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

PMID: 29706639

Gene: ABCA4

HGNCID: HGNC:34

MonDO: MONDO:0019353

Bioinformatic analyses of an SQL-based database containing 12272 variants that appear in 178 IRD genes in 5706 individuals of Ashkenazi Jewish origin based on the gnomAD database (version 2) and variants that were published in the scientific literature that was extracted from HGMD. Authors extracted information regarding IRD variants from various sources (including data of 5706 Ashkenazi Jewish (AJ) samples and a large cohort of Israeli patients with IRDs) to estimate carrier frequency of IRD mutations in different subpopulations in Israel. Two major databases aiming to estimate carrier frequency of IRD mutations in the Israeli population (Fig. 1): “gnomAD-AJ-IRD DB” containing data of 5706 AJ controls extracted from gnomAD and “HW-IRD DB” containing data extracted from our cohort of Israeli patients with IRDs.

See Fig 2 for breakdown of variants analyzed.

The final DB (IRDB) (Fig. 1 and Table S7) includes all 399 variants from “gnomAD-AJ-IRD DB” and “HW-IRD DB” that were considered here as pathogenic mutations in 111 known IRD genes.

To establish the “HW-IRD DB” (Fig. 1), we collected data on Israeli IRD patients with a known cause of disease (a cohort of >2000 IRD families). The HW-IRD DB includes 289 pathogenic mutations (Fig. 1) that were identified in IRD patients who have biallelic variants.

SupplementalData: S7, carrier frequency data for each mutation in all nine studied subpopulations. Carrier frequency was calculated as 2pq where p = 1 − q and q was calculated as the root square of the number of homozygous patients plus half the number of compound heterozygous patients divided by the population size

Variant: NM_000350.2:c.4895dup,p.Asn1632fs

CAID: CA915941330

Case: Ashkenazi Jewish patient with inherited retinal disease, STGD, CRD

CasePresentingHPOs: HP:0000548 (Cone/cone-rod dystrophy, CRD)

CaseHPOFreeText: Stargardt disease (STGD)

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#: Patient #15, Moorfields Eye Hospital, London, UK, female, 39yo at onset, 51yo at report,

DiseaseAssertion: ABCA4-Associated Retinopathy, clinical diagnosis of STG

FamilyInfo: no additional family-member WGS data available

CasePresentingHPOs:

CaseHPOFreeText: BCVA= OD: 6/9, OS: 6/9, Fishmann Classification=2 (fleck-like lesions anterior to the vascular arcades and/or nasal to the optic disc), early changes to foveal photoreceptors, Extent of FAF abnormalities with Regard to Vascular Arcades: beyond. ffERG Group: 1(normal). PERG: Abnormal. FAF in Fig. 1B. characteristic yellow-white pisciform flecks in the RPE of the posterior pole that were hyperautofluorescent on FAF imaging or progressive atrophy of the macular RPE

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Haplotype analysis, ABCA4 mutation screening was performed by next-generation sequencing, sequenced as part of the retinal panel at the Molecular Vision Lab

PreviouslyPublished:

Variant: c.5196+1137G>A p.[=,M1733Efs∗78] c.[1715G>A;2588G>C] p.[(R572Q;G863A,G863del]

ClinVar: 7900

CAID: CA226918

SupplementalData:

Case#: Case 3, male, onset at 24yo, Italy

DiseaseAssertion: STGD1

FamilyInfo: third-degree consanguineous parents; both parents healthy heterozygous carriers of the ABCA4 variant

CasePresentingHPOs: HP:0000529, HP:0007754, HP:0000518

CaseHPOFreeText: progressive deterioration of vision at age 24. Bilateral macular dystrophy and diffuse lens opacities on ophthalmologic examination. OCT, ERG, and VEP consistent with Stargardt maculopathy.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: NGS (custom enrichment panel), Illumina NextSeq550; variant confirmed by Sanger sequencing.

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.2828G>A (p.Arg943Gln), homozygous; rs1801581

ClinVar: Variation ID: 7913

CAID: n/a

SupplementalData: n/a

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

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#: 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 #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#: 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)

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#: Liu Proband A034, Chinese, female

DiseaseAssertion: Stargardt

FamilyInfo: Mother has the Pro68Leu variant, but the father was not genotyped to know the phase of the second variant. Proband's daughter also has the Pro68Leu variant, but is unaffected.

