Case#: Case 4, Sex: Female, Age:34

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Text mentions BCVA 20/100 in both eyes later became 20/240. Bilateral atrophic-appearing foveal lesions associated with yellowish-white fundus flecks at the posterior pole. Subnormal scotopic and photopic responses. Subretinal fibrosis in left eye. Hypofluorescence due to hyperplasia of RPE in left eye.

CaseNotHPOs:n/a

CaseNotHPOFreeText: No ocular trauma.

Genotyping Method: genetic analysis

PreviouslyPublished: n/a

Variant: Variant is a heterozygous mutation given as NM_000350.3(ABCA4):c.3113C>T (p.Ala1038Val)

ClinVar: Variation ID: 7894

CAID: CA119135

SupplementalData: n/a

Case#: Case1, Sex:Female, Age:35

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Clinical Notes: the patient reported an ocular trauma in the right eye, which required hospitalization and caused sudden loss of vision at the age of 9 years. In 1998, at our first observation, visual acuity was 20/1,000 in the right eye and 20/600 in the left eye.

CaseNotHPOs:n/a

CaseNotHPOFreeText: n/a

Genotyping Method: genetic analysis

PreviouslyPublished: n/a

Variant: Variant is a heterozygous mutation given as (N965S/G1961E); NM_000350.3(ABCA4):c.2894A>G (p.Asn965Ser) /NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)

ClinVar: Variation ID: 236096 / Variation ID: 7888

SupplementalData: n/a

Case#: Case 3, Sex: Male, Age:21

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs:

CaseHPOFreeText: Text mentions BCVA of 20/200 in both eyes. Pigmentary changes in macula associated with flecks, small inferior juxta-papillar area of subretinal fibrosis in right eye, left eye legion localized in posterior pole macula temporally. Instable fixation in right eye. Low retinal mean sensitivity in both eyes.

CaseNotHPOs:n/a

CaseNotHPOFreeText: Healthy ocular adnexa and specular transparent and 'in situ' lens. Visual acuity stable. Stable fixation in left eye.

Genotyping Method: genetic analysis

PreviouslyPublished: n/a

Variant: Variant is a heterozygous mutation given as NM_000350.3(ABCA4):c.3212C>T (p.Ser1071Leu) / NM_000350.3(ABCA4):c.667A>C (p.Lys223Gln) / NM_000350.3(ABCA4):c.3607G>A (p.Gly1203Arg)

ClinVar: Variation ID: 99208 / Variation ID: 845426/ Variation ID: 417989

SupplementalData: n/a

Case#: Case1, Sex:Male, Age:19

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Clinical Notes: Peripapillary sparing, discrete flecks; nummular atrophy. General notes: Panretinal cone dysfunction with preserved rod function was documented by ERG

CaseNotHPOs:n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Whole exome sequencing data generation. Additional sequencing targeted amplification fo PRPH2 and ELOVL4 using PCR.

PreviouslyPublished: n/a

Variant: Variant 1 given as p.N965S; NM_000350.3(ABCA4):c.2894A>G (p.Asn965Ser). Variant 2 given as p.R2038W; NM_000350.3(ABCA4):c.6112C>T (p.Arg2038Trp)

ClinVar: Variation ID: 236096; Variation ID: 99430

CAID: CA958124; CA227368

SupplementalData: Proband variant information given in Table 1.

Case#: Case 6, Sex:Female, Age:34

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Clinical Notes: Classic Stargardt. General notes: participant had classic features of STGD and field ERG showed abnormal cone responses with preserved rod function.

CaseNotHPOs:n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Exome sequencing data generation. Additional sequencing targeted amplification fo PRPH2 and ELOVL4 using PCR.

PreviouslyPublished: n/a

Variant: ABCA4, NM_000350.3(ABCA4):c.2966T>C (p.Val989Ala)

ClinVar: Variation ID: 99180

SupplementalData: Proband variant information given in Table 1.

