PMID: 33899203

Gene: ABCA4

HGNC ID: 34

PMID: 26527198

Gene: ABCA4

HGNC ID: 34

PMID: 35243166

Gene: ABCA4

HGNC: 34

PMID: 30186147

Gene: ABCA4

HGNC ID: 34

Case#: 43 year old woman II:2

DiseaseAssertion: Stargardt disease (STGD1)

FamilyInfo: none of family had co-existing systemic disorders, father carried variant, probands affected suster did not

CasePresentingHPOs:HP:0000007

CaseHPOFreeText: loss of ellipsoid zone, mascular dystrophy with features of bull's eye maculopathy,

CaseNotHPOs: na

CaseNotHPOFreeText: na

Genotyping Method: sanger sequencing

PreviouslyPublished: n/a

Variant: c.4685 T > C, p.(I1562T)

ClinVar: not found

CAID: not found

SupplementalData: probands affected sister did not carry the ABAA4 variant, indicating ABCA4 was not relevant to mascular dystrophy in family, CRX variant was also found

PMID: 20149343

Gene: ABCA4

HGNC ID: 34

PMID: 10612508

Gene: ABCA4

HGNC ID: 34

PMID: 31130284

Gene: ABCA4

HGNCID: HGNC:34

SupplementalData: Table S4. Variant S2255I downgraded from Pathogenic to LB due to its high allele frequency.

Case#: 55 year old female

DiseaseAssertion: Stargardt

FamilyInfo: no significant ocular disease shown.

CasePresentingHPOs: difficulty reading materials 6 inches from her eyes, decreased visual acuity from age seven. BCVA was 20/150 OU. Posterior segment exam and autofluorescence was significant for bilateral central atrophy and pisciform fleck atrophy involving the peripapillary, macular, and peripheral regions.

CaseHPOFreeText: NR

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

Genotyping Method: ABCR400 microarray

PreviouslyPublished: NR

Variant: NM_000350.3:c.4139C>T, NM_000350.3(ABCA4):c.6089G>A

ClinVar: 7904, 99428

CAID: CA129033

SupplementalData: NR

Case#: a 46-year-old male

DiseaseAssertion: Stargardt Disease

FamilyInfo:visual acuity loss by his brother and father

CasePresentingHPOs: HP:0007663

CaseHPOFreeText: visual acuity measured 20/400 bilaterally

CaseNotHPOs: NR

CaseNotHPOFreeText:NR

Genotyping Method: ABCA4 microarray (ABCR5000 chip)

PreviouslyPublished: NR

Variant: c.5714+5G>A

ClinVar: 99403

CAID: CA227338

SupplementalData:NR

PMID:18854780

Gene: ABCA4

HGNC ID: 78

Disease: Stargardt

PMID: 41063816 Gene:ABCA4 HGNC:34

PMID: 41063816

Gene: ABCA4

HGNC ID: 34

PMID: 19352439

Gene: ABCA4

PMID: 41458191 Gene: ABCA4 HGNC: 34

PMID: 25375877

Gene: ABCA4, RPGR

HGNC ID: 34, 10295

PMID: 28611652

Gene: ABCA4

HGNC ID: 34

PMID: 29765157

Gene: ABCA4

HGNC ID: 34

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)

PMID: 34008801

Gene: ABCA4

HGNC ID: 34

PMID: 34008801

Gene: ABCA4

HGNC ID: 34

Case#:case 1 II:4

DiseaseAssertion: Stargardt disease (STGD1)

FamilyInfo: mother has identical phenotype as proband, dad and sister asymptomatic, brother was symptomatic at 8 years old, other brother symptomatic at 15 years old.

