Case#: 25 year old Female, Sikh, India, Punjab

DiseaseAssertion: EORSD

FamilyInfo: Family history for other disease were negative

CasePresentingHPOs: HP:0007401, HP:0007913

CaseHPOFreeText: Macular atrophy, scar and pigment OU, plus midperipheral pigmentation OU

CaseNotHPOs: N/a

CaseNotHPOFreeText: N/a

Genotyping Method: BGISeq-500 2 x 100-bp paired-end module, Burrows-Wheeler Aligner and Genome Analysis Tooklit HaploptypeCaller

PreviouslyPublished: N/a

Variant: NM_000350.3(ABCA4):c.6729+5_6729+19del

ClinVar: 283573

CAID: CA501163

SupplementalData: Family reported never saw well and had poor vision and nystagmus before the age of one.

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#: Case 2, Sex: Male, Age:20

DiseaseAssertion: STGD

FamilyInfo: n/a

CasePresentingHPOs: HP:0007663, HP:0007401

CaseHPOFreeText: Text mentions visual acuity of 20/32 in right eye and 20/50 in left eye but later degrades to 20/200 in both eyes. pigmented changes in macula associated with flecks. Area of subretinal fibrosis in right eye. Subnormal scotopic and photopic responses. Instable fixation in both eyes with low retinal mean sensitivity. Hypofluorescent central area corresponding to macular atrophy and corresponding to flecks. Atrophic areas, some with pigment, localized in the temporal sector of the left eye which have become areas of subretinal fibrosis.

CaseNotHPOs:n/a

CaseNotHPOFreeText: Anterior segment showed a healthy ocular adnexa, and specular, transparent and 'in situ' lens, absence of any ocular trauma.

Genotyping Method: genetic analysis

PreviouslyPublished: n/a

Variant: Variant is a homozygous mutation given as NM_000350.3(ABCA4):c.571-2A>T

ClinVar: Variation ID: 1048133

CAID: CA958800

SupplementalData: n/a

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#: 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 Annotation Template

Case#: Patient 40, female, Caucasian, onset at 2-3yo, Spain

DiseaseAssertion: STGD

FamilyInfo: Brother and Sister not affected showed heterozygous patterns of (p.His423Arg (c.1268A>G), IVS33+48 C>T) mutations. R1129L mutation heterozygous in the unaffected father; mutation not found in the unaffected mother. Patient has 4yo asymptomatic female child

CasePresentingHPOs: HP:0000505, HP: 0011463, HP:0030786, HP:0007641, HP:0007663, HP: 0000610, HP: 0007814, HP:0000007

CaseHPOFreeText: Macular yellow flecks, macular dystrophy

CaseNotHPOs: N/A

CaseNotHPOFreeText: Normal biomicroscopy

Genotyping Method: Conventional mutational screening on 77 STGD families and screened on the ABCR400 Microarray. Haplotype analyses, HR karyotypes, and MLPA were also performed.

PreviouslyPublished: N/A

Variant: p.Arg1129Leu (c.3386G>T)

CAID: CA227116

SupplementalData:N/A

Case#: German/British, 76

DiseaseAssertion: EOSRD

FamilyInfo: Grandparents from Germany and the United Kingdom

CasePresentingHPOs: HP:0007401, HP:0007913

CaseHPOFreeText: Macular atrophy and pigmentation, peripheral pigmentation, early-onset severe retinal dystrophy

CaseNotHPOs: N/a

CaseNotHPOFreeText: N/a

Genotyping Method: BGISeq-500 2 x 100-bp paired-end module, Burrows-Wheeler Aligner and Genome Analysis Tooklit HaploptypeCaller

PreviouslyPublished: n/a

Variant: c.1622T>C, c.4326C>A, and c.3113C>T

ClinVar: 99067, 417991, 7894

CAID: CA226911, CA957653, CA119135

SupplementalData: The c.1622T>C variants and c.3133C>T are thought to be same gene copy

Case#: 39 Year Old Female, India Punjab

DiseaseAssertion: EORSD

FamilyInfo: Family history for other disease was negative, husband was first cousin and their son had normal vision

CasePresentingHPOs: HP:0007401, HP:0007913

CaseHPOFreeText: Macular atrophy and pigmentation, yellowish flecks

CaseNotHPOs: N/a

CaseNotHPOFreeText: N/a

Genotyping Method: BGISeq-500 2 x 100-bp paired-end module, Burrows-Wheeler Aligner and Genome Analysis Tooklit HaploptypeCaller

PreviouslyPublished: N/a

Variant: NM_000350.3(ABCA4):c.6729+5_6729+19del

ClinVar: 283573

CAID: CA501163

SupplementalData: Confirmed that she had never seen properly or normally, marked horizontal nystagmus and poor pupil reaction to light

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#: 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#: An 8-year old Hispanic female

DiseaseAssertion: Whole exome sequencing identified a homozygous ABCA4 missense variant (p.Arg602Trp) that has been identified as a Stargardt Disease mutation

FamilyInfo: consanguinity, her parents being first cousins, no family history of blindness. Familial cosegregation analysis was used, with both parents being heterozygous carriers.

