Supplementary table 2 lists this variant as previously reported in 3 individuals from PMID: 19365591

This variant was not evaluated.

This variant is found in table S2A to have an OR of 47.7 with a CI (4.71-2311.43).

This variant was not evaluated.

This variant was not evaluated.

This variant was not evaluated.

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:

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

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

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

another case with 541 variant potentially not in cis with 1038

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:

another case with 541 variant potentially not in cis with 1038

This paper was listed under this variant in LOVD, but I cannot find it in the main text or supplemental documents.

This individual appears to be the same as in PMID: 23755871. Same author in both papers

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

ATPase activity in COS7 cells showed decreased activity (68.1% of wild-type), indicating that this variant impacts protein function (PS3_Supporting; PMIDs). However, this is not a cell type that is counted for PS3 evidence by the ABCA4 VCEP.

This variant is listed for Stargardt DNAID#070949 in trans with c.3682G>A p.(Glu1228Lys). No phenotype information provided.

This variant is listed for Stargardt DNAID#070982 in trans with c.4253+43G>A. No phenotype information provided. This genotype was also reported in PMID: 32619608 and the first author of that paper is listed under authorship for this paper. Cannot confirm this isn't the same individual

This variant is listed for Stargardt DNAID#067322 in trans with c.5603A>T p.(Asn1868Ile). No phenotype information provided.

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

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

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

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"

This variant was mentioned in reference to a previous publication. PMID: 23419329

This variant is in supplementary table S1 as being found in an Italian IRD "solved" case with AR inheritance, but no further details are provided.

Case#: Patient #14, female, 34yo

DiseaseAssertion: Stargardt

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: stage 3, BCVA: OD=20/200 OS=20/250, fundus findings: OU: Severe RPE and choroidal atrophic changes in macula and throughout posterior pole and midperiphery, flecks throughout posterior pole, full field ERG: Subnormal rod, subnormal cone,

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: direct sequencing of the ABCA4 gene

PreviouslyPublished:

Variant: Compound heterozygous: G818E and C1488R

ClinVar:

CAID:

SupplementalData:

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.

This variant is found in homozygosity in family MD-0084 in a previous publication (PMID: 23755871)

This variant was found in homozygosity 3 times in table S1 (Families MD-0991, MD-1164, and MD-1302). All with a STGD1 phenotype.

MD-0991 had onset of VA loss at 25yo, cone-rod pattern on ERG, and BCVA was 1.2/1.2. Segregation was mentioned, but no details provided.

MD-1164 had onset of VA loss at 42yo, no VF loss, and BCVA was 0.2/0.3. Segregation was not mentioned.

MD-1302 had no clinical details available.

GenotypingMethod: Index cases were studied by different next-generation sequencing (NGS) strategies, including targeted gene panels, clinical exome, and/or whole-exome sequencing

Case#: Zhao Case Rp125, N. Ireland

DiseaseAssertion: arRP

FamilyInfo: familial case. affected sister with the same genotype

CasePresentingHPOs:

CaseHPOFreeText: "Retinitis pigmentosa was diagnosed on the basis of the typical fundal features (bone spicule retinal pigmentation, arteriolar attenuation, and optic disc pallor), visual field constriction, and an attenuated or abolished electroretinogram." 7yo at onset. BCVA= CF, HM. ERG findings: extinguished OU

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Targeted next-generation sequencing using a retinal capture panel to test 55 RP genes and 131 other retinal disease genes. All putative mutations identified by NGS were validated using Sanger sequencing and tested for co-segregation if additional affected family members are available

PreviouslyPublished: n/a

Variant: NM_000350 c..6416G>C p.(Arg2139Pro); c.1519G>T p.(Asp507Tyr)

CAID: CA956878

SupplementalData: table s6, figure s1

Case#: Pt 13, 34yo, female

DiseaseAssertion: Stargardt

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: stage 3 (resorbed flecks), logMAR acuity: OD=1.02 OS 1.06, FST Rod Blue Stimulus (dB) OD= −68.3, FST Cone Red stimulus (dB) OD=−23.3, FST Group 2 (elevated cone and normal rod FST thresholds)

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod:

PreviouslyPublished:

Variant: p.Gly818Glu; p.Cys1488Arg

ClinVar: 99135

CAID: CA227000

SupplementalData: n/a

This variant was transfected into HEK 293 cells and appears to show reduced expression and ATP-binding capacity, but no quantities were provided

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:

The effects of this variant on 11-cis-retinal interaction with the NBD1 was evaluated via fluorescence anisotropy. The binding of mutant G863A was significantly attenuated (Kd was ≥1.0 × 10−5 m) as indicated by the drastic right shift of the binding isotherm as well as its inability to achieve saturation in the presence of a high concentration of protein (Fig. 6A).

