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:

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

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

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

PMID: 10612508

Gene: ABCA4

Case#: Patient 1, 40-year-old female

DiseaseAssertion: STGD1

FamilyInfo: One of four affected siblings in a family of eight. Segregation consistent with autosomal recessive inheritance.

CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0000612 — Central scotoma HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology

CaseHPOFreeText: Progressive decline in visual acuity since age 15. Best-corrected visual acuity RE 20/400, LE 20/150. Central scotomas reported. Fundus exam showed bilateral central macular atrophy (worse in right eye), pigment deposits at the level of the retinal pigment epithelium, and numerous yellow flecks in the midperiphery. Fluorescein angiography demonstrated central hypofluorescence corresponding to atrophy with surrounding hyperfluorescence and peripheral dark choroid.

CaseNotHPOs: HP:0000662 — Night blindness (absent)

CaseNotHPOFreeText: Patient denied nyctalopia.

GenotypingMethod: PCR amplification and direct sequencing of all 50 exons of ABCA4 following SSCP screening.

PreviouslyPublished: Yes

Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)

ClinVar: Not reported

CAID: Not reported

SupplementalData: Segregation demonstrated in pedigree (Figure 1); mutation confirmation by sequencing (Figure 4)

Case#: Patient 4, Female, Caucasian, 33yo

DiseaseAssertion: STGD1

FamilyInfo: One of eight siblings; four affected. Disease segregates with ABCA4 variants consistent with autosomal recessive inheritance. Parents are deceased and can't be tested.

CasePresentingHPOs: HP:0007663, HP:0007754, HP:0025147, HP:0007924, HP:0011507

CaseHPOFreeText: gradual decline in visual acuity over 9 years, BCVA 20/300 OU, bilateral beaten-bronze appearance of the macula, numerous perimacular yellow flecks, fluorescein angiography showing hyperfluorescence in the posterior pole and dark choroid in the periphery

CaseNotHPOs: N/A

CaseNotHPOFreeText: absence of central hypofluorescence on fluorescein angiography (present in affected siblings but not this patient)

Genotyping Method: SSCP analysis; Taq Dyedeoxy Terminator Cycle Sequencing kit

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.2588G>C (p.Gly863Ala), NM_000350.3(ABCA4):c.161G>A (p.Cys54Tyr)

ClinVar: ClinVarID:7879, ClinVarID:99065

CAID: N/A

SupplementalData: Segregation and sequencing data (Figures 1, 4)

PMID: 10612508

Gene: ABCA4

Case#: Patient 2, 46-year-old female

DiseaseAssertion: STGD1

FamilyInfo: One of four affected siblings in a family consistent with autosomal recessive inheritance.

CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology

CaseHPOFreeText: Progressive visual decline since age 16. Best-corrected visual acuity 20/400 in both eyes. Fundus examination showed bilateral symmetrical central chorioretinal atrophy (~3 disc diameters) with prominent pigment deposits and numerous yellow flecks in the posterior pole. Fluorescein angiography demonstrated central hypofluorescence with surrounding hyperfluorescence and peripheral dark choroid.

CaseNotHPOs: Not reported

CaseNotHPOFreeText: Not reported

GenotypingMethod: PCR amplification and direct sequencing of ABCA4 after SSCP screening

PreviouslyPublished: Yes

Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)

ClinVar: Not reported

CAID: Not reported

SupplementalData: Segregation and sequencing data shown in Figures 1 and 4

Case#: Patient 3, 37-year-old female

PMID: 10612508

DiseaseAssertion: STGD1

FamilyInfo: Affected sibling in autosomal recessive family.

CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology

CaseHPOFreeText: Gradual visual decline beginning at age 12. Visual acuity 20/400 in both eyes. Fundus examination revealed bilateral macular atrophy with pigment deposits and numerous yellow flecks in the posterior pole and midperiphery. Fluorescein angiography showed large hypofluorescent regions with surrounding hyperfluorescence and peripheral dark choroid.