CasePresentingHPOs:

CaseHPOFreeText: no individual details provided

CaseNotHPOs:

CaseNotHPOFreeText: patients with other ocular diseases, such as choroidal neovascularization, glaucoma, and diabetic retinopathy, or were undergoing treatments/therapeutic trials were excluded.

GenotypingMethod: Either eye gene-enriched (from 36 to 450 target genes) panel-based next-generation sequencing (NGS). Sanger bi-directional sequencing was conducted to confirm the rare candidate variants (allele frequency: less than 1.0% of the general population) and to perform the co-segregation analysis

PreviouslyPublished: n/a

Variant: c.203C>T p.(Pro68Leu); c.3883_3884del p.(Glu1295Lysfs*126)

ClinVar: 99113

CAID: CA226972

SupplementalData: S1 only provides group demographics for the different clinical classifications (fundus grade, FAF type, etc)

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

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 on pg 16 in proband 14075. Compound heterozygous for c.6817-2A>C. MEH institute (UK). Said to have Stargardt based on the following criteria: "(1) patients (at least 6 years old) with at least two ABCA4 variants or one ABCA4 variant associated with a typical STGD1 phenotype and (2) presence of a well-defined atrophic lesion with/without flecks at the most recent visit of at least 300 µm in diameter (the total area of all lesions <12 mm2)." No additional details provided

This variant is found on pg 11 in proband 18034. Compound heterozygous for c.2588G>C p.Gly863Ala. Said to have Stargardt based on the following criteria: "(1) patients (at least 6 years old) with at least two ABCA4 variants or one ABCA4 variant associated with a typical STGD1 phenotype and (2) presence of a well-defined atrophic lesion with/without flecks at the most recent visit of at least 300 µm in diameter (the total area of all lesions <12 mm2)." No additional details provided

Case#: Pt 7, male, 60yo at report, onset between 6-49yo, Irish

DiseaseAssertion: Stargardt

FamilyInfo: family 5

CasePresentingHPOs:

CaseHPOFreeText: VA: OD=6/36 OS=6/120, FAF and OCT in figure 2, FAF WRT vascular arcades=beyond, beaten bronze appearance, yellow flecks centrally, peripapillary sparing, central retinal thickness: OD=100 microns OS=117 microns, optical coherence tomography (OCT) atrophy horizontal width: OD=6000 microns OS=5446 microns

CaseNotHPOs:

CaseNotHPOFreeText: bulls eye pattern, flecks peripherally

GenotypingMethod: Target capture NGS of the exons and known pathogenic intronic regions of ABCA4, whole-gene single molecule molecular inversion probe (smMIP) based sequencing of ABCA4 as well as 40 kb of flanking sequence, direct Sanger sequencing, or WGS

PreviouslyPublished: n/a

Variant: c.4539 + 2028C > T p.[= ,Arg1514Leufs*36]; c.2453G> A p.(Gly818Glu)

ClinVar: 99135; 236116

CAID: CA227000; CA10576057

SupplementalData: n/a

Case#: Klevering Patient 9369, female, Netherlands, 40yo at report, 8yo at onset

DiseaseAssertion: cone-rod degenerations/ ABCA4-associated retinal dystrophy resembling CRD

FamilyInfo: "In view of the reputedly normal visual acuity of the parents and the molecular defects, the inheritance pattern of the gene defects in these patients (individuals 9303, 9369, 9553, and 13163) was classified as autosomal recessive."