Case#: Case2, Sex:Female, Age:15

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Clinical Notes: Few yellowish Flecks without autofluorescence. General notes: participant presented with atypical macular degeneration.

CaseNotHPOs:n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Exome sequencing data generation. Additional sequencing targeted amplification fo PRPH2 and ELOVL4 using PCR.

PreviouslyPublished: n/a

Variant: Variant 1 given as p.G1961E; NM_000350.3:c.5882G>A p.(Gly1961Glu) . Variant 2 given as p.Q636X; NM_000350.3(ABCA4):c.1906C>T (p.Gln636Ter).

ClinVar: Variation ID: 7888 ; Variation ID: 265012

CAID: ; CA10588302

SupplementalData: Proband variant information given in Table 1.

Case#: Patient 8 yo, F, Turkiye, onset at 8yo (early onset)

DiseaseAssertion:STGD1

FamilyInfo: no consanguinity between parents, neither parents are affected or show symptoms

CasePresentingHPOs: HP:0008035, HP:0011504

CaseHPOFreeText: vision of 6/10

CaseNotHPOs: HP:0000007, HP:0000608

CaseNotHPOFreeText: normal movements and mobility, unremarkable slit-lamp, no fundoscopy changes, unremarkable OCT

Genotyping Method: N/A

PreviouslyPublished: N/A

Variant: NM_000350.3a: c.3322C>T,p.(Arg1108Cys)rs61750120

CAID: CA220683

SupplementalData: N/A

Case#: Patient 10, female, Lithuanian, onset at 6yo

DiseaseAssertion: STGD

FamilyInfo:Both parents and older brother healthy; no clinical signs in grandparents or extended family; inheritance most likely autosomal recessive

CasePresentingHPOs: HP:0000505, HP:0012508, HP:0001105, HP:0025148, HP:0000662

CaseHPOFreeText: progressive central vision loss from age 6; visual acuity dropped from OD=0.3, OS=0.3 to OD=0.08, OS=0.1 over 4 years; fundus examination: yellow pisciform flecks at the maculae; OCT: thin atrophic neurosensory retina in foveal region, altered photoreceptor reflectivity, thinner RPE; ERG: loss of scotopic b-waves, attenuated scotopic a-wave, missing oscillatory potentials, loss of photopic a- and b-waves; “bull’s eye” maculopathy noted

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: RetChip v1.0 STGD-module array and confirmation by Sanger sequencing

PreviouslyPublished: n/a

Variant: ABCA4 NM_000350.2 c.1622T>C p.(L541P), NM_000350.2 c.3113C>T p.(A1038V)

CAID: CA226911, CA119135

SupplementalData: clinical images, OCT, ERG, and pedigree information included in supplemental data (Figs. 1–5)

Case Annotation Template

Case#: Patient 2, female, age 62

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: ENST00000370225.4:c.1222C>T

ClinVar: NM_000350.3(ABCA4):c.1222C>T (p.Arg408Ter)

CAID: CA179692

SupplementalData: composite mask analysis shown in figure 3 for patient 2, "Both patient 2 and 14 show foveal preservation of IS/OS and RPE," "Patients 2, 19, and 11 show large areas of matched degeneration and isolated IS/OS loss, "

Case#: Patient 10, female, age 19

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.2588G>C Allele 2: NM_000350.3:c.1222C>T

ClinVar: Allele 1: NM_000350.3(ABCA4):c.2588G>C (p.Gly863Ala) Allele 2: NM_000350.3(ABCA4):c.1222C>T (p.Arg408Ter)

CAID: Allele 1: CA119128 Allele 2: CA179692

SupplementalData: composite mask analysis shown in figure 3 for patient 10

Case#: Patient 11, male, age 53

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: NM_000350.3:c.5461-10T>C

ClinVar: NM_000350.3(ABCA4):c.5461-10T>C

CAID: CA220687

SupplementalData: composite mask analysis shown in figure 3 for patient 11, show large areas of matched degeneration and isolated IS/OS loss

