 (24%), ¶ 9633 M 22 1622T→C; 3113C→T 4469G→A 20/400 20/200 12 Atrophy of retinal pigment epithelium in posterior pole. Early stages of bull’s eye maculopathy Red-green defect Central scotoma of 20° 12 (16%) 12 (16%), ¶ 61 (62%) 39 (39%), ¶ 9650 F 20 3364G→A 20/400 20/400 5 Central granular aspect Red-green defect Large central scotoma of 30° and relative constriction of III-4 70 (39%) 106 (59%), ‡ 272 (nl) 115 (76%), ‡ 10125 M 30 IVS30+1G→T 3085C→T 20/200 20/200 8 Central hypopigmentation with dark surrounding, resembling bull’s eye. Later in life: peripheral changes characteristic of RP Severe red-green defect; mild blue-yellow defect Central scotoma of 10–15° with mild peripheral restriction 75 (75%) 80 (80%), ∥ 130 (87%) 140 (93%), ∥ 11872 M 30 634C→T 20/200 20/200 10 Bull’s eye pattern Severely disturbed; blue-yellow more than red-green Central scotoma of 25° 23 (23%) 35 (35%), ∥ 110 (73%) 95 (63%), ∥ 13163 M 15 1622T→C;3113C→T IVS36+1G→A 20/400 20/200 6 Granular aspect of retinal pigment epithelium in macula. Slightly pale optic disc Severely disturbed Central scotoma of 10–15,° no peripheral involvement ND, ¶ ND, ¶ CF, count fingers; LP, light perception; ND, not detectable; NP, not performed. * Allele 1, first line; allele 2, second line. † Between parentheses: percentage of the ERG value compared to the lower limit of the normality; normal ERG values are indicated nl. ‡ Minimal values for ERG recordings: 150 μV for the photopic ERG, 180 μV for the scotopic ERG. § ERG performed with skin electrodes. ∥ Minimal values for ERG recordings: 100 μV for the photopic ERG, 150 μV for the scotopic ERG. ¶ Minimal values for ERG recordings: 99 μV for the photopic ERG, 75 μV for the scotopic ERG. Figure 1. View OriginalDownload Slide (A–D) Fundus photographs and fluorescein angiograms in eyes of patients with (atypical) CRD. (A) Patient 11872 with bull’s eye maculopathy. (B) Patient 9369, demonstrating CRD in the later stages with attenuation of the retinal arterioles and irregular pigmentation temporal to the macula. (C) Fluorescein angiograms in patient 9378 showing confluent patches of chorioretinal atrophy. (D) Patient 10125 with central hypofluorescence enclosed by an ellipsoid hyperfluorescent area. In the surrounding area, hyperfluorescent flecks are visible, and the choroidal background fluorescence seems blocked, as seen in STGD.
Case#: Klevering Patient 9369, female, Netherlands, 40yo at report, 8yo at onset
DiseaseAssertion: cone-rod degenerations/ ABCA4-associated retinal dystrophy resembling CRD
FamilyInfo: "In view of the reputedly normal visual acuity of the parents and the molecular defects, the inheritance pattern of the gene defects in these patients (individuals 9303, 9369, 9553, and 13163) was classified as autosomal recessive."