Patient 38 has this variant and also c.5882G>A p.(Gly1961Glu) (Supplement 4-supplementary table 1). Phase is unknown and more specific phenotype information is not provided.

clinical diagnosis of STGD1 was supported by the presence of ≥1 (likely) pathogenic ABCA4 variants with a follow-up data of ≥6 months on FAF imaging.

Case#: OGI802_001554

DiseaseAssertion: IRD

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: detection of CNVs on the panel-based NGS Genetic Eye Disease (GEDi) diagnostic test that involves sequencing the exons of all known IRD disease genes

PreviouslyPublished: n/a

Variant: c.1715G>C; c.5196+1137G>A

ClinVar: 99073

CAID: CA226919

SupplementalData: Table S2

Case#:two cases from two additional families (case 3, 11 years and case 4, 11 years).

DiseaseAssertion: Stargardt’s Disease

FamilyInfo: NR

ParentalTesting: NR

CasePresentingHPOs: HP:0030500, HP:0011507

CasePhenotypeFreeText: LogMAR visual acuity for the right and left eye of cases 1–4 was 0.3 and 0.2, 0.1 and 0.1, 0.5 and 0.4, and 0.3 and 0.4, respectively. Gross disruption of the outer retinal layers at the macula in all cases; in two (cases 2 and 4), the presumed external limiting membrane (ELM) peak was broadened with the inner segment ellipsoid band (ISe) missing. Subtle white-yellowish fine dots at the macula and numerous white-yellowish flecks extending anterior to the arcade are shown in the colour fundus photograph of case 1. Autofluorescence (AF) imaging of case 1 detected well-defined dots with high signal at the central macula surrounded by a ring of increased signal and numerous foci with high or low signal extending to the peripheral retina. Case 2 also had subtle white-yellowish fine dots at the central macula and numerous white-yellowish flecks extending anterior to the arcade, both associated with high signal on AF imaging. In addition, case 3 had white-yellowish fine dots at the macula and numerous white-yellowish flecks extending to the periphery, both of which had high or low signal on AF imaging. Case 4 showed subtle fine macular dots mainly in a para-foveal location, which are well-defined on AF imaging.

CaseNotHPOs: HP:0007401, HP:0000505

CaseNotPhenotypeFreeText: Most cases with STGD have central macular atrophy with numerous more peripheral flecks (Michaelides et al. 2003). Given their relatively good visual acuity, it is likely that the central macular dots observed in our cases may be an early sign of macular dysfunction before the development of macular atrophy. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases

CasePreviousTesting: The age of disease onset in cases 1–4, defined as either the age at which visual loss was first noted by the subject or in the asymptomatic subjects when abnormal retinal appearance was first detected, was 5, 7, 8, and 6 years old, respectively.

GenotypingMethod: After informed consent was obtained, blood samples were taken from probands of 2/3 families for ABCA4 screening. A full medical history was obtained, and a full ophthalmologic examination was performed in all cases. Mutation screening of ABCA4 was performed in two probands of the three families, and two likely disease-causing variants were identified in each case; c.768G > T, p.V256V (a previously reported splicing-altering synonymous variant) and c.4363T > C, p.C1455R (a missense variant) in case 1, and c.1906C > T, p.Q636* (a non-sense variant) and c.5461-10 T > C (a disease-associated intronic variant with uncertain effect) in case 3. A blood sample was not available in one proband (case 4).

