** PMID** : 35004917

** Gene** :MYH7

** HGNC ID** : HGNC:7577

Case#: Pedigree I-1; 74-year-old Korean male; admitted for dyspnea (NYHA III), palpitations, and bilateral pitting leg edema over several months

DiseaseAssertion: Idiopathic restrictive cardiomyopathy (RCM) with biatrial enlargement, in a family with MYBPC3-related cardiomyopathy

FamilyInfo: Family history of heart disease with two affected daughters (II-2 and II-4), both heterozygous for the same variant and both diagnosed with HCM. Unaffected granddaughter (III-3) tested negative. Both daughters showed asymmetric septal hypertrophy on TTE (18 mm and 17 mm) with mildly dilated LA; daughter II-2 had grade I diastolic dysfunction and mild exertional chest discomfort. CMR confirmed reverse septal curvature hypertrophy consistent with HCM in both daughters, with no LGE in either.⁠

ParentalTesting: Not performed; the proband is the index case in generation I; his parents were not evaluated. Phase established only through the daughters and granddaughter.

CasePresentingHPOs:HP:0002094; HP:0001962; HP:0001677; HP:0001635; HP:0001639; HP:0001698

CaseHPOFreeText: Exertional dyspnea NYHA class III, palpitations, and bilateral leg pitting edema for several months; dyspnea refractory to heart failure medication, with pulmonary venous congestion. ECG and Holter: atrial fibrillation with rare premature ventricular complexes. TTE: RCM with biatrial enlargement and small pericardial effusion. CMR: normal LV chamber size, borderline diffuse LV hypertrophy, very large atria, extensive transmural LGE in the apical wall and mid-myocardial patchy LGE in the ventricular septum. Coronary angiogram normal; no secondary cause of RCM found.⁠

CaseNotHPOs: HP:0000822; HP:0000819; HP:0001658; HP:0001678

CaseNotHPOFreeText: Coronary angiogram normal, so no obstructive coronary disease. No secondary cause of RCM identified; no inflammatory, infiltrative, or systemic disease found. No AV block; the rhythm disturbance was atrial fibrillation.

CasePreviousTesting: Whole exome sequencing (Agilent SureSelect XT Human All Exon v5, Illumina HiSeq2500, GATK. Sanger sequencing of family members showed only the MYBPC3 variant tracked with disease; the other four (KALRN c.1702C>T, KCNH2 c.442C>T, SKI c.30T>G, TTN c.54293T>C) did not correlate with phenotype.⁠

Genotyping Method: WES in the proband, with annotation via dbNSFP and Ensembl VEP; Sanger sequencing confirmed the MYBPC3 frameshift in the proband (I-1), daughters II-2 and II-4, and its absence in granddaughter III-3 (Fig. 3B).⁠

FunctionalAnalysis: None performed. CMR showed extensive LGE in the apical LV, and the authors propose that advanced myocardial fibrosis in end-stage HCM can provoke myocardial atrophy, explaining the relatively normal LV chamber size with a predominantly restrictive phenotype hypothesis.⁠

Variant: MYBPC3 NM_000256.3:c.3313_3314insGG (p.Ala1105Glyfs*85); heterozygous frameshift insertion; absent from gnomAD and the Korean Reference Genome Database.

ClinVar: 1473634

CAID: Not reported.

Gene:MYBPC3

HGNC: HGNC: 7551

PMID: 33803538

gnomAD: Absent per the authors' check of gnomAD as of 8 November 2020, and absent from KRGDB.

AdditionalInfo: Authors conclude the MYBPC3 frameshift is the pathogenic variant, with the same allele producing RCM in the proband and HCM in both daughters; an example of pleiotropy and variable expressivity within one family. The frameshift has previously been reported in Korean HCM. Poor-prognosis features in RCM cited by the authors: male sex, age over 70, high NYHA class, and LA dimension >60 mm.