CasePresentingHPOs:
CaseHPOFreeText: Visual acuity: light perception OU. Fundoscopy: Irregular hypopigmentation, mainly in the posterior pole. In later stages: attenuated vessels and bone spicula temporal to the macula. Red-green defect of color vision. Perimetry: Central scotoma varying from 10–30°. ERG Cone (μV): OD-80 (80%), OS-140 (90%) from 12 yo (all ERG responses had been non-detectable since the age of 21). ERG Rod (μV): 160 (nl). Fundus photographs and fluorescein angiograms show CRD in the later stages with attenuation of the retinal arterioles and irregular pigmentation temporal to the macula. Narrowing of retinal vessels and bone spicula (Fig 1B). Fundus description (PMID: 10958761): atrophy of the RPE around the optic disk, bone spicules along arteries and venules in the mid-periphery, and attenuated arterioles (Fig 1D)
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: single-strand conformation polymorphism (SSCP) and direct-sequencing techniques to look for mutations in the 50 exons and flanking intron sequences of the ABCA4 gene
PreviouslyPublished: Maugeri et al (PMID: 10958761)
Variant: c.6601_6602delAG
CAID: CA227421
SupplementalData: n/a
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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20/28/2/18/ female CRD c.1654 G>A c.4363 T>C 35, 35 38, 34 52, 57 4, 5 45.0, 42.5 1.0, 0.7
Case#: Subject 20, 28yo, 18yo at first ffERG, Sweden, female
DiseaseAssertion: CRD, group 2
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: extensive atrophies in the posterior pole. peripheral pigmentations. few peripapillary changes. Normal thickness of the most central segment recorded on OCT. total absence of the PIL (photoreceptor integrity line) and RPE atrophy on the OCT B-scans. ETDRS VA score= 35, 35. Rod ffERG= 38, 34 Ampl (µV). Combined ffERG= 52, 57 Ampl (µV). Cone ffERG= 4, 5; 45.0, 42.5 Amp IT (µV; ms). mERG sum= 1.0, 0.7 Ampl (µV). Group 2 with larger central scotomas from 10° to 35°
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Sequence analysis of the entire coding region of the ABCA4 gene was performed.
PreviouslyPublished: n/a
Variant: c.1654G>A; c.4363T>C
CAID: CA239745
SupplementalData: n/a
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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Sixteen patients from 13 families with signs of Stargardt macular dystrophy/fundus flavimaculatus and known mutations on both alleles of the ABCA4 gene (15 compound heterozygous, one homozygous) were characterized by clinical examination, fundus autofluorescence, psychophysics (color vision, kinetic and two-color dark- and light-adapted static threshold perimetry), and electrophysiology (Ganzfeld, multifocal ERG, EOG).
Article is a PDF, so annotating here.
ClinVar assertion listed this paper; however looking at the genotype table, none of the variants appear to match the variant in question.
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Additional file 2: All supplemental tables cited in the text. Enclosed data include data set meta-information, CAP scores for all drug-related genes, DRP scores for all drugs, CAP and DRP differences between populations, and a comparison between allele frequencies in the studied data set and CPIC guidelines. (XLSX 776 kb)13073_2017_502_MOESM2_ESM.xlsx (776K)GUID: B02AAF40-A613-411F-A471-357C45A33F82
This variant is mentioned in the supplemental table, S1 CAP. No additional details provided
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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A cohort of 12 unrelated STGD families diagnosed on the basis of clinical manifestations underwent analysis by targeted exome or whole-exome sequencing. Bioinformatics analysis, Sanger sequencing, and cosegregation analysis of available family members were used to validate sequencing data and confirm the presence of disease-causing genes. Results: Using targeted exome and whole-exome sequencing, we found that eight families had disease-causing variants in the ABCA4 gene, one family had only one heterozygous variant in the ABCA4 gene, and the remaining three families have not been identified with any disease-causing variants for STGD. We identified 15 variants in the ABCA4 gene; of these, five variants have not been previously described for STGD.
Unable to annotate on PDF, so annotating here.
Case#: Proband #4, male, Chinese, onset at 12yo
DiseaseAssertion: stargardt
FamilyInfo: parents are deceased, so phase is unknown. daughter is an unaffected carrier of this variant
CasePresentingHPOs: HP:0025147, HP:0011507, HP:0000608
CaseHPOFreeText: BCVA=0.3/CF, mean retinal nerve fiber layer(µm)=167/154, Visual field(mean deviation)= 7.52/NA, fundus fluorescein angiography=type C (a pattern of speckled hypofluorescence and hyperfluorescence without central hypofluorescence)
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
Variant: c.6289C > T p.(Pro2097Ser); c.4720G > T p.(Glu1574*) on targeted exome sequencing or WES
ClinVar: 2202780; 1460063
CAID: CA341277622; CA341283936
SupplementalData: n/a
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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To determine the overall CF for all AR-IRD–causing mutations in different subpopulations, we initially calculated CF for each of the 10,044 likely pathogenic variants in each subpopulation (SI Appendix, Tables S2 and S3).