Variant: NM_000350.3(ABCA4):c.1906C>T (p.Gln636Ter) and NM_000350.3:c.5461-10T>C

LegacyVariant: c.1906C>T (p.Gln636Ter) and c.5461-10T>C

ClinVar: 265012 and 92870

CAID: CA10588302 and CA220687

gnomeAD: 1:94528164 G / A and 1:94476951 A / G

MultipleGeneVariants:No

PreviouslyPublished: No

AdditionalInfo: Most symptoms/diagnoses are consistent with Stargardt’s Disease 3, however the probands in the study were younger in age, so many of the symptoms hadn’t progressed much. Also, all of the cases had decent visual acuity, which contradicts a symptom of Stargardt’s Disease 3. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases, for example, in those caused by mutations in RDH5 or RPE65, both of which encode proteins with known function in the visual cycle. The thickening of the ELM may be an OCT abnormality that precedes atrophy in the early stages of STGD

Case#: two siblings (female) were from one consanguineous family (case 1, 11 years and case 2, 9 years)

DiseaseAssertion: Stargardt’s Disease

FamilyInfo: NR

ParentalTesting: NR

CasePresentingHPOs: HP:0030500, HP:0011507

CasePhenotypeFreeText: LogMAR visual acuity for the right and left eye of cases 1–4 was 0.3 and 0.2, 0.1 and 0.1, 0.5 and 0.4, and 0.3 and 0.4, respectively. Gross disruption of the outer retinal layers at the macula in all cases; in two (cases 2 and 4), the presumed external limiting membrane (ELM) peak was broadened with the inner segment ellipsoid band (ISe) missing. Subtle white-yellowish fine dots at the macula and numerous white-yellowish flecks extending anterior to the arcade are shown in the colour fundus photograph of case 1. Autofluorescence (AF) imaging of case 1 detected well-defined dots with high signal at the central macula surrounded by a ring of increased signal and numerous foci with high or low signal extending to the peripheral retina. Case 2 also had subtle white-yellowish fine dots at the central macula and numerous white-yellowish flecks extending anterior to the arcade, both associated with high signal on AF imaging. In addition, case 3 had white-yellowish fine dots at the macula and numerous white-yellowish flecks extending to the periphery, both of which had high or low signal on AF imaging. Case 4 showed subtle fine macular dots mainly in a para-foveal location, which are well-defined on AF imaging.

CaseNotHPOs: HP:0007401, HP:0000505

CaseNotPhenotypeFreeText: Most cases with STGD have central macular atrophy with numerous more peripheral flecks (Michaelides et al. 2003). Given their relatively good visual acuity, it is likely that the central macular dots observed in our cases may be an early sign of macular dysfunction before the development of macular atrophy. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases

CasePreviousTesting: The age of disease onset in cases 1–4, defined as either the age at which visual loss was first noted by the subject or in the asymptomatic subjects when abnormal retinal appearance was first detected, was 5, 7, 8, and 6 years old, respectively.

GenotypingMethod: After informed consent was obtained, blood samples were taken from probands of 2/3 families for ABCA4 screening. A full medical history was obtained, and a full ophthalmologic examination was performed in all cases. Mutation screening of ABCA4 was performed in two probands of the three families, and two likely disease-causing variants were identified in each case; c.768G > T, p.V256V (a previously reported splicing-altering synonymous variant) and c.4363T > C, p.C1455R (a missense variant) in case 1, and c.1906C > T, p.Q636* (a non-sense variant) and c.5461-10 T > C (a disease-associated intronic variant with uncertain effect) in case 3. A blood sample was not available in one proband (case 4).

Variant: NM_000350.3(ABCA4):c.768G>T (p.Val256=) and NM_000350.3(ABCA4):c.4363T>C (p.Cys1455Arg)

LegacyVariant: c.768G>T (p.Val256=) and c.4363T>C (p.Cys1455Arg)

ClinVar: 99505 and 377404

CAID: CA227458 and CA957621

gnomeAD: 1:94564350 C / A and 1:94495177 A / G

MultipleGeneVariants:No

PreviouslyPublished: No

AdditionalInfo: Some symptoms/diagnoses are consistent with Stargardt’s Disease 3, however the probands in the study were younger in age, so many of the symptoms hadn’t progressed much. Also, all of the cases had decent visual acuity, which contradicts a symptom of Stargardt’s Disease 3.

Case#: Patient P28592/1,

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Custom 300-kb retinal resequencing chip. PCR amplification, DNA fragmentation, and chip hybridization. Hybridization signals were analyzed using Sequence pilot module seq-C mutation detection software (2009). This resequencing approach was validated by Sanger sequence technology.