Case#: 33 year-old female; first cardiologic evaluation at age 24 (LV wall thickness 13 mm); re-evaluated at 33 after recurrent palpitations

DiseaseAssertion: Noonan syndrome (PTPN11) with sarcomeric hypertrophic cardiomyopathy (MYBPC3); non-obstructive HCM, mild phenotype

FamilyInfo: Father carries the MYBPC3 c.1790G>A variant and has HCM; the PTPN11 variant was absent in both parents, consistent with de novo. Both parents and the proband's brothers underwent full cardiologic evaluation, no cardiovascular disease in the other family members. Parents declined genetic testing of the underage siblings. Grandparents (I-1, I-2) and II-2, II-3 have unknown phenotypes (pedigree Fig. 2).

ParentalTesting: Both parents genotyped for the two proband variants (Table 1). Father heterozygous for MYBPC3 c.1790G>A; neither parent carries PTPN11 c.1510A>G, supporting de novo status. Phase between the two variants therefore established as in trans (different genes).

CasePresentingHPOs: HP:0001639; HP:0001962; HP:0004322; HP:0000271; HP:0001647; HP:0000508

CaseHPOFreeText: Regular psychophysical development. First echo at 24 showed mild increase in LV wall thickness (13 mm). At 33, presented with several episodes of palpitations; exam showed mild facial dysmorphisms (wide mouth, sloping forehead, prominent nasal bridge, prominent nose, low-set ears), short stature, and a systolic heart murmur. Echo: asymmetric LV hypertrophy, maximum wall thickness 16 mm at the anterior interventricular septum, mild mitral regurgitation, non-obstructive. No other cardiovascular signs.

CaseNotHPOs: HP:0001635; HP:0001650; HP:0001642; HP:0001250

CaseNotHPOFreeText: No heart failure, no LV outflow obstruction, no pulmonary stenosis, no other congenital heart defect. No intellectual disability; psychophysical development was regular. No other signs of cardiovascular disease on examination.

CasePreviousTesting: NGS panel of 325 cardiomyopathy-associated genes (Supplementary Table S1); MAF threshold 5%; variants validated by Sanger sequencing; cascade testing restricted to the two proband variants.

Genotyping Method: NGS targeted panel (Maxwell 16 DNA extraction, Agilent Alyssa analysis, Illumina Variant Interpreter, in-house pipeline) with Sanger validation; parental Sanger genotyping for the same two variants.

FunctionalAnalysis: None performed by the authors. They cite prior HeLa cell work showing the MYBPC3 c.1790G>A change causes exon 18 inclusion in the transcript and an almost undetectable 248 bp product.

Variant 1: PTPN11 NM_002834.3:c.1510A>G (p.Met504Val); heterozygous missense; de novo; classified pathogenic, explains Noonan syndrome

ClinVar: Not stated in the paper; verify the current record before submitting.

CAID: N/A

gnomAD: Not reported in the paper; I have not checked gnomAD for this variant.

Variant 2: MYBPC3 NM_000256.3:c.1790G>A (p.Arg597Gln); heterozygous missense; exon 18, last nucleotide of the exon, affecting a highly conserved residue and causing a splicing variation; inherited from the father

ClinVar: Not stated in the paper; authors note it is classified pathogenic/likely pathogenic for HCM in several genetic databases.

CAID: N/A

gnomAD: N/A

PMID: 32824488

Gene: MYBPC3

AdditionalInfo: Authors describe this as the first reported young adult with HCM and mild NS carrying variants in both PTPN11 and MYBPC3. Note the terminology problem: the abstract calls them "compound heterozygous," but the variants are in different genes on different chromosomes, so this is digenic (double heterozygosity), not compound heterozygosity. The authors argue the mild phenotype contrasts with the usual expectation that multiple sarcomeric hits worsen the disease, and that red flags justified the broad panel.

PMID: 41726140

Gene: MYBPC3

HGNC ID: 7551

Case#: Pedigree III:2; male; HCM diagnosed clinically at age 39 (1998); heart transplant after progression to end-stage heart failure

DiseaseAssertion: Hypertrophic cardiomyopathy (HCM), progressed to end-stage heart failure with systolic dysfunction

FamilyInfo: No family history of heart disease reported at diagnosis; no known consanguinity. Parents deceased and unavailable for testing. 12 relatives genotyped: one brother (III:3) homozygous, seven first- and second-degree relatives heterozygous. All heterozygotes have normal ECG, normal echo, and no cardiac symptoms. Three children of generation IV (IV:7, IV:8, IV:9) still awaiting results.⁠

ParentalTesting: Not performed; both parents deceased. Absence of consanguinity stated but not genetically confirmed; parental phase therefore inferred rather than tested.