Case#: Patient 14, female, age 42

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.4222T>C Allele 2: NM_000350.3:c.4918C>T

ClinVar:Allele 1: NM_000350.3(ABCA4):c.4222T>C (p.Trp1408Arg) Allele 2: NM_000350.3(ABCA4):c.4918C>T (p.Arg1640Trp)

CAID:Allele 1: CA227166 Allele 2: CA227253

SupplementalData: composite mask analysis shown in figure 3 for patient 14, show diffusely intact IS/OS and RPE with central area of mixed types of degeneration. Both patient 2 and 14 show foveal preservation of IS/OS and RPE

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

DiseaseAssertion: STGD1

FamilyInfo: n/a

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

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

CaseNotHPOs: HP:0000510, HP:0007984

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

Genotyping Method: ABCR 600 micro-array chip

PreviouslyPublished: n/a

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

ClinVar: 99403

SupplementalData: n/a

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

DiseaseAssertion: STGD1

FamilyInfo: n/a

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

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

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

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

Genotyping Method: ABCR 600 micro-array chip

PreviouslyPublished: n/a

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

ClinVar: 99259, 7888

SupplementalData: n/a

Case#: 80 yo M, siagonosed at 18 yo

DiseaseAssertion: Stargardt

FamilyInfo: one of his 2 sisters had same mutation to ABCA4

CasePresentingHPOs:,HP:0007663, HP:0008002

CaseHPOFreeText: RPE hyperplasia, atrophy of the inner and outer photoreceptor segments, the outer nuclear layer, and the outer plexiform layer, with scanty RPE cells in the macular area

CaseNotHPOs: NA

CaseNotHPOFreeText: NA

Genotyping Method: N/A

PreviouslyPublished: none

Variant: G1961E

ClinVar: 7888

SupplementalData: See supplemental Material for further look at the probands Human Embryonic Stem Cell-derived Retinal Pigment Epithelium Transplantation

Case#: Female, 69yo, Puerto Rican

DiseaseAssertion: STDG1

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

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

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

CaseNotHPOs: HP:0000510

CaseNotHPOFreeText: normal rod response on full-field electroretinogram

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

PreviouslyPublished: N/A

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

ClinVar: ClinVarID:99403

CAID: N/A

SupplementalData: N/A

Case#: Male, mid-40s

DiseaseAssertion: STGD1

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

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

CaseHPOFreeText: n/a

CaseNotHPOs: HP:0007843, HP:0011507

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

Genotyping Method: Sanger Sequencing

PreviouslyPublished: n/a

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

ClinVar: 99052, 1275798

SupplementalData: n/a

Case#: patient, 11, Somali, onset 8yo

DiseaseAssertion: STGD

FamilyInfo: parents and four siblings did not report visual issues

CasePresentingHPOs: HP:0000007, HP:0011504, HP:0000608

CaseHPOFreeText: BCVA 20/70 OD, 20/80 OS. Bull's eye maculopathy. Outer retinal and RPE atrophy. Slight opacity at level of RPE; loss of outer retinal structures in central area. Normal peripheral retina.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: whole genome

PreviouslyPublished: PMID:28559085

Variant: NM_000350.3:c.5882G>A p.(Gly1961Glu) ; NM_000350.3:c.634C>T p.(Arg212Cys)

ClinVar:7888; 7898

CAID:n/a

SupplementalData:n/a

Case#: 12, Somali, onset 5 years old

DiseaseAssertion: STGD

FamilyInfo: Parents were heterozygous for Arg212Cys, no family history of IRD

CasePresentingHPOs: HP:0011504, ORPHA:827, HP:0000608

CaseHPOFreeText: Bull's eye maculopathy, macular degredation, red-green color defecit, reduced cone function

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Whole exome sequencing

PreviouslyPublished: N/a

Variant:

ClinVar: NM_000350.3:c.5882G>A p.(Gly1961Glu) ; NM_000350.3:c.634C>T p.(Arg212Cys)