CasePresentingHPOs: HP:0000529, HP:0000662, HP:0000556, HP:0002017,HP:0008046, HP:0031528, HP:0003678

CaseHPOFreeText: rapidly progressive vision loss, nyctalopia and retinal dystrophy, bilateral decreased vision following a febrile gastrointestinal illness with nausea and vomiting, Initial visual acuity was 20/60 at distance and 20/30 at near in both eyes, after 2 years visual acuities of 20/200 at distance in both eyes, attenuated vessels and multiple subretinal blister-like elevations, Cycloplegic retinoscopy detected very mild hyperopia and astigmatism in both eyes (OD: + 1.00 sphere + 1.00 cylinder axis 110 degrees; OS: + 0.75 sphere + 0.50 cylinder axis 60 degrees)

CaseNotHPOs: NR

CaseNotHPOFreeText: no evidence of a diffuse post-infectious/inflammatory process

Genotyping Method: DNA analysis by whole exomic sequencing

PreviouslyPublished: No

Variant: NM_000350.3:c.1804C>T

ClinVar:99084

CAID:CA226932

SupplementalData:

Case#: a 12-year-old female admitted to the B Department Hédi Raies institut of Ophtalmology in Tunis, Tunisia

DiseaseAssertion: Cone rod dystrophy

FamilyInfo: No parental consanguinity nor pathological or opthalmological history in the family

CasePresentingHPOs: HP:0000529, HP:0000662, HP:0001141, HP:0000543,HP:0007737, HP:0030602

CaseHPOFreeText: progressive visual loss, poor night vision, 1/20 visual acuity in both eyes, pallor of the optic disk, attenuated retinal vessels, paravascular bone spiculed pigmentations and an epimacular membrane, paravascular and macular heterogeneous hypoautofluorescence, diffuse alteration of ellipsoid zone, decreased photopic and scotopic responses.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

Genotyping Method: Whole exome sequencing, Sanger sequencing

PreviouslyPublished: NR

Variant: c.885delC, NM_000350.3

ClinVar: 438109

CAID: CA958684

SupplementalData: Karyotyping showed monosomy 45,X in the patient

Case#: Patient 9, female, Mexican, symptoms onset 6 yrs. ago, Mexico City

DiseaseAssertion: IRD

FamilyInfo: parents are non-sanguineous and asymptomatic, they also denied any history related to ocular diseases. Information disclosed that the mother had one stillbirth and three miscarriages, but denied any related diseases/health issues to this child.

CasePresentingHPOs: HP:00305, HP:00080, HP:0000493, HP:0025586, HP:0030329, HP:0012713

CaseHPOFreeText: Proband presented with light sensitivity as well as adaptation difficulties when going from dark-to-light. Right eye was 20/200 and left eye was 20/160 from the visual acuity test. Macular bull's eye appearance. Subnormal rod and cone responses. Peripapillary sparing retina.

CaseNotHPOs: HP:0007737, HP:0000750, HP:0000510

CaseNotHPOFreeText: No afferent pupillary defect. No anomalies in anterior segment.

Genotyping Method: QIAamp DNA Blood Kit was used to extract gDNA and quantification/purity of the sample was found using a NanoDrop 2000 spectrophotometer. 293 genes were sequenced. gDNA was sequenced via Illumina technology. Following, certain sequences were additionally analyzed against a reference genome in order to identify changes and interpret.

PreviouslyPublished: n/a

Variant: NM_000350.3(ABCA4):c.4926C>G (p.Ser1642Arg), NM_000350.3(ABCA4):c.5044_5058del (p.Val1682_Val1686del)

ClinVar: 99332, 99340

CAID: n/a

SupplementalData: Phenotype data in results section as well as figures 1, 2, and 3 showing phenotypic testing results.