PreviouslyPublished: n/a

Variant: c.635G>A p.(R212H); c.6445C>T p.(R2149X); c.6285T>C p.(D2095D)

CAID: CA285825

SupplementalData: n/a

This patient was later phenotypically characterized in more depth (PMID: 12037008)

Case#: Patient #34, female, 61yo at baseline visit, "intermediate" age of onset

DiseaseAssertion: ABCA4-related retinopathy with secondary RPE atrophy

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: Inclusion criteria were defined as 1) presence of at least one mutated allele in ABCA4 (NM_000350.2) in Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing 2) a compatible phenotype with flecks at the level of the RPE consistent with ABCA4 -related Stargardt disease 3) presence of RPE atrophy, and 4) serial examinations with an interval of at least 6 months. RPE atrophy to the end-stage (i.e., demarcated lesions with ≥90% darkness of the optic disc under short-wavelength excitation light, DDAF) that previously showed highest interreader agreement.7 The size of DDAF has to be at least 0.05 mm 2 (each single atrophic area in cases of multifocality), and the entire lesion must be completely visualized on the AF image at each visit to be advanced for analysis. Self-reported symptom onset into early-onset (≤10 years), intermediate-onset (11–44 years), and late-onset (≥45 years). ff-ERG based Category: Group 1 contained eyes with normal scotopic and photopic responses; Group 2, eyes with normal scotopic responses, but reduced (over 2 SDs) photopic B-wave and 30-Hz flicker amplitudes; and Group 3, eyes with impairment of both rod- and cone-driven responses. BCVA: OD=n/a, OS=1 [LogMAR] .

CaseNotHPOs:

CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting image quality led to exclusion from the study

GenotypingMethod: Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing

PreviouslyPublished: possible since Birtel is an author on this paper and the probands both have the same second variant as in PMID: 29555955

Variant: allele 1: c.3468C>G p.(Tyr1156*) allele 2: c.5059A>T p.(Ile1687Phe)

ClinVar: n/a

CAID: CA341290648

SupplementalData: The supplemental table linked here contains genotype and phenotype information.

Case#: Patient #32, male, 60yo at baseline visit, "late" age of onset

DiseaseAssertion: ABCA4-related retinopathy with secondary RPE atrophy

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: Inclusion criteria were defined as 1) presence of at least one mutated allele in ABCA4 (NM_000350.2) in Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing 2) a compatible phenotype with flecks at the level of the RPE consistent with ABCA4 -related Stargardt disease 3) presence of RPE atrophy, and 4) serial examinations with an interval of at least 6 months. RPE atrophy to the end-stage (i.e., demarcated lesions with ≥90% darkness of the optic disc under short-wavelength excitation light, DDAF) that previously showed highest interreader agreement.7 The size of DDAF has to be at least 0.05 mm 2 (each single atrophic area in cases of multifocality), and the entire lesion must be completely visualized on the AF image at each visit to be advanced for analysis. Self-reported symptom onset into early-onset (≤10 years), intermediate-onset (11–44 years), and late-onset (≥45 years). ff-ERG based Category: Group 1 contained eyes with normal scotopic and photopic responses; Group 2, eyes with normal scotopic responses, but reduced (over 2 SDs) photopic B-wave and 30-Hz flicker amplitudes; and Group 3, eyes with impairment of both rod- and cone-driven responses. BCVA: OD=0, OS=0 [LogMAR] .

CaseNotHPOs:

CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting image quality led to exclusion from the study

GenotypingMethod: Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing

PreviouslyPublished: n/a

Variant: allele 1: c.52C>T/p.(Arg18Trp) // c.1715G>A/p.(Arg572Gln) // c.2828G>A/p.(Arg943Gln) allele 2: c.1588G>A/p.(Gly863Ala) // c.5603A>T/p.(Asn1868Ile)

ClinVar: 7900

CAID: CA226918

SupplementalData: The supplemental table linked here contains genotype and phenotype information.

Case#: Patient #33, female, 64yo at baseline visit, "late" age of onset

DiseaseAssertion: ABCA4-related retinopathy with secondary RPE atrophy

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: Inclusion criteria were defined as 1) presence of at least one mutated allele in ABCA4 (NM_000350.2) in Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing,9 2) a compatible phenotype with flecks at the level of the RPE consistent with ABCA4 -related Stargardt disease,9 3) presence of RPE atrophy, and 4) serial examinations with an interval of at least 6 months. RPE atrophy to the end-stage (i.e., demarcated lesions with ≥90% darkness of the optic disc under short-wavelength excitation light, DDAF) that previously showed highest interreader agreement.7 The size of DDAF has to be at least 0.05 mm 2 (each single atrophic area in cases of multifocality), and the entire lesion must be completely visualized on the AF image at each visit to be advanced for analysis. Self-reported symptom onset into early-onset (≤10 years), intermediate-onset (11–44 years), and late-onset (≥45 years). ff-ERG based Category: Group 1 contained eyes with normal scotopic and photopic responses; Group 2, eyes with normal scotopic responses, but reduced (over 2 SDs) photopic B-wave and 30-Hz flicker amplitudes; and Group 3, eyes with impairment of both rod- and cone-driven responses. BCVA: OD=0.4, OS=1.1 [LogMAR] .