This variant is found in Supplemental Table S3, but this table lists frequencies and does not give case information
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To determine the overall CF for all AR-IRD–causing mutations in different subpopulations, we initially calculated CF for each of the 10,044 likely pathogenic variants in each subpopulation (SI Appendix, Tables S2 and S3).
This variant is found in Supplemental Table S3, but this table lists frequencies and does not give case information
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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The proband
Case#: two affected sisters
DiseaseAssertion: Stargardt Disease
FamilyInfo: compound heterozygotes for the mutations. Unaffected family members did not carry either or had one of the two mutations.
CasePresentingHPOs: NR
CaseHPOFreeText: NR
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
Genotyping Method: ABCA4 408 microsatellite
PreviouslyPublished: NR
Variant: NM_000350.3(ABCA4):c.5018+2T>C , NM_000350.3(ABCA4):c.655A>T
ClinVar: 265008, 632118
CAID: CA10588304, CA645372240
SupplementalData: NR
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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a 45-year-old man
Case#: a 45-year-old man from Sardinia, Italy
DiseaseAssertion: Cone rod dystrophy
FamilyInfo: Five members, this patient is the only one affected by CRD
CasePresentingHPOs: HP:0000505, HP:0007663, HP:0000603, HP:0001123, HP:0000608, HP:0007401, HP:0011504, HP:0000548, HP:0030329, HP:0000543
CaseHPOFreeText: 1998: Subacute central vision loss in both eyes, choroidal and RPE atrophy surrounding left fovea and small white patches of atrophy around right fovea. Pale appearance of optic disc in both eyes. Punctate retinal pigment epitheliopathy observed bilaterally in midperipheral retina, hyperfluorescent macular regions suggesting bull's eye maculopathy. Paracentral ring scotoma, surrounded by a relative annular scotoma, early and predominant involvement of photopic over scotopic responses; 2018: BCVA was bilateral light perception with visual field extinction. FAF showed a central round area of decreased autofluorescence corresponding to area of macular atrophy, surrounded by an area of relatively increased autofluorescence. Several roundish areas of reduced autofluorescence in midperipheral retina. Severe macular atrophy surrounded by a ring of preserved RPE in both eyes. Sparse pigmentary deposits in midperipheral retina of both eyes. Severe bilateral retinal thinning with disappearance of external retinal layers. Outer retina tubulations
CaseNotHPOs: HP:0025148
CaseNotHPOFreeText: No pigment deposits on optic disc, no dark choroid
Genotyping Method: Candidate gene approach on ABCA4 followed by whole exome sequencing
PreviouslyPublished: NR
Variant: NM_000350, c.4535C>G, p.P1512R
ClinVar: 99291
CAID: CA227203
SupplementalData: Patient's healthy brother showed the same molecular condition for ABCA4. Patient also has 2 novel frameshift mutations in C2orf71.
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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An eight year-old Hispanic female
Case#: An 8-year old Hispanic female
DiseaseAssertion: Whole exome sequencing identified a homozygous ABCA4 missense variant (p.Arg602Trp) that has been identified as a Stargardt Disease mutation
FamilyInfo: consanguinity, her parents being first cousins, no family history of blindness. Familial cosegregation analysis was used, with both parents being heterozygous carriers.