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

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

Case#: 10 years old

DiseaseAssertion:See Table 1

FamilyInfo: Not Mentioned

CasePresentingHPOs: Not specified

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/a

CasePreviousTesting: See Table 2

Variant: NM_000350.3(ABCA4):c.4139C>T (p.Pro1380Leu)

ClinVar: 7904 https://www.ncbi.nlm.nih.gov/clinvar/variation/7904/

CAID: CA129033

gnomAD: 0.00030430 https://gnomad.broadinstitute.org/variant/chr1-94031110-G-A?dataset=gnomad_r4

SupplementalData: Table 2

Case#: Age is not specified (Age of onset: 15 years old, with the time from onset: 8 years)

DiseaseAssertion: Presented with macular flecks and alterations in the retinal pigment epithelium (RPE) subretinal deposits.

FamilyInfo: Consanguinity within the family

CasePresentingHPOs: HP:0000608, HP:0008035 (Macular Degeneration, Retinis pigmentosa inversa)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: Visual Acuity: 20/20

CasePreviousTesting: See Table 2

Variant: NM_000350.3(ABCA4):C.4793C>A (p.Ala1598Asp)

ClinVar: 99321 https://www.ncbi.nlm.nih.gov/clinvar/variation/99321/

CAID: CA227239

gnomAD: 0.00002631 https://gnomad.broadinstitute.org/variant/1-94021695-G-T?dataset=gnomad_r3

SupplementalData: Table 2, Results Section

Case#: male, onset at or before age 12 months, ethnicity not specified DiseaseAssertion: Patient is asserted to have both "SHORT syndrome" and "X-linked agammaglobulinemia (XLA)" due to "absence of peripheral B cells" and "features of SHORT syndrome such as hyperextensibility, vision abnormalities, lack of fat tissue, triangular face, extroverted ears, ocular depression, [and] developmental and teething delay" CasePresentingHPOs: HP:0000974 (Hyperextensible skin), HP:0000504 (Abnormality of vision), HP:0005320 (Lack of facial subcutaneous fat), HP:0000325 (Triangular face), HP:0000430 (Underdeveloped nasal alae), HP:0000490 (Deeply set eye), HP:0000750 (Delayed speech and language development), HP:0002719 (Recurrent infections), HP:0030084 (Clinodactyly), HP:0045075 (Sparse eyebrow), HP:0000540 (Hypermetropia), HP:0000696 (Delayed eruption of permanent teeth) CaseHPOFreeText: A current 9 year old was diagnosed with XLA with SHORT at age 15 months after presenting with skin lesions, scrotal swelling and ulcers along with recurring upper and lower tract infections after 6 months of age. Evaluations for immunodeficiencies were performed. Basic immunoglobulin levels and lymphocyte subsets were measured, which suggested an XLA diagnosis. Delays in developmental milestones observed by the mother and physical examination suggested SHORT syndrome. CaseNotHPOs: HP:0000558 (Rieger anomaly), HP:0000364 (Hearing abnormality) GenotypingMethod: Genotyping was performed by whole exome sequencing, whivh revealed a novel pathogenic homozygous frameshift mutation in the PIK3R1 gene. PreviouslyPublished: No prior article is known to contain information on the same proband. Variant: The patient harbors NM_181523.3:c.244dup(p.(lle82Asnfs24) chr5:67522740) variant in the homozygous state. ClinVar: This variant was not found in ClinVar CAID: This variant was not found in the ClinGen Allele Registry. gnomAD:* The variant was not found in gnomAD v4.1.0.

Case#: 36 y.o male European

DiseaseAssertion: Limb Girdle

FamilyInfo: None

CasePresentingHPOs: HP:0003701,HP:0003560, HP:0006785, HP:0003236,HP:0003325, HP:0008981,

CaseHPOFreeText: Experienced two episodes of atrial fibrillation. High CADD scores. Exercise-induced myalgia and/or rhabdomyolysis

CaseNotHPOs:

CaseNotHPOFreeText:

MotorAchievement: Age 20 he developed exercise intolerance and sporadic myoglobinuria after intense exercise. Able to walk and cycle for long distances with little muscle pain.

CreatineKinase: Ranging from 1700 to 8000 UI/L), at the age of 10 years

CasePreviousTesting: Last neurological examination there was moderate calf hypertrophy.

GenotypingMethod: Muscle Biopsy using next generation sequencing and multiple gene panel. Minimal myopathic changes on histological assessment and normal immunofluorescence staining for muscle proteins including α-sarcoglycan

PreviouslyPublished:

Variant: NM_000023.4(SGCA):c.850C>T (p.Arg284Cys)

ClinVar: 9439

CAID:

gnomAD: 0.0007716