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Case#: Duno Patient D015, Danish

DiseaseAssertion: Stargardt flavimaculatus phenotype

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: The diagnosis was based on standard ophthalmological examinations including fundus photography, colour vision assessment, dark adaptometry, and full field ERG.

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: ABCA4 mutation microarray and High-resolution melting (HRM) in patients in whom the array analysis identified either a heterozygous mutation (n = 50) or no mutation (n = 30).

PreviouslyPublished: n/a

Variant: c.1654G>A p.V552I; c.6478A>G p.K2160E; c.3380G>A p.G1127E phase unknown

CAID: CA239745

SupplementalData:

Case#: Muller Subject #8, 34yo, qAF=590

DiseaseAssertion: ABCA4-related retinopathy

FamilyInfo: mother was 59yo at report with qAF=399

CasePresentingHPOs:

CaseHPOFreeText: "ABCA4-related retinopathy was diagnosed based on characteristic findings on indirect ophthalmoscopy, optical coherence tomography, and conventional fundus AF imaging. The clinical diagnosis was confirmed by the presence of biallelic mutations in ABCA4, and segregation analysis was carried out with samples of the parents."

CaseNotHPOs:

CaseNotHPOFreeText: age ≥ 65 years, ethnicity other than Caucasian, significant lens opacities, dilated pupil diameter below 7 mm, unstable fixation, refractive error > ±6 diopters (spherical equivalent), and any other additional known ocular pathology or prior intraocular surgery.

GenotypingMethod: ABCA4 sequence analysis of all coding exons and flanking splice junctions was performed either by Sanger chain-terminating dideoxynucleotide sequencing after PCR amplification, by multiplex ligation-dependent probe amplification (MLPA) analysis (performed when only a single mutation was detected), or by next-generation sequencing (NGS) including a quantitative readout to detect large structural rearrangements using a gene panel covering 120 genes associated with inherited retinal disease as described previously.23 Validation of identified putatively pathogenic variants and segregation analysis were carried out by conventional sequencing

PreviouslyPublished: n/a

Variant: maternal allele: [c.1622T>C (p.Leu541Pro); c.3113C>T (p.Ala1038Val)]; paternal allele: c.1654G>A (p.Val552Ile); c.4771G>A (p.Gly1591Arg)

CAID: CA239745

SupplementalData:

3 STGD patients have this variant but no specific clinical details (supplemental table s5).

Patient 79: c.1654G>A p.(V552I); c.5196+1013A>G

Patient 265: c.1654G>A p.(V552I) only

Patient 320: c.1654G>A p.(V552I); c.4254-1G>C; c.6230G>A p.(R2077Q)

Case#: Patient 817, female, 33yo at entry

DiseaseAssertion: Stargardt disease

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText: category IIA (autosomal recessive stargardt disease)

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: one or more of the following approaches: automated Sanger sequencing with an ABI 3730xl sequencer, allele-specific genotyping with a Fluidigm EP1, amplification refractory mutation system (ARMS 17), chromosomal microarray analysis, and/or plasmid cloning of PCR products followed by Sanger sequencing. WES, WGS

PreviouslyPublished: n/a

Variant: c.1654G>A (p.Val552Ile); second variant not identified

CAID: CA239745

SupplementalData: supplemental table 1

Case#: Bauwens Case ID #20864, German

DiseaseAssertion: Simplex Retinitis Pigmentosa

FamilyInfo:

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: Screening for V1-V7 (deep intronic variants) negative, sequencing of the coding exons and intron–exon boundaries of ABCA4, Sanger sequencing

PreviouslyPublished:

Variant: c.1654G>A p.(Val552Ile), no second allele

CAID: CA239745

SupplementalData: supplemental table s3

Case#: Eisenberger Patient 92, female, 31yo, German

DiseaseAssertion: Autosomal dominant RP

FamilyInfo: non-consanguineous

CasePresentingHPOs:

CaseHPOFreeText: "The diagnoses of all patients were established by medical history, family history and detailed clinical evaluation of vision. Ophthalmological examination included stereoscopic funduscopy, standard ERG, perimetry, measurement of dark adaptation, and determination of best-corrected visual acuity in most patients."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: NGS for the exons of 55 RP and LCA genes, Sanger for confirmation

PreviouslyPublished: n/a

Variant: Allele 1: RHO c.180C>A p.Tyr60; Allele 2*: ROM1: c.178C>A p.Pro60Thr; c.323C>T p.Thr108Met;

ABCA4: c.1654G>A p.Val552Ile; c.5714+5G>A; <br /> RP2: c.844C>T p.Arg282Trp; <br /> RPGRIP1: c.2510C>G p.Ala837Gly

ClinVar:

CAID: CA239745

SupplementalData: n/a

In HEK293T cells, p.Val552Ile expresses at close to WT levels, exhibits normal N-Ret-PE binding properties, and has only a modest reduction in ATPase activity. Consistent with mild disease phenotype

Case#: Garces Patient 4, Canada

DiseaseAssertion: mild STGD1

FamilyInfo:

CasePresentingHPOs:

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

CaseNotHPOs:

CaseNotHPOFreeText:

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

PreviouslyPublished: n/a

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

CAID: CA239745

SupplementalData:

Case#: Aguirre-Lamban Unlabeled Proband, Spanish

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: "Diagnosis of STGD was determined according to a bilateral central vision loss with a beaten-bronze appearance and/or the presence of orange-yellow flecks in the retina from the posterior pole to the mid-periphery; typical dark choroid observed by fluorescein angiography; and normal to subnormal electroretinograms (ERGs)."

CaseNotHPOs:

CaseNotHPOFreeText:

GenotypingMethod: ABCR400 microarray, direct sequencing, dHPLC, haplotype analysis

PreviouslyPublished: n/a

Variant: c.1654G>A p.Val552Ile, interpreted as non-pathogenic, suggested to be a polymorphism

CAID: CA239745

SupplementalData: n/a

This variant is reported to be found in 1 individual in heterozygous or compound heterozygous form, but there is no patient identifier, so impossible to know whether they have a second variant

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#: 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

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

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#: 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