CasePresentingHPOs: HP:0000007

CaseHPOFreeText: at age 50, with central visual imparement in right eye, 20/40 right, 20/20 left, linear and branching hyperautofluorescent subretinal deposits and extrafoveal RPE atrophy in both eyes,

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method:

PreviouslyPublished: n/a

Variant: c.6031_6044delins18M/p.(Ile2003LeufsTer41)

ClinVar: not found

CAID: not found

SupplementalData:

PMID: 22060670

Gene: ABCA4

HGNC ID: 34

PMID: 28726568

Gene: ABCA4

HGNC ID: 34

PMID: 24020726

Gene: ABCA4

HGNC ID: 34

PMID: 28050124

Gene: ABCA4

HGNC ID: 34

PMID: 40401218

Gene: ABCA4

HGNC ID: 34

PMID: 31819343

Gene: ABCA4

HGNC ID: 34

PMID: 40465261

Gene: ABCA4

HGNC ID: 34

PMID:39917552

Gene: ABCA4

HGNC ID: 34

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.

PMID: 34513887

Gene: ABCA4

HGNC ID: 34

PMID: 34440443

Gene: ABCA4

Disease: Retinal Dystrophies

PMID: 34679498

Gene: ABCA4

HGNC ID: 34

PMID: 38607040

Gene: ABCA4

HGNC ID: 34

PMID: 41561667

Gene: ABCA4

HGNC ID: 34

Case#: patient 66, male, Italy

DiseaseAssertion: STGD

FamilyInfo: N/A

CasePresentingHPOs: HP:0000505, HP:0000551, HP:0000546

CaseHPOFreeText: best-corrected visual acuity (BCVA) was 20/400 in both eyes, mild myopia, both eyes were pseudophakic, extensive bilateral chorioretinal atrophy involving both the posterior pole and the peripheral retina, widespread mottled hypoautofluorescence in the mid-periphery, along with pronounced macular hypoautofluorescence, significant central retinal thinning, an enlarged foveal depression, outer retinal hyper-reflectivity associated with extensive atrophy of both the RPE and the underlying choroid, dense epiretinal membrane (ERM) was also identified in the right eye, large central hypofluorescent zone involving the macular region and extending beyond the vascular arcades

CasePreviousTesting: n/a

GenotypingMethod: Next-Generation Sequencing

PreviouslyPublished: n/a

Variant: c.1714C > T p. (Arg572∗)

ClinVar: 620085 https://www.ncbi.nlm.nih.gov/clinvar/variation/620085/?term=620085%5BVariation+ID%5D

gnomAD: 0.000001859 https://gnomad.broadinstitute.org/variant/1-94063158-G-A?dataset=gnomad_r4

Variant: c.2461T > A p. (Trp821Arg)

ClinVar: 99136 https://www.ncbi.nlm.nih.gov/clinvar/variation/99136/?term=99136%5BVariation+ID%5D

gnomAD: 0.000008054 https://gnomad.broadinstitute.org/variant/1-94055237-A-T?dataset=gnomad_r4

Variant: c.4417C>А p. (Leu1473Met)

ClinVar: 546600 https://www.ncbi.nlm.nih.gov/clinvar/variation/546600/?term=546600%5BVariation+ID%5D

gnomAD: 0.00005762 https://gnomad.broadinstitute.org/variant/1-94029567-G-T?dataset=gnomad_r4

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

PMID: 24444108

Gene: ABCA4

HGNC ID: 34

PMID: 33909047

Gene: ABCA4

HGNCID: HGNC:34

PMID: 19352439

Gene: ABCA4

HGNC ID: 34

PMID: 24509150

Gene: ABCA4

HGNC ID: 34

PMID: 17277736

Gene: ABCA4

HGNC ID: 34

PMID: 31456290

Gene: ABCA4

HGNCID: HGNC:34

SupplementalData: as applicable Table S2. Variant found in cohort of 2,420 families including 3,413 individuals with inherited retinal diseases in Israel. Likely, this is the same family reported in PMID 29706639.