CaseNotHPOs:

CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting image quality led to exclusion from the study

GenotypingMethod: Sanger sequencing with multiplex ligation-dependent probe amplification analysis or next-generation sequencing

PreviouslyPublished: possible since Birtel is an author on this paper and the probands both have the same second variant as in PMID: 29555955

Variant: allele 1: c.3468C>G p.(Tyr1156*) allele 2: c.5059A>T p.(Ile1687Phe); c.4297G>A p.(Val1433Ile)

ClinVar: n/a

CAID: CA341290648

SupplementalData: The supplemental table linked here contains genotype and phenotype information.

Case#: Patient #9, female, 23yo at onset, 32yo 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.1654G>A p.Val552Ile; c.4771G>A p.Gly1591Arg; c.1622T>C p.Leu541Pro; c.3113C>T p.Ala1038Val

CAID: CA239745

SupplementalData: Supplementary table 1

Supplementary table 4 contains this variant, but this table is for single variants found in a recessive gene. Thus, PM3 would not be able to be used and neither would PP4

Case#: Patient #42, female, 31yo at onset, German

DiseaseAssertion: macular dystrophy or cone-rod dystrophy

FamilyInfo: phase not confirmed, but assumed in case of parental consanguinity or if only siblings were affected

CasePresentingHPOs: HP:0012508

CaseHPOFreeText:

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

PreviouslyPublished: n/a

Variant: c.3468C>G (p.Tyr1156Ter); c.5059A>T (p.Ile1687Phe) Sanger sequencing of ABCA4

ClinVar: n/a

CAID: CA341290648

SupplementalData: Supplementary table 1

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

Paper is said to contain this variant based on LOVD entry, but this paper is not publicly available. Requested from library. Annotation on stable PDF. No individual phenotype provided

This variant was listed in a supplemental table under "autosomal recessive variants" but there are no patient IDs to be able to know if the person who had this variant had another variant. There was also no phenotype information provided

Case#: Sporadic Patient #4, female, Chinese, 30yo at report

DiseaseAssertion: STGD

FamilyInfo: n/a, sporadic case

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: WES with Sanger sequencing confirmation

PreviouslyPublished: no

Variant: c.4555delA p.(T1519Rfs*5); c.6397T>C p.(C2133R)

ClinVar: 2021273; 2733921

CAID: CA341277387; CA645372203

SupplementalData:

Case#: Patient female, 10y, ethnicity not reported

DiseaseAssertion: Stargardt disease (STGD1), early onset

FamilyInfo: autosomal recessive inheritance; co-segregation of variants in parents (each heterozygous). Pedigree shown in Figure 1A. One unaffected sibling reported.

CasePresentingHPOs: HP:0007663, HP:0007754, HP:0002587, HP:0030636, HP:0000548

CaseHPOFreeText: early-onset visual decline (age 7), symmetric disease in both eyes, hyperautofluorescent ring surrounding macular atrophy, lipofuscin accumulation, photoreceptor degeneration.

CaseNotHPOs: HP:0007707

CaseNotHPOFreeText: normal anterior segment on slit lamp exam; no external ocular abnormalities reported.

Genotyping Method: Sanger sequencing confirmation; variant identification likely via next-generation sequencing (not explicitly stated).

PreviouslyPublished: n/a

Variant: ABCA4 NM_000350.2: c.6817-713A>G; c.3259G>A (p.Glu1087Lys)

ClinVar: n/a

CAID: CA2837995439, CA227097

SupplementalData: phenotype and validation data in Figures 1–5 and Supplemental Figures S1–S5

Case#: Family F23 Patient P26, 42yo

DiseaseAssertion: MD-C

FamilyInfo: family f23

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: capture-based next-generation sequencing (NGS) testing

PreviouslyPublished: n/a

Variant: c.4555del(;)6119G>A genotype b (a patient harboring a severe/null variant and a missense or in-frame insertion/deletion variant)

CAID: CA232815

SupplementalData: table s2

This variant was found in 92 of the 670 alleles in this cohort (Supplement 4). Supplement 5 has the individuals listed with their genotypes, but only mentions variants that were classified as VUS/LP/P, so it is unknown which individuals specifically had this variant or which other variants they also had.