CaseNotHPOs: Not reported

CaseNotHPOFreeText: Not reported

GenotypingMethod: PCR and direct sequencing of ABCA4

PreviouslyPublished: Yes

Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)

ClinVar: Not reported

CAID: Not reported

SupplementalData: Segregation and sequencing data (Figures 1, 4)

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

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

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

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

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

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

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

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

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

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:

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

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:

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:

Case#: MD-0324 Proband,

DiseaseAssertion: STGD

FamilyInfo: Family MD-0324

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, NGS

PreviouslyPublished: n/a

Variant:c.3386G>T p.Arg1129Leu; c.3G>A p.Met1Ile

ClinVar: n/a

CAID: CA341289040

SupplementalData: n/a

Case#: Family MD-0247 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: Aguirre-Lamban et al. 2009 (8); PMID: 19959634

Variant: c.6410G>A (p.Cys2137Tyr); c.3386G>T (p.Arg1129Leu) found by ABCR400 + dHPLC + HRM

ClinVar: 2202779; 99224

CAID: CA341277358; CA227116

SupplementalData:

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).

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

Case#: Two affected sisters/Female siblings/Progressive onset initially presenting as Stargardt disease

DiseaseAssertion: ABCA4

FamilyInfo: Large American family pedigree with two affected sisters. Both sisters were compound heterozygous for two novel ABCA4 variants. Unaffected relatives carried one variant or neither variant, supporting autosomal recessive inheritance.

CasePresentingHPOs: HP:0000556, HP:0000572, HP:0007754, HP:0000648, HP:0000510, HP:0001133, HP:0000610

CaseHPOFreeText: Proband initially showed phenotype compatible with Stargardt disease with progressive central vision loss. Over several years disease advanced into severe cone-rod dystrophy with worsening retinal degeneration, abnormal visual fields, and reduced electroretinography responses.

CaseNotHPOs: n/a

CaseNotHPOFreeText: Unaffected family members with only one mutation had no retinal disease phenotype.

Genotyping Method: Genome-wide linkage analysis using 408 microsatellite markers followed by direct Sanger DNA sequencing of all ABCA4 exons and exon-intron boundaries. Segregation analysis performed in family members.

PreviouslyPublished: No, both variants were novel at time of publication.

Variant: ABCA4 (RefSeq: NM_000350.3): c.655A>T ; ABCA4 (RefSeq: NM_000350.3): c.5312+3A>T

ClinVar: 632118

CAID: n/a

SupplementalData: Variants absent in 200 unrelated controls. Clinical testing included visual acuity, fundus examination, fluorescein angiography, visual field testing, and electroretinography. Compound heterozygous state associated with severe progressive phenotype.

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)

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.

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.

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.

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.

This variant is found in compound heterozygosity with c.3386G>T p.(Arg1129Leu) in family MD-0723 in this study. Proband is 13yo at onset of VA loss and VF loss with night blindness. 15yo at opthalmological exam. Cone pattern on ERG. BCVA=0.2/0.2. Eligible for PP4.

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:

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

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

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

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.

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.

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.

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

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: PMID: 19028736

Variant: c.6410G>A (p.Cys2137Tyr); c.3386G>T (p.Arg1129Leu) found by ABCR400 + dHPLC + HRM

ClinVar: 2202779

CAID: CA341277358

SupplementalData: n/a

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

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

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

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

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

Case#: Braun Family 2 Proband (from left to right, top to bottom of available pedigrees), female

DiseaseAssertion: Stargardt

FamilyInfo: Both parents are unaffected carriers. c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variants were paternally inherited, c.5196+1137G>A maternally 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.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variant

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

Case#: Braun Family 3 Proband (from left to right, top to bottom of available pedigrees), female

DiseaseAssertion: Stargardt

FamilyInfo: Both parents are unaffected, but only mother has genotype information available since father is deceased. c.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variants were maternally 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.1622T>C (p.L541P) and c.3113C>T (p.A1038V) complex variant

