MonDO: MONDO:0019353

Case: Family SG-04 Patient II:1. Indian Male, 26 years old diagnosed with Stargardt's disease DiseaseAssertion: Stargardt disease

FamilyInfo: Only child of nonconsanguineous parents. Proband's unaffected mother (I:1) harbored only one heterozygous variant (p.Gly1961Glu) in ABCA4. His father (I:2) was clinically normal and was not included for genetic testing.

CasePresentingHPOs: HP:0001129, HP:0007401 (Large central visual field defect, Macular atrophy)

CaseHPOFreeText: atrophic macular lesions

CaseNOTHPOs: HP:0011507 (macular flecks)

CasePreviousTesting: Five clinically confirmed unrelated patients with Stargardt disease and their available family members were enrolled for genetic analysis. Study subjects underwent a complete ophthalmic examination including measurement of visual acuity, intraocular pressure, slit lamp biomicroscopy, detailed fundus examination, fundus photography, fundus autofluorescence (FAF), spectral domain optical coherence tomography (SD-OCT), and full field electroretinography (ERG). Fifty normal controls without any history of eye diseases were included.

GenotypingMethod: NGS panel testing targeting 184 genes with previously known pathogenic variations associated with multiple eye disorders. Peripheral blood samples were obtained from all subjects.

MultipleGeneVariants:

(1) GeneName: ABCA4

(1) Variant: p.Gly1961Glu

(1) CAID: CA119132

(1) gnomAD: The total minor allele frequency in gnomAD v4.1.0 is 0.003406 (5498/1614012 alleles).

(2) GeneName: ABCA4

(2) Variant: p.Tyr872X

(2) CAID: CA341276149

(2) gnomAD: Not found in gnomad v. 4.1

PMID: 37510299 Gene: ABCA4 CAID: CA119132

MonDO: MONDO_0800406

GenotypingMethod: combined SSCP and heteroduplex analyses of all 50 exons of ABCA4, Sanger sequencing

For PP4: Patients harbored heterozygous or homozygous ABCA4 variants in addition to G1961E.

Case 7-1: Male, Jordanian, born to consanguineous parents, disease onset at 4 years (PP4 +0.5 pts), Stage 3 STGD, Compound Hmz G1961E and H1838D. PP4: 2.5 points.

Phenotype: central macular atrophy (PP4 +0.5 pts) with parafoveal or perifoveal flecks, severe fundus abnormalities, complete resorption of flecks with choriocapillaris atrophy also within the macula

Patient was previously reported in review article by Iannaccone A. The genetics of hereditary retinopathies and optic neuropathies. Compr. Ophthalmol Update. 2005;6:39–62. (No PMID). Fig 1C: "View of the right macula of a 10-year-old Jordanian male with autosomal recessive cone-rod dystrophy. There are atrophic changes, a beaten-bronze appearance (PP4 +0.5pts), and abnormal vitreoretinal interface reflexes. The central lesion is surrounded by a halo of coarse deep mottling (PP4 +0.5pts) and there were pigmentary deposits in the retinal midperiphery (not shown). Electroretinogram testing revealed a cone-rod pattern of severe retinal dysfunction. This patient was homozygous for a previously reported ABCA4 mutation resulting in a glycine-to-glutamate amino acid substitution at codon 1961 (G1961E), as well as a previously unreported change at codon 1838, predicting a histidine-to-aspartate amino acid change (H1838D) and seven additional polymorphisms. (PP4 +0.5pts)"

CasePresentingHPOs: HP:0007401, HP:0011507, HP:0001098, HP:0000548, HP:0025147, HP:0007793, HP:0001098 (Macular atrophy, Macular flecks, Abnormal fundus morphology, Cone/cone-rod dystrophy, Beaten bronze macular sheen, Granular macular appearance, Abnormal fundus morphology)

CaseHPOFreeText: abnormal vitreoretinal interface reflexes, chroiocapillaris atrophy

Case 7-2: Female, sibling of 7-1, Jordanian, born to consanguineous parents, disease onset at 7 years (PP4 +0.5 pts), Stage 4 STGD, Compound Hmz G1961E and H1838D (PP4 +0.5pts)

Phenotype: severe central macular atrophy (PP4 +0.5 pts), peripheral intraretinal pigmentation on fundus photography, extensive atrophy of the RPE, Central scotomata (PP4 +0.5pts) with reduced visual sensitivity more peripherally, severe fundus abnormalities, central macular atrophy with parafoveal or perifoveal flecks (PP4 +0.5pts), Widespread RPE and chorioretinal atrophy throughout the fundus

Case 8-1: Female, Italian, disease onset at 7 years (PP4 +0.5pts), Stage 3 STGD, Compound G1961E Hmz and N96K Het (PP4 +0.5 pts); PP4 = 3.5 pts

Phenotype: severe central macular atrophy (PP4 +0.5pts), peripheral intraretinal pigmentation on fundus photography, extensive atrophy of the RPE, Central scotomata (PP4 +0.5pts) with reduced visual sensitivity more peripherally, severe fundus abnormalities, central macular atrophy with parafoveal or perifoveal flecks (+PP4 0.5pts), complete resorption of flecks with choriocapillaris atrophy also within the macula, Decreased central acuity (VA score of 20/2000 in both eyes) (PP4 +1 pts)

CasePresentingHPOs: HP:0007401, HP:0000603, HP:0001098, HP:0011507, HP:0001141, HP:0030491 (Macular atrophy, Central scotoma, Abnormal fundus morphology, Macular flecks, Severely reduced visual acuity, chroiocapillaris atrophy)