CasePresentingHPOs:

CaseHPOFreeText: Visual acuity: light perception OU. Fundoscopy: Irregular hypopigmentation, mainly in the posterior pole. In later stages: attenuated vessels and bone spicula temporal to the macula. Red-green defect of color vision. Perimetry: Central scotoma varying from 10–30°. ERG Cone (μV): OD-80 (80%), OS-140 (90%) from 12 yo (all ERG responses had been non-detectable since the age of 21). ERG Rod (μV): 160 (nl). Fundus photographs and fluorescein angiograms show CRD in the later stages with attenuation of the retinal arterioles and irregular pigmentation temporal to the macula. Narrowing of retinal vessels and bone spicula (Fig 1B). Fundus description (PMID: 10958761): atrophy of the RPE around the optic disk, bone spicules along arteries and venules in the mid-periphery, and attenuated arterioles (Fig 1D)

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: single-strand conformation polymorphism (SSCP) and direct-sequencing techniques to look for mutations in the 50 exons and flanking intron sequences of the ABCA4 gene

PreviouslyPublished: Maugeri et al (PMID: 10958761)

Variant: c.6601_6602delAG

CAID: CA227421

SupplementalData: n/a

Case#: Subject 20, 28yo, 18yo at first ffERG, Sweden, female

DiseaseAssertion: CRD, group 2

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: extensive atrophies in the posterior pole. peripheral pigmentations. few peripapillary changes. Normal thickness of the most central segment recorded on OCT. total absence of the PIL (photoreceptor integrity line) and RPE atrophy on the OCT B-scans. ETDRS VA score= 35, 35. Rod
ffERG= 38, 34 Ampl
(µV). Combined ffERG= 52, 57 Ampl
(µV). Cone
ffERG= 4, 5; 45.0, 42.5 Amp IT
(µV; ms). mERG sum= 1.0, 0.7 Ampl (µV). Group 2 with larger central scotomas from 10° to 35°

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Sequence analysis of the entire coding region of the ABCA4 gene was performed.

PreviouslyPublished: n/a

Variant: c.1654G>A; c.4363T>C

CAID: CA239745

SupplementalData: n/a

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

Unable to annotate on PDF, so annotating here.

Case#: Proband #4, male, Chinese, onset at 12yo

DiseaseAssertion: stargardt

FamilyInfo: parents are deceased, so phase is unknown. daughter is an unaffected carrier of this variant

CasePresentingHPOs: HP:0025147, HP:0011507, HP:0000608

CaseHPOFreeText: BCVA=0.3/CF, mean retinal nerve fiber layer(µm)=167/154, Visual field(mean deviation)= 7.52/NA, fundus fluorescein angiography=type C (a pattern of speckled hypofluorescence and hyperfluorescence without central hypofluorescence)

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

Variant: c.6289C > T p.(Pro2097Ser); c.4720G > T p.(Glu1574*) on targeted exome sequencing or WES

ClinVar: 2202780; 1460063

CAID: CA341277622; CA341283936

SupplementalData: n/a

Case#: Cideciyan Case #86, male, 20.5yo at report

DiseaseAssertion: "clinical diagnosis within the spectrum of Stargardt disease or cone–rod dystrophy caused by ABCA4 mutations."

FamilyInfo: Parental segregation of the reported alleles confirmed. P87 is the proband's sibling, affected, same genotype

CasePresentingHPOs:

CaseHPOFreeText: LDF eccentricity along principal meridians [deg]: superior=16.9, inferior=11.7, temporal=18.9, inner nasal=9.6, outer nasal=18.9

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: NGS

PreviouslyPublished: PMID: 24550365

Variant: c.203 C>T p.Pro68Leuc.5882 G>A p.(Gly1961Glu); c.5882 G>A p.(Gly1961Glu). Phase confirmed.

ClinVar: 99113

CAID: CA226972

SupplementalData: table s1

Case#: Family MD-0247/ARDM-247 Proband, 12yo at onset

DiseaseAssertion: AR cone rod dystrophy

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: STGD diagnosed based on "bilateral central vision loss; fundus presenting with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; fluorescein angiography showing typical dark choroid; and normal to subnormal electroretinogram (ERGs)." VA loss, VF loss, BCVA=0.05/0.1, cone-pattern on ERG

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: n/a

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

ClinVar: 2202779

CAID: CA341277358

SupplementalData: n/a

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

In supplemental table S2, Case LL291 is a female listed as "likely solved" with a clinical diagnosis of CRD. Proband is compound heterozygous for c.32T>C p.(Leu11Pro) and c.5196+1137G>A.