ClinVar: 7888; 7898

CAID: CA119132, CA203216

SupplementalData: N/a

Case#: patient, 12, Somali, onset 5yo

DiseaseAssertion: STGD

FamilyInfo: parents and 5 siblings did not report visual issues

CasePresentingHPOs: HP:0000007, HP:0011504, HP:0000608

CaseHPOFreeText: BCVA 20/135 OD; 20/100 OS. Red-green color deficit. Bull's eye maculopathy, but no pallor of optic disc. Normal peripheral retina. Loss of macular photoreceptor layer; severely reduced cone function.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: whole exome sequencing

PreviouslyPublished: n/a

Variant: NM_000350.3:c.5882G>A p.(Gly1961Glu) ; NM_000350.3:c.634C>T p.(Arg212Cys)

ClinVar: 7888; 7898

CAID: n/a

SupplementalData: n/a

Case#: Somali origin, 11 years of age, onset age 8

DiseaseAssertion: STGD

FamilyInfo: Parents were heterozygous for Arg212Cys, asymptoamtic 32 year old father was found to be homozygous for Gly1961Glu

CasePresentingHPOs: HP:0011504, ORPHA:827, HP:0000608

CaseHPOFreeText: BCVA 20/70 and 20/80, atrophic zone of outer retinal and RPE atrophy, Bull's Eye Maculopathy, Macular atrophy

CaseNotHPOs: N/a

CaseNotHPOFreeText: N/a

Genotyping Method: Whole genome sequencing

PreviouslyPublished: N/a

Variant: NM_000350.3:c.5882G>A p.(Gly1961Glu) ; NM_000350.3:c.634C>T p.(Arg212Cys)

ClinVar: 7888; 7898

CAID: CA119132, CA203216

SupplementalData: N/a

Case#: Male, 60

DiseaseAssertion: Stargardt disease

FamilyInfo: Possible macular degeneration in father

CasePresentingHPOs: HP:0007401, HP:0025010

CaseHPOFreeText: Vision was 20/40 in the right eye and 20/20 in the left eye. Dilated examination revealed scattered subretinal yellow flecks and macular atrophy bilaterally. The flecks were hyperautofluorescent. Fluorescein angiography showed obscuration of background choroidal fluorescence and window defects associated with the atrophy. Optical coherence tomography showed foveal atrophy and hyperreflective deposits at the level of the retinal pigment epithelium.

CaseNotHPOs: N/A

CaseNotHPOFreeText: Anterior segment examination was unremarkable. Normal cone and rod responses.

CasePreviousTesting: Target enrichment and next-generation sequencing were performed.

GenotypingMethod: N/A

PreviouslyPublished: N/A

Variant: Variant 1: NM_000350.3:c.5461-10T>C Variant 2: NM_000350.3:c.5603A>T

ClinVar: Variant 1: 92870 Variant 2: 99390

gnomAD: N/A

SupplementalData: Figure 1 shows fundus photographs (A and B), fundus autofluorescence (C and D), fluorescein angiography (E and F), near-infrared reflectance imaging (G), and an optical coherence tomography scan (H).

Case #: Male, 60 years old

DiseaseAssertion: He was diagnosed with late-onset Stargardts disease.

FamilyInfo: Has a family history with his father possibly having macular degeneration.

CasePresentingHPOs: HP:0007401, HP:0025010, HP:0012045 (sub-retinal/yellow), HP:0030602

CaseHPOFreeText: Proband presents with blurry vision (right eye) from over the past two years, with the right eye having 20/40 vision, while the left was 20/20. In addition to this, through dilation scattered subretinal yellow flecks and macular atrophy bilaterally, were revealed. The flecks were hyperautofluorescent. Obscuration of background choroidal fluorescence and window defects were also found. As well as foveal atrophy and hyperreflective deposits (RPE).

CaseNotHPOs: None found

CaseNotHPOFreeText: No abnormalities in the anterior segment examination. Through a full-field electroretinogram, normal rod and cone responses were found.