CasePresentingHPOs: HP:0001639; HP:0002094 (Dyspnea); HP:0001658; HP:0001678

CaseHPOFreeText: Exertional dyspnea at age 39 with systolic murmur; IVS 26 mm, posterior wall >16 mm, LVOT peak velocity 2.8 m/s. Pacemaker 1999, extracted 2010 for infection. 2013 circumflex occlusion treated with stent (cholesterol 6.8 mmol/L, LDL 4.6 mmol/L; former smoker). Septum 27 mm, moderate systolic dysfunction, NSVT on Holter → ICD. 2014 AF with severe dyspnea; on beta-blocker, ACE inhibitor, and aldosterone antagonist. 2016 VO₂max 14 mL/kg/min; LVEDP 24 mmHg rising to 38 with exercise, pulmonary pressure 56/27 rising to 70/… systolic. Biopsy: moderate interstitial fibrosis, focal hypertrophy and atrophy, no infiltrative disease.

CaseNotHPOs: HP:0000822; HP:0000819

CaseNotHPOFreeText: BP normal throughout, no hypertension. No storage or infiltrative disease on biopsy. Spirometry normal. Narrow QRS, so CRT not indicated.

CasePreviousTesting: 84-gene cardiomyopathy NGS panel (MYBPC3 100% coverage); MLPA confirmed true homozygosity rather than hemizygous deletion; Sanger cascade in 12 relatives.

Genotyping Method: NGS panel followed by MLPA confirmation of homozygosity; Sanger for family cascade.

FunctionalAnalysis: None performed. Biopsy showed interstitial fibrosis with hypertrophy and atrophy, no infiltrative disease. Dominant-negative mechanism proposed, untested.

Variant: MYBPC3 NM_000256.3:c.2618C>A (p.Pro873His); homozygous missense; C7 domain. (Paper writes "c.2618 G>A" once, C>A is correct.)

ClinVar: Not stated; conflicting interpretations noted in the literature. Pepper please verifiy for me!

CAID: N/A

gnomAD: AF 0.00006781 (14/206,446; 13/97,288 European non-Finnish) per the authors.

AdditionalInfo: ACMG Class 2 (likely pathogenic) heterozygous. Authors argue homozygosity drove progression to end-stage failure; alternative triggers considered, prior myocarditis (1989) and the 2013 infarct; but judged insufficient to explain severity.

PMID: 29663722 Gene: MYBPC3 HGNC: HGNC:7551

PMID: 35029218

Gene: TPM1

HGNC ID: 12010

PMID: 30923642

Gene: TPM1

HGNC ID: 12010

PMID: 37122207

Gene: TNNT2

HGNC ID: 11949

Case#: 4 month old boy

DiseaseAssertion: Polymorphic ventricular tachycardia

FamilyInfo: His father carried the RYR2 variant and had ventricular premature beats. His mother carried the SCN10A variant and was asymptomatic.

ParentalTesting: Yes. Familial genetic testing showed the RYR2-A1855D variant was inherited from the father and the SCN10A-Q1362H variant was inherited from the mother.

CasePresentingHPOs: HP:0004756

CaseHPOFreeText: 4-month-old male presenting with polymorphic ventricular tachycardia.

CaseNotHPOs: not reported

CaseNotHPOFreeText: not reported

CasePreviousTesting: Clinical cardiac evaluation followed by genetic testing

Genotyping Method: Genetic testing identified novel heterozygous RYR2-A1855D and SCN10A-Q1362H variants.

FunctionalAnalysis: Functional studies showed abnormal calcium handling, prolonged action potentials, increased susceptibility to early afterdepolarizations, and disrupted Ca2+ homeostasis in cells carrying both variants.

Variant: RYR2 (heterozygous) SCN10A

ClinVar: not found

CAID: not found

gnomAD: not found

AdditionalInfo:

PMID: 28265379

Gene: MYBPC3

HGNC ID: 7551

PMID: 35004917

Gene: TPM1

HGNC ID: 12010

PMID: 36613463

Gene: TPM1

HGNC ID: 12010

PMID: 31179125

Gene: TPM1

HGNC ID: 12010

Article not publicly available through PubMed.