In Supplemental table S1, this proband is a female, 54yo at report, 50yo at onset. Nyctalopia, visual acuity=0.05/0.6, OD: extremely high myopia OS: high myopia, no family information

Case#: P3, male, 16yo at report, 9yo at dx, US with Indian ethnicity

DiseaseAssertion: Stargardt

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: BCVA (logMAR)= OD=20/160 (0.90), OS=20/125 (0.80)

CaseNotHPOs:

CaseNotHPOFreeText: ocular comorbidities such as diabetic retinopathy, uveitis, or glaucoma

GenotypingMethod: "genetic testing"

PreviouslyPublished: n/a

Variant: c.2453G>A; c.4532C>A (p.Pro1511His)

ClinVar: 99135

CAID: CA227000

SupplementalData: table 1

Case#: MD-0790, Spanish

DiseaseAssertion: STGD1

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: "STGD1 was determined according to initial symptoms of VA loss; fundus images showing orange-yellow flecks in the retina, a beaten-bronze appearance; and normal or cone-altered ffERG results"

CaseNotHPOs:

CaseNotHPOFreeText:

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

PreviouslyPublished: n/a

Variant: c.1715G>C p.(Arg572Pro); c.4918C>T p.(Arg1640Trp)

ClinVar: 99073

CAID: CA226919

SupplementalData: Table S1

Supplemental Table 1. Patient WHP103 has this variant in compound heterozygosity with c.4720G>T(p.E1574*). Cannot confirm this is not the same proband as in PMID 31674661 since both have the same genotype and are of Chinese ancestry

Case#: QT959, Chinese

DiseaseAssertion: Cone-rod dystrophy

FamilyInfo: no pedigree provided for this family in this paper

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

PreviouslyPublished: 23776498-more phenotype information available there

Variant: c.[1957C > T];[4605insT] on WES

ClinVar: n/a

CAID: CA645372205

SupplementalData: n/a

PCMID:*PMC12657203

PMID41323838

Gene: ABCA4

HGNC ID: 34

Case#:80 year old man,

DiseaseAssertion:NA

FamilyInfo:NA

CasePresentingHPOs:NA

CaseHPOFreeText:Diagnosed w/ targardt disease at the age of 18 years, medical retierment at 64 as result

CaseNotHPOs:*parkinsons at 80

CaseNotHPOFreeText:NA

Genotyping Method:NA

PreviouslyPublished:NA

Variant:after gentic testing (unspecified) a pathogenic heterozygous mutation (G1961E) in ABCA4 gene a substiution, GAA) at amino acid position 1961, or c.5882 G>A at the complementary DNA level, or pGly1961Glu or G1961E at the protein level. No second mutation was identified. One of his 2 sisters had the same mutation.

ClinVar:NA

CAID:NA

SupplementalData:this goes into how eye retina transplant results and outcomes.

PMID: 28600779

Gene: ABCA4

HGNCID: HGNC:34

MonDO:

Case: 16N-0520, Male, Saudi Arabia, 1 yo

DiseaseAssertion:

FamilyInfo: Consanguineous parents, positive family history

CasePresentingHPOs: HP:0000618, HP:0000648 (Blindness, Optic atrophy)

CaseHPOFreeText: Coloboma of eye

GenotypingMethod: WES, analysis of Vision Panel, constituent genes are described in PMID 26112015.

SupplementalData: Supplemental table

Variant: ABCA4:NM_000350:exon49:c.6764G>T:p.S2255I

CAID: CA202970

gnomAD: 0.4845 (gnomAD v4.0.0, Grpmax Filtered AF African/African-American) https://gnomad.broadinstitute.org/variant/1-93996161-C-A?dataset=gnomad_r4

VariantEvidence: Authors classified as VOUS. But later downgraded to LB in PMID 31130284.