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

Case#: Braun Family 4 Proband (from left to right, top to bottom of available pedigrees), male

DiseaseAssertion: Stargardt

FamilyInfo: Both parents are unaffected, but only mother has genotype information available since father is deceased. c.5196+1137G>A maternally inherited. c.1022-1035fs inferred to be inherited from the father since other siblings also have this variant. Proband has 1 affected sister with the same genotype, and 2 siblings that were unaffected heterozygotes

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.1022-1035fs

ClinVar: 438100

CAID: CA26843511

SupplementalData: pedigree in fig s2

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

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

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

Case#: Maia-Lopes Family 17 Proband 5137, Portuguese, 25yo at onset

DiseaseAssertion: STGD

FamilyInfo: Family 17

CasePresentingHPOs:

CaseHPOFreeText: moderate central fundus changes, vision: 3/10 / FC

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: ABCR400 microarray, dHPLC

PreviouslyPublished: n/a

Variant: ND / c.32T>C(1); ND/p.Leu11Pro

ClinVar: 99217

CAID: CA227106

SupplementalData: n/a

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

Case#: Patient 231, Female, age of onset at 7 y.o, Poland

DiseaseAssertion: STGD1

FamilyInfo: Mother was a carrier, unaffected father.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.4234C>T , p.(Gln1412*)

ClinVar: 99263

gnomeAD 0.00001984 allelic frequency

CAID: n/a

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

Case#: Patient 225, Female, age of onset 7 y.o, Poland

DiseaseAssertion: STGD-1

FamilyInfo: no given family information.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.634C>T,p.(Arg212Cys)

ClinVar: 7898

CAID: n/a

gnomeAD 0.0001177 allele frequency

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

Case#: Patient 231, Female, age of onset at 7 y.o, Poland

DiseaseAssertion: STGD1

FamilyInfo: Mother was a carrier, unaffected father.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.5882G>A

ClinVar:7888

gnomeAD: 0.00310 allelic freq.

CAID: n/a

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

Case#: Patient 225, Female, age of onset 7 y.o, Poland

DiseaseAssertion: STGD-1

FamilyInfo: no given family information.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.[1622T>C;3113C>T]

ClinVar: 99067, 7894

CAID: n/a

gnomeAD 0.0001266 allele frequency

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

Case#: 32-year old woman, onset in early twenties

DiseaseAssertion: STGD1

FamilyInfo: n/a

CasePresentingHPOs: HP:0011462, HP:0011507, HP:0000505, HP:0007722, HP:0030500, HP:0030329, HP:0030610, HP:0000575, HP:0030602

CaseHPOFreeText: Patient’s best-corrected visual acuity was OD: 20/200 and OS: 20/40. Refractive error was OD: −5.25/−0.75 × 4° and OS: −5.75/−0.50 × 133°. Flecks in macular area extended anterior to the vascular arcades and the optic disc in both eyes. Atrophic lesion in the macula with flecks observed across the posterior pole. IS/OS junction loss central macular area bilaterally. Absolute scotoma in left eye (ie total deviation −20 dB). Defect in the RPE/Bruch membrane complex was observed on SD-OCT in both eyes in the central macula. The defects in the RPE-Bruch membrane complex measured OD: 332 um and OS: 266 um in maximum horizontal diameter. Herniation of the retina through these defects into the sub-RPE/choroidal space. Abnormal thickening of the RPE in the parafoveal region. Normal amplitudes and implicit times in both rod and cone photoreceptor systems were detected by ERG.

CaseNotHPOs: HP:0000510, HP:0007984

CaseNotHPOFreeText: Normal amplitudes and implicit times in both rod and cone photoreceptor systems were detected by ERG. There was no evidence of sub-RPE choroidal neovascularization (CNV), pigment epithelial defects (PED) or subretinal fluid.