Case#: Patient 19, female, age 16

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.5714+5G>A Allele 2: NM_000350.3:c.4469G>A

ClinVar: Allele 1: NM_000350.3(ABCA4):c.5714+5G>A Allele 2: NM_000350.3(ABCA4):c.4469G>A (p.Cys1490Tyr)

CAID: Allele 1: CA227338 Allele 2: CA227198

SupplementalData: composite mask analysis shown in figure 3 for patient 19, show large areas of matched degeneration and isolated IS/OS loss

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#: 14-year-old, female, asian (Chinese) patient

DiseaseAssertion: ABCA-4 associated retinal dystrophy

FamilyInfo: The effect of the deep intronic variant on splicing was validated by a minigene assay in our previous study (Tian et al., 2022). Co-segregation analysis result exhibited that the variant c.1222C>T p.(Arg408Ter) came from the female parent, and the deep intronic variant c.2919-884G>T p.[Phe973LeufsTer3,=] from the male parent

ParentalTesting: Co-segregation analysis result exhibited that the variant c.1222C>T p.(Arg408Ter) came from the female parent, and the deep intronic variant c.2919-884G>T p.[Phe973LeufsTer3,=] from the male parent

CasePresentingHPOs: HP:0000556

CasePhenotypeFreeText: ABCA4-associated retinal dystrophy

CaseNotHPOs: NR

CaseNotPhenotypeFreeText: NR

CasePreviousTesting:NR

GenotypingMethod:

In the present study, we recruited a 14-year-old female patient diagnosed with ABCA4-RD. Biallelic variants were found in this patient, including the nonsense variant c.1222C>T p.(Arg408Ter) detected by Sanger sequencing and the deep intronic variant c.2919-884G>T p.[Phe973LeufsTer3,=] identified by next-generation sequencing.

We isolated peripheral blood mononuclear cells (PBMCs) from the patient’s peripheral venous blood and introduced three episomal plasmids containing transcription factors OCT4, SOX2, NANOG, LIN28, c-MYC, KLF4, and SV40LT into PBMCs. The reprogramming iPSC line, named BIOi003-A, showed stabilized morphology (Fig. 1A) and a normal karyotype in culture (Fig. 1B). Then, the endogenous expression of two pluripotent biomarkers, POU5F1 and NANOG, was detected (Table 2). The expression levels were compared with human embryonic stem cell line H1(hESC-H1) and mesenchymal stem cell line P3 (MSC-P3) by qRT-PCR (Fig. 1C). Surface markers SSEA4 and TRA-1–81 were analyzed by flow cytometry (Fig. 1D). the ABCA4 compound heterozygous variants c.(1222C>T;2919-884G>T) p.[Arg408Ter;Phe973LeufsTer3,=] were verified by Sanger sequencing (Fig. 1E). Furthermore, the teratoma assay exhibited the differentiation capacity of this iPSC line in vivo (Fig. 1F). Short tandem repeats (STR) analysis exhibited that the PBMCs and the iPSC line came from the same patient. PCR proved negative for mycoplasma contamination

Variant: NM_000350.3(ABCA4):c.1222C>T (p.Arg408Ter) and NM_000350.3(ABCA4):c.2919G>T (p.Leu973Phe)

LegacyVariant: c.1222C>T (p.Arg408Ter) and c.2919G>T (p.Leu973Phe)

ClinVar: 99035 and NR

CAID: CA179692 and CA341275270

gnomeAD: 1:94544895 G / A and NR

MultipleGeneVariants: No

PreviouslyPublished:No

AdditionalInfo: One patient was homozygous at the ABCA-4 gene, so there is information about both variants in one annotation because there is only one patient.

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#: 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

This variant was found in 2 control alleles. No additional details

Case#:2, 29-year-old woman

DiseaseAssertion:NR

FamilyInfo:NR

CasePresentingHPOs:

CaseHPOFreeText:decreased ability to focus, increasing difficulty to adapt in the dark, normal visual acuity in both eyes (logMar BCVA OD/OS: 0.02), PERG responses were diminished in both eyes.