Genotyping Method: The genotyping was done through the use of target enrichment and next-generation sequencing.

PreviouslyPublished: N/a

Variant: 1) NM_000350.3(ABCA4):c.5461-10T>C 2) NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)

ClinVar: 1) 92870 2) 99390

CAID: N/a

gnomAD: 1) Highest minor allele frequency was 0.00031 (https://www.ncbi.nlm.nih.gov/clinvar/variation/92870/) 2) Highest minor allele frequency was 0.05787 (https://www.ncbi.nlm.nih.gov/clinvar/variation/99390/)

SupplementalData: I was able to find a variant (NM_000350.3(ABCA4):c.[5461-10T>C;5603A>T]) that addresses both of the variants. Also, Fig.1 shows the phenotype of the proband through tests.

Case#: Patient 66yo, M, Japan, Symptoms in teens

DiseaseAssertion: Stargardt (STGD) Heterozygous, Autosomal recessive

FamilyInfo: No family with similar symptoms

CasePresentingHPOs: HP:0008002, HP:0007722, HP:0000610, HP:0000602

CaseHPOFreeText: Ring shaped paracentral scotoma

CaseNotHPOs: HP: 0030329, HP:0000608, HP:0000493

CaseNotHPOFreeText: Well preserved foveal function, well preserved retinal, and normal thickness RPE

Genotyping Method: N/A

PreviouslyPublished: 4 other polymorphisms

Variant: c.839T>C p.Met280Thr Heterozygous

ClinVar: 1349490

SupplementalData: see tables 1 for gene variant and found polymorphisms

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

DiseaseAssertion: STGD1

FamilyInfo: Family pedigree shown in Figure 1.

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

CaseHPOFreeText: Retinal vessels were visibly attenuated.

CaseNotHPOs: n/a

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

Genotyping Method: Illumina MiSeq platform, Array-CGH analysis

PreviouslyPublished: n/a

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

ClinVar: 99065, 236116

SupplementalData: n/a

Case#: 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#: 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#: 1 male, 24 years old, from consanguineous parents, Somali ancestry.

DiseaseAssertion: ABCA4-related retinopathy Stargardt disease

FamilyInfo: Single affected individual consanguineous parents, Somali ancestry. No additional information about family is provided in text.

CasePresentingHPOs: HP:0000572- reduced central vision, HP:0001102- Angioid streaks, HP:0007980- retinal pigment epithelium atrophy, HP:0007401- Macular atrophy, HP:0000630- Abnormal retinal arterial/arteriolar morphology

CaseHPOFreeText: Presents with reduced central vision, Fundus autofluorescence (FAF) showed angioid streaks, reduced signal in the central macula indicative of retinal pigment epithelium atrophy. Electrophysiological testing showed severe macular dysfunction with generalized retinal involvement.

CaseNotHPOs: HP:0200070- Peripheral retinal atrophy

CaseNotHPOFreeText: Peripheral retina appears unaffected after ultra-widefield FAF imaging

Genotyping Method: PCR-amplification and Sanger sequencing of ABCA4 on Exon 42, Stargardt/Macular dystrophy SmartPanel v5; Molecular Vision Laboratory, Hillsboro, Oregon tested DNA for mutations which confirmed findings of ABCA4, with no additional pathogenic mutations found.

PreviouslyPublished: PMID: 22261738, 1 male, 24 years old, from consanguineous parents, Somali ancestry presenting with reduced vision.

Variant: NM_000350.3(ABCA4):c.5882G>A (p.Gly1961Glu)

ClinVar: Variation ID: 7888

CAID: N/A

SupplementalData: N/A

Case#: Female, age 44 years old

DiseaseAssertion: Discordant STGD phenotype

FamilyInfo: Information revolving the sister of this patient is given as well as they both have a discordant STGD phenotype. Additionally, it mentions that the parents each harboured a mutation but were asymptomatic/had normal examination results.