Total number of families: 1; phenotype/s: CRD; NM_000350.2:c.4895dup, p.(Asn1632Lysfs*14)

Case#: 1

DiseaseAssertion: stargardt disease originally but didn;t have fishtail flecks

FamilyInfo: both unaffected parents carrying heterozygous MFSD8 variants

CasePresentingHPOs:HP:0001272

CaseHPOFreeText:at 5 years old BCVA was measured at a Snellen equivalent at 0.13 in both eyes, at age 8, BCVA had decreased to 0.07 in both eyes, complete absence of all retinal responses on full‐field flash ERG, No fishtail flecks typical of Stargardt disease were observed

CaseNotHPOs: n/a

CaseNotHPOFreeText:n/a

Genotyping Method: HaloPlex target enrichment kit amplified and sequenced using illumina, then WES

PreviouslyPublished: n/a

Variant: c.3113C>T p.(Ala1038Val)

ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/variation/7894/

SupplementalData: MFSD8 variants identified

PMID: 37628710

Gene: ABCA4

HGNC ID: 34

PMID: 36471740

Gene: ABCA4

HGNC ID: 34

Case#: 1

DiseaseAssertion: stargardt disease originally but didn;t have fishtail flecks

FamilyInfo: both unaffected parents carrying heterozygous MFSD8 variants

CasePresentingHPOs:HP:0001272

CaseHPOFreeText:at 5 years old BCVA was measured at a Snellen equivalent at 0.13 in both eyes, at age 8, BCVA had decreased to 0.07 in both eyes, complete absence of all retinal responses on full‐field flash ERG, No fishtail flecks typical of Stargardt disease were observed

CaseNotHPOs: n/a

CaseNotHPOFreeText:n/a

Genotyping Method: HaloPlex target enrichment kit amplified and sequenced using illumina, then WES

PreviouslyPublished: n/a

Variant: c.3113C>T p.(Ala1038Val)

ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/variation/7894/

SupplementalData: MFSD8 variants identified

Case#: 19 year old woman

DiseaseAssertion: Stargardt disease (STGD)

FamilyInfo: no family history of ocular disease

CasePresentingHPOs:HP:0025158

CaseHPOFreeText:20/25 in the right eye and 20/25-1 in the left eye, small irregular perifoveal lesions of both increased and decreased autofluorescence

CaseNotHPOs:na

CaseNotHPOFreeText:na

Genotyping Method: next gen sequencing

PreviouslyPublished: na

Variant: c.6079C > T, p.(Leu2027Phe) c.4139C > T, p.(Pro1380Leu)

ClinVar: not found not found

CAID: not found not found

SupplementalData: “black shadow” in the right eye after getting hit by a volley ball

PMID:39917552

Gene: ABCA4

HGNC ID: 34

Case#: 43 year old woman II:2

DiseaseAssertion: Stargardt disease (STGD1)

FamilyInfo: none of family had co-existing systemic disorders, father carried variant, probands affected suster did not

CasePresentingHPOs:HP:0000007

CaseHPOFreeText: loss of ellipsoid zone, mascular dystrophy with features of bull's eye maculopathy,

CaseNotHPOs: na

CaseNotHPOFreeText: na

Genotyping Method: sanger sequencing

PreviouslyPublished: n/a

Variant: c.4685 T > C, p.(I1562T)

ClinVar: not found

CAID: not found

SupplementalData: probands affected sister did not carry the ABAA4 variant, indicating ABCA4 was not relevant to mascular dystrophy in family, CRX variant was also found

Case#:case 1 II:4

DiseaseAssertion: Stargardt disease (STGD1)

FamilyInfo: mother has identical phenotype as proband, dad and sister asymptomatic, brother was symptomatic at 8 years old, other brother symptomatic at 15 years old.

CasePresentingHPOs: HP:0000007

CaseHPOFreeText: at age 50, with central visual imparement in right eye, 20/40 right, 20/20 left, linear and branching hyperautofluorescent subretinal deposits and extrafoveal RPE atrophy in both eyes,

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method:

PreviouslyPublished: n/a

Variant: c.6031_6044delins18M/p.(Ile2003LeufsTer41)

ClinVar: not found

CAID: not found

SupplementalData:

PMID:328843395

Gene: ABCA4

HGNC ID: 34