Genotyping Method: ABCR 600 micro-array chip

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.5714+5G>A

ClinVar: 99403

SupplementalData: n/a

Case#:48-year old man, onset at 13-years old

DiseaseAssertion: STGD1

FamilyInfo: n/a

CasePresentingHPOs: HP:0003621, HP:0025147, HP:0011507, HP:0030329, HP:0030610, HP:0007722, HP:0007703, HP:0007663

CaseHPOFreeText: BCVA was 20/200 bilaterally and refractive error was OD: −1.50/+0.50 × 149° and OS: −1.50/+0.25 × 161°. Hyperautofluorescent transitional zone in each eye more pronounced in right eye. The left eye showed a complete defect of the RPE-Bruch membrane complex with herniation of the outer retina. Maximum horizontal diameter of this RPE-Bruch membrane complex defect was 266um.

CaseNotHPOs: HP:0000510, HP:0000548, HP:0007984

CaseNotHPOFreeText: No defect observed in the RPE and Bruch membrane in right eye. Patient had normal cone and rod responses on ERG

Genotyping Method: ABCR 600 micro-array chip

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.4216C>T (p.His1406Tyr), NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)

ClinVar: 99259, 7888

SupplementalData: n/a

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

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

Case#: Female, 69yo, Puerto Rican

DiseaseAssertion: STDG1

FamilyInfo: Parents were first cousins (consanguinity), no other family history reported

CasePresentingHPOs: HP:0030603, HP:0007754, HP:0000512, HP:0008020, HP:0000603

CaseHPOFreeText: progressive vision loss, severe reduction in visual acuity (counting fingers at 5’ and 3’), bilateral central scotoma, extensive central macular atrophy, retinal pigment epithelium atrophy and pigment hyperplasia, multifocal retinal atrophy, central hypoautofluorescence with peripheral expansion, reduced macular thickness and volume on OCT, abnormal visual field (marked mean deviation)

CaseNotHPOs: HP:0000510

CaseNotHPOFreeText: normal rod response on full-field electroretinogram

Genotyping Method: Next-generation sequencing (Invitae Corporation, San Francisco, California)

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.5714+5G>A

ClinVar: ClinVarID:99403

CAID: N/A

SupplementalData: N/A

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

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

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

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

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

Variant detected in one allele (heterozygous) in Czech patient with Stargardt disease. No other ABCA4 variants detected.

Case#: Male, mid-40s

DiseaseAssertion: STGD1

FamilyInfo: Retinal disease reported in sibling and material grandfather. Mother exhibited decreased visual acuity, BEM in right eye, and tapetal reflex in both eyes.

CasePresentingHPOs: HP:0000622, HP:0000613, HP:0000662, HP:0011504, HP:0007663, HP:0011463

CaseHPOFreeText: n/a

CaseNotHPOs: HP:0007843, HP:0011507

CaseNotHPOFreeText: Autofluorescence(qAF): 381.5. The Case's qAF was noted to be in the range observed in healthy eyes, and also lower than many other STGD1 patients with the same age. There were no flecks, intraretinal pigment migration, retinal vessel attenuation, or optic nerve pallor (Figure 1).

Genotyping Method: Sanger Sequencing

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.1411G>A (p.Glu471Lys), NM_001034853.2(RPGR):c.3070G>T (p.Glu1024Ter)

ClinVar: 99052, 1275798

SupplementalData: n/a

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

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

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

Case #: Eldest sister/Female/Onset at 3yo

DiseaseAssertion: SLC26A2

FamilyInfo: Family pedigree showing consanguinity of the proband's parents. The osteochondrodysplasia genotype, derived from a homozygous variant in the SLC26A2 gene and compound heterozygous variants in the ABCA4 gene, is responsible for the retinal phenotype

CasePresentingHPOs: HP:0034345, HP:0000556, HP:0002098, HP:0001903, HP:0001385, HP:0007754, HP:0002650, HP:0000939, HP:0025388, HP:0007987, HP:0003124, HP:0007401

CaseHPOFreeText: Visual acuity was 1/50 and 2/50 for both eyes, knee dysplasia, sticky platelet syndrome type II

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

GenotypyingMethod: genetic screening by next‐generation sequencing (NGS) was performed on a panel of genes involved in retinal dystrophy and macular degeneration

PreviouslyPublished: n/a

Variant: ABCA4 (RefSeq: NM_000350.3(ABCA4):c.203C>T (p.Pro68Leu))

CAID: n/a

SupplementalData: Comparison of phenotypes (table 1)

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.

