PMID:39991341

Gene: ABCA4

Disease: Stargardt

Case#: Male, Family#3, Proband M1, M2: II,1 on pedigree

DiseaseAssertion: STGD

FamilyInfo: mother of proband has p.N18681 and p.P1380L mutations and is asymptomatic with no changes to NIR-AF and SD-OCT. Treated with 400mg of hydroxychloroquine for lupus prior to imaging. Non-affected father.

CasePresentingHPOs:HP:0007663, HP:0000493

CaseHPOFreeText: Proband has reduced visual acuity and issues reading with BCVA 20/200 in R.E and 20/50-2 in L.E. Oval foveal lesions with stage 2 flecks. Visual acuity reducing starting at age 10.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Genotyping performed at Columbia University, sequencing technology used is not disclosed.

PreviouslyPublished: n/a

Variant: M1:p.P1380L, complex allele: M2: p.N18681 and IVS38:c.5461-10T>C. M3: c.4139C>T(p.P1380L)

ClinVar: M1) 99390 M2) 99067 M3) Variation ID: 7904

CAID: n/a

SupplementalData: Fig 1: Pedigree illustrating ABCA4 variants and the associated Stargardt phenotype for 5 families. Proband Labeled w/ white arrow for each family. Fig 2: retinal scan measuring melanin in 4 patients of family 2. Panel shows bull's-eye ring of RPE atropy. Fig 3: Macular SD-OCT line profile from b-scans. Reflectivity plotted against function of retinal depth. Table 1: table shows patients with p.N18681 variant, type of mutation, and pathogenicity class. Table 2: Patients, age on-set and first symptom

Case#: Patient 1, Female, age 40

DiseaseAssertion: STGD1

FamilyInfo: n/a

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0000007

CaseHPOFreeText: Patient diagnosed with STGD type 1, presenting with retinal pigment atrophy as well as other symptoms typical of STGD1 with reduced visual acuity. Patient daignosed at age 16.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Patient ABCA-4 gene sequenced via Sanger sequencing of all 50 exons, Splice variants were identified by synthesized cDNA from RNA isolation with RT-PCR analysis with exonic primers.

PreviouslyPublished: Variant 1 identified in association with retinal dystrophy in these PMC articles: 23982839, 25082829, 25082885, 28327576

Variant: NM_000350.3(ABCA4):c.859-9T>C, NM_000350.3(ABCA4):c.303-3C>G

ClinVar: 3249248, 859348

gnomAD total allele frequency: 0.005% of var . 1

CAID: n/a

SupplementalData: Fig 1: Minigene RNA analysis of splice variants. A: genomic region of exon 40 on ABCA-4. B: genomic regions of exons 39-41 to investigate specific variant:oncanonical splice site variant c.5714+5G>A Fig 2: overview of wild-type midigene splice constructs of ABCA-4 and locations of 47 different non canonical splice site variants Fig 3: Overview of splice defects from nine different non canonnical splice variants in ABCA-4 gene. Fig 4: percentages of normal ABCA-4 transcripts as a result of noncanonical splice variants using electrophoresis system analysis. Table 1: Non canonical splice variants and observed protein affects.

**Case#: ** Female, 35yo

FamilyInfo: Unremarkable

CasePresentingHPOs: HP:0000529 Progressive visual loss, HP:0030532 Visual acuity, HP:0007401 Macular atrophy

CaseHPOFreeText: 35-year-old woman presented with symptom of gradually progressive diminution of vision in both eyes since childhood. Patient gave no history of defective night vision.

CaseNotHPO n/a

GenoTypeMethod: n/a (optical coherence tomography (OCT))

PMID:36910710 Gene: ABCA4 HGNC: 34

PMID: 10612508

Gene: ABCA4

Case#: Patient 2, 46-year-old female

DiseaseAssertion: STGD1

FamilyInfo: One of four affected siblings in a family consistent with autosomal recessive inheritance.

CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology

CaseHPOFreeText: Progressive visual decline since age 16. Best-corrected visual acuity 20/400 in both eyes. Fundus examination showed bilateral symmetrical central chorioretinal atrophy (~3 disc diameters) with prominent pigment deposits and numerous yellow flecks in the posterior pole. Fluorescein angiography demonstrated central hypofluorescence with surrounding hyperfluorescence and peripheral dark choroid.