CasePresentingHPOs: HP:0001141, HP:0007401, HP:0030602

CaseHPOFreeText: At 23 central vision was deteriorating and patient had a VA of 6/36 in the right eye and 6/60 in the left. Through fundus photography, bilateral yellow/white flecks were found at the posterior pole. 12 years later, her VA was retested and it was 6/60 in both eyes. After autofluorescnece (AF) imaging was done, there was localized low signal at the macula found with abnromal foci. In 2008 her macular atrophy had enlarged and the flecks were less apparent.

CaseNotHPOs: N/a

CaseNotHPOFreeText: In this article there was not a phenotype presented that was normal.

CasePreviousTesting: It mentioned that there were two previously reported variants on the same allele detected in the siblings and one unique novel variant on the second allele for this patient. However, the testing they used was not listed, it just stated that the variants were found through sequencing. For this patient the variants were p.L541P/p.A1038V and p.R881C.

GenotypingMethod: Just mentioned sequencing and ABCA4 screening to look for two variants p.L541V and p.A1038V and a third novel variant p.R881C.

PreviouslyPublished: N/a

Variant: 1) NM_000350.3(ABCA4):c.1622T>C (p.Leu541Pro) 2) NM_000350.3(ABCA4):c.3113C>T (p.Ala1038Val) 3) N/a

ClinVar ID: 1) 99067 2) 7894 3) N/a

**CAID: ** 3) Because there was not a reference or alternate allele provided in this article I was unable to find a CAID for p.R881C.

gnomAD: 1) Highest minor allele frequency was 0.00017 (https://www.ncbi.nlm.nih.gov/clinvar/variation/99067/) 2) Highest minor allele frequency was 0.00188 (https://www.ncbi.nlm.nih.gov/clinvar/variation/7894/) 3) N/a

SupplementalData: Figure 1 had information regarding imaging and other testing done on the patient that is vital for phenotypic characterization. Also, it mentions a variant known as p.R881C, but was unable to find anything on ClinVar or gnomAD.

Case#: Patient 66yo, M, Japan, Symptoms in teens

DiseaseAssertion: Stargardt (STGD) Heterozygous, Autosomal recessive

FamilyInfo: No family with similar symptoms

CasePresentingHPOs: HP:0008002, HP:0007722, HP:0000610, HP:0000602

CaseHPOFreeText: Ring shaped paracentral scotoma

CaseNotHPOs: HP: 0030329, HP:0000608, HP:0000493

CaseNotHPOFreeText: Well preserved foveal function, well preserved retinal, and normal thickness RPE

Genotyping Method: N/A

PreviouslyPublished: 4 other polymorphisms

Variant: c.839T>C p.Met280Thr Heterozygous

ClinVar: 1349490

SupplementalData: see tables 1 for gene variant and found polymorphisms

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

Case#: Patient female, 48y, ethnicity not reported

DiseaseAssertion: Stargardt disease (STGD1) with unusual phenotype resembling pattern dystrophy

FamilyInfo: autosomal recessive inheritance; segregation analysis confirms each parent carries one variant (heterozygous). Pedigree shown in Figure 3. Proband is compound heterozygous for ABCA4 variants.

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

CaseHPOFreeText: mild visual impairment (BCVA 20/25 and 20/20), perifoveal yellow fleck-like lesions, hyperautofluorescent lesions with lipofuscin accumulation, foveal sparing, subretinal material accumulation, phenotype resembling pattern dystrophy, bilateral macular involvement, decreased p50 values on pattern ERG

CaseNotHPOs: HP:0000510 (normal ERG responses except pattern ERG component)

CaseNotHPOFreeText: normal full-field ERG (scotopic and photopic responses), normal electrooculography, preserved outer retina structure, minimal photoreceptor disruption at fovea

Genotyping Method: targeted next-generation sequencing (Illumina NextSeq500) with SeqCap EZ enrichment panel; Sanger sequencing used for confirmation and segregation analysis

PreviouslyPublished: n/a

Variant: ABCA4 NM_000350.2: c.428C>T (p.Pro143Leu); c.3113C>T (p.Ala1038Val)

ClinVar: 99273; 7894

CAID: n/a

SupplementalData: clinical imaging and genetic/segregation data in supplemental data (Figures 1–3, Table 1)

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#: 1 male, 6 years old, from Taiwanese and Korean decent.