CaseHPOFreeText: peripheral intraretinal pigmentation on fundus photography, atrophy of RPE

Case 8-2: Male, Italian, sibling of 8-1, disease onset at 10 years, Stage 4 STGD, N96K Het Central scotomata with reduced visual sensitivity more peripherally, severe fundus abnormalities, central macular atrophy with parafoveal or perifoveal flecks, Widespread RPE and chorioretinal atrophy throughout the fundus

Case 9: Female, Italian, disease onset set 12 years (PP4 +0.5pts), Stage 4 STGD, G1961E Hmz and N96K Hmz (PP4 +0.5pts); PP4 = 3 points history of early central vision loss (PP4 +1 pts), severe fundus abnormalities, central macular atrophy (PP4 +0.5pts) with parafoveal or perifoveal flecks (PP4 +0.5 pts), Widespread RPE and chorioretinal atrophy throughout the fundus.

Family members (parents and siblings) were available in all cases except for patients 6 and 10. The phase and true homozygosity of the G1961E mutation were determined by segregation analyses. Hemizygosity, that is the homozygous appearance due to the deletion on the other chromosome, was ruled out in all cases.

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#:5-year-old girl

DiseaseAssertion: Asymptomatic

FamilyInfo: Mother was diagnosed with STGD1 and She was homozygous for a (severe) splice site mutation, IVS 35+2 T>C, Maternal uncle was diagnosed with STGD1. Father passed down the G1961E variant.

CasePresentingHPOs: HP:0030630, HP:0011504

CaseHPOFreeText: The ELM in the central macula appeared thickened with indistinct borders, particularly along its inner border (Fig. 2C), horizontal diameter for the region of thickened ELM was 1113 μm, FAF revealed Bull’s Eye Maculopathy (BEM) (Fig. 2B),

CaseNotHPOs:

CaseNotHPOFreeText: No retinal, vasculature, pigmentary or optic nerve head abnormalities were detected on clinical examination, no focal abnormality observed in the outer nuclear layer (ONL) or RPE (Fig. 2C), There was no FAF evidence of flecks or GA

Genotyping Method:

PreviouslyPublished: No

Variant:NM_000350.3:c.5882G>,

ClinVar:7888

CAID:CA119132

SupplementalData:

Case#: a 29-year-old man

DiseaseAssertion: Stargardt Disease

FamilyInfo: NR

CasePresentingHPOs: HP:0007663

CaseHPOFreeText: 20/70 visual acuity in both eyes

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

Genotyping Method: ABCA4 microarray (ABCR5000 chip)

PreviouslyPublished: NR

Variant: NM_000350.3:c.5882G>A, p.G1961E and c.5018+2C>T (rare splice variant)

ClinVar: 7888, NR

CAID: CA119132, NR

SupplementalData: No CAID or ClinVar ID were found for the rare splice variant c.5018+2C>T

Case#:3, 34–year-old woman

DiseaseAssertion:NR

FamilyInfo: no family history of an ocular disease

CasePresentingHPOs: HP:0007663, HP:0030506, HP:0030528, HP:0000603

CaseHPOFreeText:bilateral markedly decreased vision (logMar BCVA OD:0.93, OS:0.95), bilateral atrophic lesions of the macula accompanied by yellow-white stellate flecks at the level of the retinal pigment epithelium, Atrophic lesions and flecks were also extending to the mid-periphery of both retinae, bilateral absolute central scotoma and relative paracentral scotomas as well in both eyes, PERG was significantly reduced, while scotopic and photopic amplitudes were also lower than normal.

CaseNotHPOs:

CaseNotHPOFreeText:NR

Genotyping Method: “Analysis of the ABCA4 gene”

PreviouslyPublished: No

Variant: NM_000350.3:c.5882G>A, NM_000350.3:c.6709dup

ClinVar: ​​7888, 99485

CAID: CA119132, CA227437

SupplementalData:

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

Analysis of ABCA4 variants in 150 families with Stargardt disease. Most of which were of northern or central European ancestry. For comparison, 220 racially matched individuals with no personal history or known family history of STGD served as controls (Anderson et al. 1995; Allikmets et al. 1997b).

PMID: 9973280

Gene: ABCA4

HGNCID: HGNC:34

GenotypingMethod: combined SSCP and heteroduplex analyses of all 50 exons of ABCA4, Sanger sequencing

Pedigree AR417: onset at 8 years 2 segregations, 2 out of 3 offspring affected by STGD, parents and grandmother unaffected Variant: G1961E, A1038V CAID: CA119132, CA119135)

Pedigree AR427: onset at 12 years 1 segregation, 1 out of 2 offspring affected by STGD, parents unaffected Variant: G1961E, C75G CAID: CA119132, CA226985

Pedigree AR370: onset at 13 years 1 segregation, 1 out of 3 offspring affected by STGD, parents and grandparents unaffected Variant: G1961E, C1490Y CAID: CA119132, CA227198

Pedigree AR 218: onset at 14 years family history of AMD, was first reported by Anderson et al. [1995] Variant: G1961E, 2160+1G>C CAID: CA119132, CA226984

Pedigree AR 373: onset at 19 years 2 segregations, 2 out of 3 offspring affected by STGD, parents and grandparents unaffected Variant: G1961E, 4253+5G>T CAID: CA119132, CA227174

Pedigree AR 274: onset at 20 years 1 segregation, 1 out of 4 siblings affected by STGD, parents and grandparents unaffected Variant: G1961E, A1038V CAID: CA119132, CA119135