CaseNotHPOs: Not reported

CaseNotHPOFreeText: Not reported

GenotypingMethod: PCR amplification and direct sequencing of ABCA4 after SSCP screening

PreviouslyPublished: Yes

Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)

ClinVar: Not reported

CAID: Not reported

SupplementalData: Segregation and sequencing data shown in Figures 1 and 4

Case#: Patient 3, 37-year-old female

PMID: 10612508

DiseaseAssertion: STGD1

FamilyInfo: Affected sibling in autosomal recessive family.

CasePresentingHPOs: HP:0000545 — Decreased visual acuity HP:0007754 — Macular atrophy HP:0030638 — Retinal flecks HP:0000512 — Abnormal fundus morphology

CaseHPOFreeText: Gradual visual decline beginning at age 12. Visual acuity 20/400 in both eyes. Fundus examination revealed bilateral macular atrophy with pigment deposits and numerous yellow flecks in the posterior pole and midperiphery. Fluorescein angiography showed large hypofluorescent regions with surrounding hyperfluorescence and peripheral dark choroid.

CaseNotHPOs: Not reported

CaseNotHPOFreeText: Not reported

GenotypingMethod: PCR and direct sequencing of ABCA4

PreviouslyPublished: Yes

Variant: NM_000350.2:c.2588G>C (p.Gly863Ala) NM_000350.2:c.161G>A (p.Cys54Tyr)

ClinVar: Not reported

CAID: Not reported

SupplementalData: Segregation and sequencing data (Figures 1, 4)

PMID: 17562343 GeneName: ABCA4

Case#: Female, family #5, Patient #20

DiseaseAssertion: STGD

FamilyInfo: Proband's sister presented with same clinical prognosis. Sister diagnosed with pattern dystrophy and photoaversion at age 57, with difficulty seeing at night. Sister has nuclear sclerotic and cortical cataracts in both eyes.

CasePresentingHPOs: HP:0000662, HP:0000603, HP:0000603, HP:0000493

CaseHPOFreeText: Proband presented with localized blur at age 62, (late onset) in her left eye. BVCA 20/20-3 and 20/20-2 at age 70. Also has macular lesions with stage 2 fundus flecks.

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

Genotyping Method: Genotyping performed at Columbia University, sequencing technology used is not disclosed.

PreviouslyPublished: n/a

Variant: p.N18681, IVS36:c.5196+1G>A

ClinVar: M2) 99067, M6) 99351

CAID: N/A

SupplementalData: Fig 1: Pedigree illustrating ABCA4 variants and the associated Stargardt phenotype for 5 families. Proband Labeled w/ white arrow for each family. Fig 2: retinal scan measuring melanin in 4 patients of family 2. Panel shows bull's-eye ring of RPE atropy. Fig 3: Macular SD-OCT line profile from b-scans. Reflectivity plotted against function of retinal depth. Table 1: table shows patients with p.N18681 variant, type of mutation, and pathogenicity class. Table 2: Patients, age on-set and first symptom

Case#: Patient 225, Female, age of onset 7 y.o, Poland

DiseaseAssertion: STGD-1

FamilyInfo: no given family information.

CasePresentingHPOs: HP:0007722, HP:0000608, HP:0025158

CaseHPOFreeText: RPE atrophy, macular degeneration, central hyper-autofluorescence in fundus autofluorescence

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a, non-proband identified HPO's mentioned, but not assignable to individual proband.

Genotyping Method: DNA isolated from peripheral blood from patients and relatives via MagNA Pure 24, samples screened with MIPs targeting 108 genes involved in pathogensis of IRD's. PCR completed on library, analysed with NGS fragment analysis kit.

PreviouslyPublished: yes

Variant: c.[1622T>C;3113C>T]

ClinVar: 99067, 7894

CAID: n/a

gnomeAD 0.0001266 allele frequency

SupplementalData: Fig1: List of families displaying pseudo-dominant inheritance. Fig2: Number of alleles for most common variants.

PMID: 23949494 HGNC: 34 Gene: ABCA4 DiseaseAssertion: Stargardt Disease