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

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

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

Case#: DNAID 072962/Pat272, 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>A (p.Arg2139Gln); c.6445C>T (p.Arg2149Ter)

CAID: CA956878

SupplementalData: tables s9 and s11

Case#: DNAID 072284/Pat191, 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.4139C>T (p.Pro1380Leu) phase not confirmed

CAID: CA958508

SupplementalData: tables s9 and s11

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)

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:

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

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

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

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

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

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

Case#: Hwang Case 1, US, male, 55yo at report, 18yo at onset

DiseaseAssertion: Stargardt disease

FamilyInfo: Family history was not significant for ocular disease

CasePresentingHPOs: HP:0007663, HP:0500087, HP:0000603, HP:0000512

CaseHPOFreeText: BCVA of 20/350 OD and 20/200 OS. Spherical refractive error measured −3.5 OD and −2.0 OS. Posterior segment examination and autofluorescence imaging were significant for sharply demarcated central and peripapillary zones of atrophy and the absence of fleck lesions (Figure 1, A–D). Humphrey visual fields demonstrated bilateral central scotomas with eccentric fixation at the inferior border.

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Genotyping was performed by the ABCR400 microarray followed by direct sequencing to confirm identified variants.

PreviouslyPublished: n/a

Variant: P1380L and IVS40 + 5G>A

ClinVar: 7904

CAID: CA129033

SupplementalData: n/a

previously reported in PMID: 26377081

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

Case#: Garces Patient 4, Canada

DiseaseAssertion: mild STGD1

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: 30yo, VA=20/30, FC=Stage 2 (flecks throughout the posterior pole, anterior to the vascular arcades and nasal to the optic disc and relatively normal ERGs but with prolonged dark adaptation)

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: screened for mutations in the ABCA4, CNGB3, and ELOVL4 genes

PreviouslyPublished: n/a

Variant: c.213dupG/p.Ile73Asnfs*26; c.1654G>A/p.Val552Ile

CAID: CA239745

SupplementalData:

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

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

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

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

Case#: Patient#010046, Chinese, female, 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: PMID: 26780318

Variant: p.P2097S; p.A1773V phase unknown

ClinVar: 2202780

CAID: CA341277622

SupplementalData: supplementary table S4 has phenotype information

Case#: Patient#010633, Chinese, female, 20yo 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=0.05/ 0.05

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: p.P2097S; c.3468C>G p.(Tyr1156*) phase unknown

ClinVar: 2202780;

CAID: CA341277622;

SupplementalData: supplementary table S4 has phenotype information

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

Case#: 43-year old man, German descent, onset within first decade of life

DiseaseAssertion: STGD1

FamilyInfo: Family pedigree shown in Figure 1.

CasePresentingHPOs: HP:0011463, HP:0000533, HP:0000580, HP:0030500, HP:0011507, HP:0000548, HP:0000510, HP:0007703, HP:0007663, HP:0000512, HP:0000610

CaseHPOFreeText: Retinal vessels were visibly attenuated.

CaseNotHPOs: n/a

CaseNotHPOFreeText: Peripapillary region around the optic nerve had no disease related changes.

Genotyping Method: Illumina MiSeq platform, Array-CGH analysis

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.161G>A (p.Cys54Tyr), NM_000350.3(ABCA4):c.4539+2028C>T

ClinVar: 99065, 236116

SupplementalData: n/a

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

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.

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.