PMID: 30511553

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: 2 (16 y, male - brother of Case 1, symptom onset/pain+movement limitation 8 y, diagnosis 16y)

DiseaseAssertion: Scheie syndrome

FamilyInfo: Male patient born to consanguineous parents

CasePresentingHPOs: 0034337

CaseHPOFreeText: claw hands with flexion contractures; electroneurology showed bilateral signs of mild median nerve suffering.

CaseNotHPOs: HP:0000280; HP:0001510; HP:0000943

CaseNotHPOFreeText: no coarse face, growth failure, other joint involvement, evidence of dysostosis multiplex of other bones. Normal intelligence, ophthalmologic, hearing and echocardiography, brain MRI

CaseEnzymeAssay: 0.64 (umol/g/h)

CaseUrineGAGs:

CaseERT: Yes, after diagnosis at 16y CaseBMT:

Variant1:c.1189+4A>T

Variant1ClinVarID:

Variant1CAID: CA2586965965

Variant2: 1189+4A>T

Variant2ClinVarID:

Variant2CAID: CA2586965965

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

Case#: 3 (19 y, male - cousin of Cases 1 and 2, symptom onset/pain+movement limittion 12y, diagnosis 19y))

DiseaseAssertion: Scheie syndrome

FamilyInfo: Male patient born to consanguineous parents

CasePresentingHPOs:

CaseHPOFreeText: electroneurology showed bilateral signs of mild median nerve suffering.

CaseNotHPOs: 0034337;HP:0001510; HP:0000943

CaseNotHPOFreeText: no coarse face, growth failure, other joint involvement, evidence of dysostosis multiplex of other bones. Normal intelligence, ophthalmologic, hearing and echocardiography, brain MRI

CaseEnzymeAssay: 0.57 (umol/g/h)

CaseUrineGAGs:

CaseERT: Yes, after diagnosis at 19y

CaseBMT:

Variant1:c.1189+4A>T

Variant1ClinVarID:

Variant1CAID: CA2586965965

Variant2: 1189+4A>T

Variant2ClinVarID:

Variant2CAID: CA2586965965

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

Case#: 1 (18 y, female, symptom onset/pain+movement limitation 10y, carpal tunnel syndrome surgery 16y, diagnosis 18y)

DiseaseAssertion: Scheie syndrome

FamilyInfo: "female patient, brother, and male cousin born to consanguineous parents" Based on pedigree (Figure 4), the cousins are related through their mothers but the degree of consanguinity is not clear

CasePresentingHPOs: 0034337

CaseHPOFreeText: claw hands with flexion contractures; electroneurology showed bilateral signs of severe median nerve suffering.

CaseNotHPOs: HP:0000280; HP:0001510; HP:0000943

CaseNotHPOFreeText: no coarse face, growth failure, other joint involvement, evidence of dysostosis multiplex of other bones. Normal intelligence, ophthalmologic, hearing and echocardiography, brain MRI

CaseEnzymeAssay: 0.36 (umol/g/h)

CaseUrineGAGs:

CaseERT: Yes, after diagnosis at 18y

CaseBMT:

Variant1:c.521delA

Variant1ClinVarID:

Variant1CAID: CA2586973518

Variant2: 521delA

Variant2ClinVarID:

Variant2CAID: CA2586973518

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

PMID: 24053568

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID:35614200

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

A list of 11 IDUA variants identified in cases with MPS is included in Supplemental Table 6, but the variants are not linked to specific patients and are listed individually (not as genotypes). A page note has been added for each variant.

PMID: 21410641

Gene: VWF

HGNCID: 12726

PMID: 41550885 Gene: MYBPC3 HGNC: 7551

PMID: 28790153

Gene: MYH7

HGNC:7577

PMID: 30084953

Gene: GDAP2

HGNCID: HGNC:18010

Case#: Family MI, Northern European

CasePresentingHPOs: HP:0001639

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: PCR amplification followed by Cycle Sequencing

Variant: The nucleotide variant positions here refer to those described in the initial cloning of the gene in 1988 (PMID: 3336363), but nucleotide G579A here aligns to NM_001018005.2(TPM1):c.523G>A (p.Asp175Asn).

