Case#: Patient #13

DiseaseAssertion: STGD1

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: RPE atrophy (clearly demarcated definitely decreased fundus autofluorescence (FAF) under short-wavelength excitation light (488 nm) in combination with hypertransmission in optical coherence tomography (OCT)) areas ≥0.05 mm2 secondary to STGD1 or AMD. diagnosis of STGD1 was based on (1) a compatible phenotype (yellow-white flecks that correlated with hyperautofluorescent flecks on FAF imaging) and (2) the presence of at least one mutated ABCA4 allele as well as the absence of mutations in peripherin-2 (PRPH2). Minimum age of onset (first reported subjective symptoms) of 45 years.

CaseNotHPOs:

CaseNotHPOFreeText: Insufficient pupil dilation, additional retinal pathology, previous retinal treatment, or other ocular comorbidities substantially affecting visual function or image quality (e.g., significant media opacity, amblyopia or optic nerve disease) led to exclusion from the study. “diffuse-trickling geographic atrophy”

GenotypingMethod: Analysis of all coding exons of the ABCA4 and PRPH2 genes was done by either direct chain-terminating dideoxynucleotide Sanger sequencing, a custom-designed GeneChip CustomSeq Resequencing Array, or NGS

PreviouslyPublished: possible since the study was at the same university with the same first author as PMID: 33214501

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

ClinVar: n/a

CAID: CA341290648

SupplementalData: supplement 1 has the genotype for probands

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#: 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#: 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 #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 #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