CasePresentingHPOs: HP:0000529, HP:0000662, HP:0000556, HP:0002017,HP:0008046, HP:0031528, HP:0003678
CaseHPOFreeText: rapidly progressive vision loss, nyctalopia and retinal dystrophy, bilateral decreased vision following a febrile gastrointestinal illness with nausea and vomiting, Initial visual acuity was 20/60 at distance and 20/30 at near in both eyes, after 2 years visual acuities of 20/200 at distance in both eyes, attenuated vessels and multiple subretinal blister-like elevations, Cycloplegic retinoscopy detected very mild hyperopia and astigmatism in both eyes (OD: + 1.00 sphere + 1.00 cylinder axis 110 degrees; OS: + 0.75 sphere + 0.50 cylinder axis 60 degrees)
CaseNotHPOs: NR
CaseNotHPOFreeText: no evidence of a diffuse post-infectious/inflammatory process
Genotyping Method: DNA analysis by whole exomic sequencing
PreviouslyPublished: No
Variant: NM_000350.3:c.1804C>T
ClinVar:99084
CAID:CA226932
SupplementalData:
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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the model would predict foveal disease in the first decade of life for three alleles (P68L;G1961E, L541P;A1038V, and T1019M)
Case#: Cideciyan Case #86, male, 20.5yo at report
DiseaseAssertion: "clinical diagnosis within the spectrum of Stargardt disease or cone–rod dystrophy caused by ABCA4 mutations."
FamilyInfo: Parental segregation of the reported alleles confirmed. P87 is the proband's sibling, affected, same genotype
CasePresentingHPOs:
CaseHPOFreeText: LDF eccentricity along principal meridians [deg]: superior=16.9, inferior=11.7, temporal=18.9, inner nasal=9.6, outer nasal=18.9
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: NGS
PreviouslyPublished: PMID: 24550365
Variant: c.203 C>T p.Pro68Leuc.5882 G>A p.(Gly1961Glu); c.5882 G>A p.(Gly1961Glu). Phase confirmed.
ClinVar: 99113
CAID: CA226972
SupplementalData: table s1
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pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
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In humans, clinical studies have implicated mutations in 19 of the 48 known ABC transporters in diseases such as cystic fibrosis and adrenoleukodystrophy.
Annotating here since the article is a PDF.
This variant is mentioned in table 2 as a "disease associated mutation", but only as being present in the NBD/NBD interface. No further details are provided.
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oce-ovid-com.libproxy.lib.unc.edu oce-ovid-com.libproxy.lib.unc.edu
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Patients older than 60 years or with ocular comorbidities such as diabetic retinopathy, uveitis, or glaucoma were excluded. From the remaining list, subjects for whom high-resolution SD-OCT imaging was available were selected. A review of the patient imaging and medical records was performed to identify those who received a clinical diagnosis of Stargardt macular dystrophy based on their clinical phenotype, including color fundus, infrared, FAF, and fluorescein angiography images and electroretinographic findings. 12
Case#: P3, male, 16yo at report, 9yo at dx, US with Indian ethnicity
DiseaseAssertion: Stargardt
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText: BCVA (logMAR)= OD=20/160 (0.90), OS=20/125 (0.80)
CaseNotHPOs:
CaseNotHPOFreeText: ocular comorbidities such as diabetic retinopathy, uveitis, or glaucoma
GenotypingMethod: "genetic testing"
PreviouslyPublished: n/a
Variant: c.2453G>A; c.4532C>A (p.Pro1511His)
ClinVar: 99135
CAID: CA227000
SupplementalData: table 1
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Supplementary Materials
Supplemental Table 1. Patient WHP103 has this variant in compound heterozygosity with c.4720G>T(p.E1574*). Cannot confirm this is not the same proband as in PMID 31674661 since both have the same genotype and are of Chinese ancestry
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www-sciencedirect-com.libproxy.lib.unc.edu www-sciencedirect-com.libproxy.lib.unc.edu
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ABCA4ARc.[1957C > T];[4605insT]WESHuang et al., 2013cHuang et al., 2013c, Rivera et al., 2000
Case#: QT959, Chinese
DiseaseAssertion: Cone-rod dystrophy
FamilyInfo: no pedigree provided for this family in this paper
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: 23776498-more phenotype information available there
Variant: c.[1957C > T];[4605insT] on WES
ClinVar: n/a
CAID: CA645372205
SupplementalData: n/a
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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a 12-year-old female
Case#: a 12-year-old female admitted to the B Department Hédi Raies institut of Ophtalmology in Tunis, Tunisia
DiseaseAssertion: Cone rod dystrophy
FamilyInfo: No parental consanguinity nor pathological or opthalmological history in the family
CasePresentingHPOs: HP:0000529, HP:0000662, HP:0001141, HP:0000543,HP:0007737, HP:0030602
CaseHPOFreeText: progressive visual loss, poor night vision, 1/20 visual acuity in both eyes, pallor of the optic disk, attenuated retinal vessels, paravascular bone spiculed pigmentations and an epimacular membrane, paravascular and macular heterogeneous hypoautofluorescence, diffuse alteration of ellipsoid zone, decreased photopic and scotopic responses.