DiseaseAssertion: ABCA4-related retinopathy Stargardt disease

FamilyInfo: Single affected individual. Paternal uncle presented with Stargart disease previously, and Taiwanese and Korean descent underwent genetic testing to identify two pathogenic variants in the ABCA4 gene. One of the variants found was the same ABCA4 variant from the originally affected individual. No additional family information is provided in text.

CasePresentingHPOs: HP:0000529 - progressive visual loss, HP:0025010 - Foveal atrophy, HP:0000603 - Central scotoma, HP:0007663 - Decreased visual acuity, HP:0030602 - Abnormal fundus autofluorescence imaging, HP:0007984 - ERG: Reduced dark-adapted b-wave amplitude, HP:0000512 - Abnormal electroretinogram, HP:0020032 - Hyperreflective retinal dots on OCT

CaseHPOFreeText: peripapillary sparing was observed on fundus autofluorescence imaging.

CaseNotHPOs: HP:0012045 - Retinal flecks

CaseNotHPOFreeText: N/A

Genotyping Method: Genetic testing was used and after sequencing two variants were found on the ABCA4 gene.

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.3523-2A>G

Variant: NM_000350.3(ABCA4):c.2249T>C (p.Leu750Pro)

ClinVar: Variation ID: 866764

ClinVar: Variation ID: 417984

CAID: N/A

SupplementalData: N/A

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#: Patient 23, Female

DiseaseAssertion: STGD

FamilyInfo: Not evaluated

CasePresentingHPOs: HP:0000609, HP:0012632, HP:0007906

CaseHPOFreeText: The patient also had a history of bilateral optic nerve hypoplasia, labile intraocular pressure (IOP), and ocular hypertension without glaucoma.

CaseNotHPOs: n/a

CaseNotHPOFreeText:n/a

Genotyping Method: Not listed

PreviouslyPublished: n/a

Variant: p.Arg2107Cys:c.6319C>T and p.Gly607Arg:c.1819G>A

ClinVar: 635988, 99087

CAID: CA956906, CA226936

SupplementalData: Phenotype shown in case report with continued treatment below

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)

PMID:39398711

Gene: ABCA4

HGNC ID: 34

Case Annotation Template

Case#: 19-year-old male

DiseaseAssertion: Stargardt disease 1 (STGD1)

FamilyInfo: No family history of eye disease reported. Autosomal recessive inheritance consistent with STGD1. Homozygous ABCA4 variant identified.

CasePresentingHPOs: DecreasedCentralVA, MacularAtrophy, MacularFlecks, PeripapillarySparing, OpticNervePallor

CaseHPOFreeText: Five-year history of progressive bilateral central vision loss, worse at near. Alternating exotropia measuring 16 prism diopters in all gazes OU. Best corrected visual acuity 20/200 OU. Fundus examination revealed pigment deposition and macular mottling. Fundus autofluorescence showed central decreased autofluorescence surrounded by increased autofluorescence. Fluorescein angiography demonstrated dark choroid. OCT showed loss of the central ellipsoid zone with hyperreflective deposits. Multifocal ERG demonstrated significant functional loss.

CaseNotHPOs: NightBlindness

CaseNotHPOFreeText: Patient denied nyctalopia, photophobia, or flashes. Color vision normal on Ishihara testing.

Genotyping Method: Genotyping Method: Next-generation sequencing (NGS) with deletion/duplication analysis (Invitae Corporation).

PreviouslyPublished: N/A

Variant: ABCA4 c.52C>T (p.Arg18Trp)

ClinVar: ClinVarID:7899

CAID: N/A

SupplementalData: N/A