CaseNotHPOs:

CaseNotHPOFreeText:

Genotyping Method: ”Analysis of the ABCA4 gene”

PreviouslyPublished:No

Variant:NM_000350.3:c.1805G>A, NM_000350.3:c.6079C>T

ClinVar: 99085, 7882

CAID:CA226933, CA119129

SupplementalData:

This variant is found on pg 2 in proband 11019. Compound heterozygous for c.4532C>A, (p.Pro1511His). JHU institute (US). 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

This variant is found on pg 21 in proband 13047. Compound heterozygous for c.5882G>A p.Gly1961Glu. 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

PMID: 16917483

Gene: ABCA4

Disease: Stargardt

This paper was referenced by PMID: 23755871 as containing variant c.6410G>A (p.Cys2137Tyr), but this variant foes not appear to be in the text or tables

Case#: Patient 13, 35yo

DiseaseAssertion: STGD

FamilyInfo: Family 8

CasePresentingHPOs:

CaseHPOFreeText: Visual acuity=0.017. OCT ft (μm)=163. MP (dB)=0. Fundus=3(extensive atrophic-appearing RPE changes). ERG=3(abnormal responses involving both rods and cones). mfERG=4(subnormal mfERG in the entire test field (0°–30°) plus pathologic Ganzfeld ERG).

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: PCR of coding regions, intron/exon boundaries, and 5′ and 3′ regions of ABCA4; Standard cycle-sequencing reactions with BigDye Terminator

PreviouslyPublished:

Variant: L541P; R1098C

CAID: CA226911;

SupplementalData: n/a

When expressed in transfected HEK293T cells and quantified by Western blotting, this variant was in the range of 40%-52%. This variant has a basal ATPase activity of 63% ± 5% compared to WT (100%) and was categorized as class 2 (partial reduction in expression and basal ATPase activity that was modestly stimulated by N-Ret-PE) with a moderate/severe predicted severity.

Case#: Case 3, 39yo

DiseaseAssertion: BEM, RCD

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: a ring of increased AF surrounding decreased foveal AF, visual acuity= 6/6, 6/6

CaseNotHPOs:

CaseNotHPOFreeText: acquired toxic aetiology

GenotypingMethod: The entire coding sequence (50 exons), including exon–intron boundaries, of the ABCA4 gene of each patient was screened using single‐stranded conformational polymorphism (SSCP) analysis and direct sequencing.

PreviouslyPublished: n/a

Variant: Val552Ile heterozygous

CAID: CA239745

SupplementalData: n/a

Case#: Family 1 proband, male, 6yo at onset, Chinese

DiseaseAssertion: CORD

FamilyInfo: heterozygous unaffected parents

CasePresentingHPOs: HP:0000613, HP:0000505, HP:0007401, HP:0012511, HP:0008043, HP:0000512

CaseHPOFreeText:  ERG responses from cones reduced, BVA=0.20/0.15

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.[1957C>T];[4604dup] phase confirmed

ClinVar: n/a

CAID: CA645372205

SupplementalData:

ATPase activity in HEK293 cells showed severely reduced basal ATPase activity, ∼30% of WT ABCA4, indicating that this variant impacts protein function (PS3_Supporting; PMIDs).

Autofluorescence and A2E production was measured in transgenic mice and showed loss of function of ABCA4 protein indicating that this variant impacts protein function (PS3; PMIDs).

Case#: Patient 24, male, Caucasian, onset at 50yo, Germany

DiseaseAssertion: STGD

FamilyInfo: co-segregation of variant in 2 family members (siblings) but they do not appear to be affected based on pedigree

CasePresentingHPOs: HP:0030528, HP:0000505, HP:0012508, HP:0001105, HP:0025148

CaseHPOFreeText: progressive paracentral scotoma OU, progressive visual impairment OU (blurry vision). BCVA: OD-0.1, OS-0.22. Tension: 13mmHg/14mmHg. FAF: bilateral hyperautofluorescent macular and peripapillary spots, few spots of paracentral retinal atrophy (foveal sparing). Autofluorescence and deposits (severity): deposits medium, atrophy low. OCT: hyperreflective spots, partially invading into the outer retina, partly confluent lesions of cRORA, foveal sparing, degenerative intraretinal fluid. Central macular thickness: 328µm/322µm. Macular volume: 9.31mm³/9.00mm³. mfERG: bilateral amplitudes in normal range, slight relative reduction in the paracentral areas. Fluorescein angiography: bilateral dark choroid, mild paracentral dye pooling in the late phase. Color vision: Inconspicuous. Clinical examination: pattern-like distribution of the lesions.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