CaseNotHPOs: NR
CaseNotHPOFreeText: NR
Genotyping Method: Whole exome sequencing, Sanger sequencing
PreviouslyPublished: NR
Variant: c.885delC, NM_000350.3
ClinVar: 438109
CAID: CA958684
SupplementalData: Karyotyping showed monosomy 45,X in the patient
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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The study cohort consisted of 643 individuals of (mostly Eastern) European descent. Of these, 2 ABCA4 mutations were identified in 437 cases (68%), 1 mutation in 117 cases (18%) and 0 mutations in 89 cases (14%) (see online supplementary table 1), leaving ~23% of disease-associated alleles in 32% of patients yet to be identified. Almost all patients with no ABCA4 mutations and ~50% of patients with 1 mutation have been screened by whole exome sequencing to determine if variants in other genes were causal in these cases. All cases, where disease-associated variants in other genes were detected, were excluded from this cohort.
Case#: Case #3483, likely European, 10yo at onset
DiseaseAssertion: ABCA4 disease
FamilyInfo: n/a
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText: foveal sparing
GenotypingMethod: NGS, Sanger
PreviouslyPublished: n/a
Variant: c.2453G>A (p.Gly818Glu); c.4462T>C (p.Cys1488Arg)
ClinVar: 99135
CAID: CA227000
SupplementalData: supplemental table 1
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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A total of 88 eyes of 44 patients (32 female [73%]) with a mean age at examination of 37.6 ± 2.5 years (±SEM; range, 9–77 years) were included in this study (Table 1, Supplementary Table S1). Forty-one patients were found to have two disease-causing mutations. Three patients had only one disease-causing mutation but showed a phenotype consistent with ABCA4-related retinopathy.
Case#: Patients #33 and 34, female, 63 and 61yo at report, respectively, German
DiseaseAssertion: ABCA4-related retinopathy
FamilyInfo: n/a but they could be related
CasePresentingHPOs:
CaseHPOFreeText: "Inclusion criteria comprised the presence of at least one disease-causing mutation in ABCA4 and a phenotype consistent with ABCA4-related retinopathy, including RPE atrophy and flecks." BCVA [LogMAR] for patient #33: OD= 0.4, OS= 0.1. BCVA [LogMAR] for patient #34: OD= 1.5, OS= 1.0. Reduced (over 2 SD) photopic B-wave and 30-Hz flicker amplitudes
CaseNotHPOs:
CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous vitreoretinal surgery, or other ocular comorbidities substantially affecting visual function (e.g., significant media opacity, amblyopia, or optic nerve disease) led to exclusion. Abnormal responses on scotopic and photopic full-field ERG
GenotypingMethod:
PreviouslyPublished: likely the same patients as other Muller papers in this curation
Variant: c.3468C>G p.(Tyr1156*) and c.5059A>T p.(Ile1687Phe)
ClinVar: n/a
CAID: CA341290648
SupplementalData: Table S1 has genotype/phenotype info for probands
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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20 c.3208_3209insGT p.S1071fs DC c.1519G>T p.D507Y
Case#: Fujinami Patient 20, British
DiseaseAssertion: ABCA4-Related Retinal Disease
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText: Dx of ABCA4-associated retinal disease. At least localized low AF signal at the fovea surrounded by a homogeneous background, but no specific information provided
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: ABCA4 microarray, PCR-enrichment–based next-generation sequencing (NGS) of ABCA4. Identified variants were confirmed by Sanger sequencing and assessed for pathogenicity by in silico analysis.