Case#: Case #3483, likely European, 10yo at onset

DiseaseAssertion: ABCA4 disease

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText: foveal sparing

GenotypingMethod: NGS, Sanger

PreviouslyPublished: n/a

Variant: c.2453G>A (p.Gly818Glu); c.4462T>C (p.Cys1488Arg)

ClinVar: 99135

CAID: CA227000

SupplementalData: supplemental table 1

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#: Patients #33 and 34, female, 63 and 61yo at report, respectively, German

DiseaseAssertion: ABCA4-related retinopathy

FamilyInfo: n/a but they could be related

CasePresentingHPOs:

CaseHPOFreeText: "Inclusion criteria comprised the presence of at least one disease-causing mutation in ABCA4 and a phenotype consistent with ABCA4-related retinopathy, including RPE atrophy and flecks." BCVA [LogMAR] for patient #33: OD= 0.4, OS= 0.1. BCVA [LogMAR] for patient #34: OD= 1.5, OS= 1.0. Reduced (over 2 SD) photopic B-wave and 30-Hz flicker amplitudes

CaseNotHPOs:

CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous vitreoretinal surgery, or other ocular comorbidities substantially affecting visual function (e.g., significant media opacity, amblyopia, or optic nerve disease) led to exclusion. Abnormal responses on scotopic and photopic full-field ERG

GenotypingMethod:

PreviouslyPublished: likely the same patients as other Muller papers in this curation

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

ClinVar: n/a

CAID: CA341290648

SupplementalData: Table S1 has genotype/phenotype info for probands

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#: 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

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

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#: 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

This variant is listed for Stargardt DNAID#070949 in trans with c.3682G>A p.(Glu1228Lys). No phenotype information 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 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#: 25-year old female, juvenile onset

DiseaseAssertion: STGD1

FamilyInfo: Figure 1 shows family pedigree. Table 1 shows clinical features of a Chinese pedigree. Cosegregation analysis was done and shown in Figure 1A, C.

CasePresentingHPOs: HP:0007663, HP:0007722, HP:0007401, HP:0030329, HP:0030610, HP:0003621, HP:0011507, HP:0007984

CaseHPOFreeText: The uncorrected visual acuity of each eye was 20/400, which has progressively decreased for 13 years.

CaseNotHPOs: n/a

CaseNotHPOFreeText: The retinal vessels were normal.

Genotyping Method: Whole Exome Sequencing, Sanger Sequencing

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.3523-2A>G, NM_000350.3(ABCA4):c.5646G>A (p.Met1882Ile)

ClinVar: 866764, 377407

SupplementalData: n/a

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

PMID: 31618812

Gene: ABCA4

HGNCID: HGNC:34

Patients: a group of 31 Stargardt disease/fundus flavimaculatus patients (14 males, 17 females) with an established ABCA4 genotype, accumulated prospectively over an interval of 12 months at the outpatient service of the Institution, were included in this study.

MonDO: MONDO:0019353

CaseInfo: Case 11, Male, 12yo. Compound het c.5882G > A; p.Gly1961glu (Pathogenic in ClinVar); c.6764G > T,p.Ser2255Ile

DiseaseAssertion: Stargardt disease/fundus flavimaculatus

FamilyInfo: Not provided

CasePresentingHPOs: HP:0007769, HP:0000608, HP:0012045 (Peripheral retinal degeneration, Macular degeneration, Retinal flecks)

CaseHPOFreeText: cone-rod pattern of retinal dysfunction

GenotypingMethod: Mutation screening was performed by single-strand conformation polymorphism (SSCP) strategy of the whole coding region of ABCA4. Direct sequencing was also performed on siblings of probands and parents, when available, to confirm segregation of alleles.

MultipleGeneVariants: (1) GeneName: ABCA4

(1)Variant: c.5882G > A; p.Gly1961glu

(1) CAID: CA119132

(1) gnomAD: 0.01250 (gnomadv4.0.0, Grpmax Filtering AF, South Asian) https://gnomad.broadinstitute.org/variant/1-94008251-C-T?dataset=gnomad_r4

(2) GeneName: ABCA4

(2) Variant: c.6764G>T (p.Ser2255Ile)

(2) CAID: CA202970

(2) gnomAD: 0.4845 (gnomadv4.0.0, Grpmax Filtering AF, African/African-American) https://gnomad.broadinstitute.org/variant/1-93996161-C-A?dataset=gnomad_r4

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

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:

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.

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#: 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#: 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

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#: 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#: 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

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 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#: 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#: 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

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

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#: 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