GenotypingMethod: WES, in-house RD-associated gene panel including 619 candidates and disease-associated genes

PreviouslyPublished: n/a

Variant: ABCA4 NM_000350.2 c.[6601_6602delAG] (p.Arg2201fs);[=], c.[4253+43G>A] p.Ile1377Hisfs3;[=]

CAID: CA227421; CA227172

SupplementalData: phenotype and segregation info in supplemental data (table s1, figure s1)

ATPase function of G863A mutant protein was reduced ∼3-fold as compared with NBD1wt, indicating ∼70% of inhibition of the ATPase activity (Fig. 3). TheVmax (ATPase) for G863A mutant was 128 pmol/min/mg and that of the wild-type NBD1 was 584 pmol/min/mg (Table II).

This variant is reported in Table S6, but only location, predictions, frequencies, etc are reported for it, not cases.

This variant is reported in Table S6, but only location, predictions, frequencies, etc are reported for it, not cases.

Unable to find this variant in the text or supplementary even though Mastermind says it's in supplemental MOESM1

Case#: Family 12 Proband, male, 43yo at onset, Portuguese

DiseaseAssertion: Stargardt

FamilyInfo: no affected family members in pedigree (Fig. 1)

CasePresentingHPOs: HP:0007663

CaseHPOFreeText: "The criteria for STGD phenotype included bilateral central vision loss and pigmentary macular lesions, normal caliber of retinal vessels, absence of pigmented bone spicules, and compatibility with recessive mode of inheritance." Moderate central retinal changes, decreased mfERG responses exclusively in the central 15 degrees

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: p.Glu1574X; p.Val931Met. Several other polymorphisms also reported. ABCR400 gene chip microarray, DHPLC

ClinVar: 1460063

CAID: CA341283936

SupplementalData: n/a

Annotating here since the full text is a PDF.

Case#: Family AR321 proband, US, 6yo at onset

DiseaseAssertion: Stargardt

FamilyInfo: proband and two other siblings are affected

CasePresentingHPOs: 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).

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText: (1) evidence of autosomal dominant inheritance; (2) any history of night blindness, loss of peripheral vision, or "retinitis pigmentosa"; (3) cataracta complicata or cells in the vitreous; (4) substantially abnormal electroretinographic or electrooculographic responses; (5) no fluorescein angiography performed or no dark choroid documented; (6) neurological disease (including loss of cognition or seizures); 7) drug exposures (especially to antimalarial and agents known to cause crystalline retinopathies); or (8) any "atypical" maculopathies in which a unique diagnosis of STGD could not be established.

PreviouslyPublished: PMID: 8533764

Variant: c.3113C>T p.A1038V; c.1715G>C p.R572P . Heteroduplex and SSCP analyses were used to screen the 50 exons of ABCA4. Linkage analysis and haplotype analysis were previously performed

ClinVar: 99073

CAID: CA226919

SupplementalData: n/a

Case#: Bryant Subject JB260, US

DiseaseAssertion: Stargardt

FamilyInfo:

CasePresentingHPOs: "Stargardt disease is a childhood-onset macular degeneration and is most commonly caused by mutations in ABCA4. Characteristic yellow flecks are typically seen under the macula during a fundus exam."

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: WES; previously screened using arrayed primer extension (APEX) multigene panels for the relevant disease and no disease-causing variants had been identified; PCR and Sanger for verification

PreviouslyPublished: n/a

Variant: c.6119G>A p.Arg2040Gln; c.2879del p.Ala960Aspfs*17

CAID: CA232815

SupplementalData:

Case#: Patients were identified from the inherited retinal disease (IRD) database at UC San Diego (UCSD).

DiseaseAssertion: RP with macular edema

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: Dx of RP based on "a history of progressive peripheral vision loss or nyctalopia, and ocular examination findings of RP including bone spicule pigmentation, disc pallor and attenuated vessels and genetic confirmation."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Next-generation sequencing (NGS), exome sequencing, and/or targeted Sanger sequencing were the primary genetic testing approaches.

PreviouslyPublished: PMID:10206579 is referenced but it seems a reference to the variant and not the proband

Variant: c.6383A>G (p.His2128Arg); c.3G>T (p.Met1?). phase unknown

ClinVar: 99455

CAID: CA227399

SupplementalData: Variant is found in table S2