PreviouslyPublished: n/a
Variant: c.3208_3209insGT (p.S1071fs) ; c.1519G>T (p.D507Y) not confirmed in trans
CAID: CA958508
SupplementalData:
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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Subjects All subjects provided written informed consent for this research study, which was approved by the University of Iowa Human Subjects Committee. The study included 176 patients with SD, 457 patients with RP, 60 patients with CRD and 272 normal control subjects. Seventeen members of this cohort (13 with SD, 1 with CRD and 3 with RP) had disease-causing mutations identified on one or both alleles in previous studies that employed single-strand conformational polymorphism analysis as the primary screening method (3). All patients and control subjects were ascertained in the outpatient ophthalmology clinic at the University of Iowa. All patients received a complete eye examination including measurement of Snellen visual acuity, slit lamp biomicroscopy of the anterior segment and fundus, and binocular indirect ophthalmoscopy. Most patients had fundus photography and Goldmann perimetry performed as well.Molecular characterization of the ABCA4 gene A multi-platform screening approach was used to genotype the ABCA4 gene in all 693 research subjects and 272 controls. Thirty-two of the most common disease-causing ABCA4 variations were selected for the initial screen. The entire research cohort was assayed for these 32 variations using a combination of SNPlex, SSCP analysis, TaqMan and automated DNA sequencing (3). The SNPlex and TaqMan assays were performed as previously described (22,23). Fourteen of the variations were compatible with Applied Biosystems SNPlex allele-specific assay platform. Nine variations were screened by SSCP analysis, three were screened using an Applied Biosystems' TaqMan assay and six were screened by automated DNA sequencing. All CRD and RP patients who had one plausible disease-causing allele identified in the first tier of screening were assayed by automated sequencing of the entire coding region of the ABCA4 gene in an effort to identify their second disease-causing allele. In addition, Stargardt patients who had one of the three most common alleles (Gly863Ala, Gly1961Glu or IVS38-10) were also sequenced through the entire coding region of the ABCA4 gene.Visual acuity The best-corrected visual acuity was recorded in each patient's medical record as a Snellen fraction (normal = 20/20). Before statistical analysis, these values were converted to the logarithm of the minimal angle of resolution (logMAR) by calculating the base 10 logarithm of the Snellen fraction [e.g. normal = log(20/20) = 0]. For patients with multiple hospital visits, the acuity measurements taken closest to the patient's 27th birthday were used for the statistical analysis. Values from the left eye and right eye were averaged.Visual field volume scores Goldmann visual fields were scanned with a Sharp scanner and analyzed with ImageJ software (available at http://rsbweb.nih.gov/ij/) as follows: transparent layers were added to each field, and the isopters of the visual fields were manually traced onto these layers. Each isopter was assigned a z-axis value according to relative luminous energy of the stimulus (I2e = 100, I3e = 31.7, I4e = 10, III4e = 0.49, V4e = 0.024, no detection = 0). The volume scores were calculated by multiplying the area of each isopter by its associated z-axis value and then summing the values for all isopters. For patients with multiple hospital visits, the visual field measurements taken closest to the patient's 27th birthday were used for the statistical analysis. Values from the left eye and right eye were averaged.Statistical analyses The frequencies of disease-causing alleles observed among the three groups of retinal disease patients were compared with the frequency in controls using Fisher's exact test. The phenotype of each patient was assumed to result from the additive effect of two alleles and one or more additional factors that were cumulatively represented by a single residual value for each subject. The values for the quantitative contribution of each allele were estimated using a multiple linear regression analysis (24). Specifically, to dissect the effect of each allele, we decomposed the mean phenotype of a person whose genotype consists of allele i and allele j into ai + aj, where ai is the effect of the i-th allele. To do this, we created a vector Yva of length 51 containing the average logMAR visual acuities for each subject, and a 51x16 matrix, X. Each cell of this matrix, Xij, indicated the number of occurrences of the j-th allele for each subject i. This system of 51 equations was solved with multiple linear regression to give estimates of a, using the statistics program R (available at http://www.R-project.org). To verify the allelic data, each row of X summed to 2, and each column summed to the corresponding number of occurrences of each allele for this cohort. These calculations were performed in the same manner for Yvol, the vector of containing each subject's visual field quantitative phenotype. The estimates of a, the coefficients for each allele, for both Yva and Yvol are given in Table 1.
Case#: Patient on line 28, US
DiseaseAssertion: retinitis pigmentosa (RP)
FamilyInfo:
CasePresentingHPOs:
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
GenotypingMethod: Thirty-two of the most common disease-causing ABCA4 variations were selected for the initial screen. The entire research cohort was assayed for these 32 variations using a combination of SNPlex, SSCP analysis, TaqMan and automated DNA sequencing. All CRD and RP patients who had one plausible disease-causing allele identified in the first tier of screening were assayed by automated sequencing of the entire coding region of the ABCA4 gene in an effort to identify their second disease-causing allele. In addition, Stargardt patients who had one of the three most common alleles (Gly863Ala, Gly1961Glu or IVS38-10) were also sequenced through the entire coding region of the ABCA4 gene.
PreviouslyPublished: n/a
Variant: c.6601_6602del (p.Arg2201AlafsTer?) "Glu2200del2 aggGA"; c.5461-10T>C "IVS38-10 T>C"
CAID: CA227421
SupplementalData: genotype in supplemental table 1
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Supplement 3iovs-63-2-11_s003.pdf (1.1M)GUID: 00045B54-7E12-4EE1-B50D-27CAC38DD633
This individual appears to be the same as in PMID: 23755871. Same author in both papers
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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A 37-year-old man presented with a 3-year history of decreased vision in the right eye, which had recently become worse.
Case#: single case, 37-year-old male, ethnicity not specified although family originally from the Middle East, examined in the UK
DiseaseAssertion: STGD
FamilyInfo: No history of consanguinity. No history of inherited retinal disease, poor vision or colour vision disturbance. Father had recent diagnosis of chronic central serous retinopathy, not consistent with STGD
CasePresentingHPOs: n/a
CaseHPOFreeText: Late-onset Stargardt disease with slowly progressive phenotype. The patient present with a 3-year history of decreased vision in the right eye that had recently significantly worsened. Visual acuity was 6.24 in right eye and 6/6 in left eye. Fundus examination reveled scattered atrophy and pisiform fundal flecks in both eye, right worse than left. Fluorescein angiography showed a silent choroid and partial bull's eye maculopathy, right worse than left. OCT showed loss of photoreceptors in both eyes and partial central sparing in the left eye. Photopic and scotopic ERG showed reduced amplitude of responses in the right eye and lower range amplitudes in the left eye, normal implicit times in both eyes. Pattern ERG and multifocal ERD showed central retinal dysfunction with preserved peripheral function. No change in vision or retinal appearance over the next 14 months of follow up.
CaseNotHPOs: n/a
CaseNotHPOFreeText: No night vision symptoms. No history of retinotoxic drug exposure.
Genotyping Method: Next-generation sequence analysis with the Oxford Genetics Testing Laboratory Macular Gene Panel.
PreviouslyPublished: Thr829Met missense mutation had been previously reported in an individual with autosomal recessive retinitis pigmentosa, but not previously associated with STGD phenotype.
Variant: ABCA4 NM_000350 c.5882G>A, p.(Gly1961Glu) c.2486C>T, p.(Thr829Met)
ClinVar: n/a
CAID: CA958261, CA119132
SupplementalData: n/a
Tags
- DecreasedCentralVA
- DecreasedERGResponses
- automated_hgnc:34
- MacularFlecks
- ClinGen ABCA4 Annotations
- InheritancePattern:AutosomalRecessive
- Bull’sEyeMaculopathy
- BeatenBronzeAppearance
- DiseaseEntity:STGD1
- automated_hgnc_source:CAID
- MacularAtrophy
- AlleleOrigin:Germline
- PreviousTesting
- Zygosity:CompoundHeterozygous
Annotators
URL
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