ClinVar: 12456

CAID: CA018106

gnomAD: Grpmax FAF = 7.900e-7, SNV: 15-63060899-G-A, gnomADv4_D175N

VariantEvidence:

CaseAddInfo:

CasePMIDs: PMID:8327508

Case#: Family MZ, Northern European

CasePresentingHPOs: HP:0001639 ( Hypertrophic cardiomyopathy)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting:

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: PCR amplification followed by Cycle Sequencing

Variant: The nucleotide variant positions here refer to those described in the initial cloning of the gene in 1988 (PMID: 3336363), but nucleotide A595G here aligns to NM_001018005.2(TPM1):c.539A>G (p.Glu180Gly).

ClinVar: 12455

CAID: CA019017

gnomAD: 15-63060915-A-G not in gnomAD v4.0.0

VariantEvidence:

CaseAddInfo:

CasePMIDs: PMID:8327508

PMID: 21167740

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: Male, first evaluated at 3.5 years, diagnostic studies described in paper at age 4.5 years, at time of report 11 years

DiseaseAssertion: Mucopolysaccharidosis Type I and Type II

FamilyInfo:Clinically normal sister, mother and father; parents denied consanguinity; extensive histocompatibility typing of all family members confirmed relationships and did not suggest consanguinity; Maternal uncle died at 11 years having "coarse facial features" but not diagnostic testing. Pedigree, Figure 7, page 82.

CasePresentingHPOs: HP:0000943 (dysostosis multiplex); HP:0000280 (course facial features)

CaseHPOFreeText: at 3.5 years "...gross motor delay, mild expressive language delay, and progressive changes in facial features and joints...noted to be a noisy breather and have a history of frequent ear infections...prominent metopic suture and facial features were said to be coarsened" Height 50th%, weight 95th%, head circumference >98th%. At 11 years of age reported to show progressive intellectual deterioration.

CaseNotHPOs:

CaseEnzymeAssay: Table 2 (page 79): leukocyte IDUA (alpha-L) activity absent (<1.0 nmol/mg/h), plasma IDUA alpha-L <0.20 MU/ml/h); plasma IDS activity was undetectable (0.0 U/mg/h)

CaseUrineAssay:Not reported

CaseERT:Don't know

CaseBMT:Don't know

Variant1:IDUA W402X

Variant1ClinVarID:11908

Variant1CAID:

Variant2: IDUA A300T

Variant2ClinVarID: 11923

Variant2CAID:

AdditionalVariants: IDS R468W (missense 1402C-->T), ClinVarID: 10497

ParentalGenoype:Mother, IDUA A300T and IDS R468W; Father, IDUA W402X

PreviouslyPublished:

PMID:20553232

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

PMID: 40123275

Gene: VWF

HGNCID: 12726

PMID: 32437512

Gene: GDAP2

HGNCID: HGNC:18010

Free, full-text NOT available. Text obtained through a University account and annotations added to the free PubMed abstract.

IDUA variants were pulled from various public databases and subjected to in silico analyses. No individual-level patient data (e.g., phenotypes) are provided.

PMID: 16085695

GeneName: ELN

HGNC: HGNC:3327

This paper is not publicly available. It was obtained via an institutional account and the relevant details annotated to the PubMed abstract.

PMID: 29393969

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Free, full-text NOT available. Full text was retrieved via a university account, and the free PubMed abstract was annotated.

This paper describes a meta-analysis of previously published data for 11 patients. PMID's for prior published reports:

25864295, 21482163, 22303797, 21167740, 19894140, 18792977, 18546328, 16601901

The above PMID's are all included in the IDUA Excel file.

Three cited manuscripts do not have a PMID and are not included in the IDUA Excel file. Links to these papers are provided below:

https://doi.org/10.1016/j.farma.2010.11.005 (in Spanish)

https://doi.org/10.1007/s10545-005-0211-x

https://doi.org/10.1016/j.jfma.2014.05.009

PMID: 32428220

Gene: GDAP2

HGNCID: HGNC:18010

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#: 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

PMID:23341817

Gene: ABCA4

HGNC ID: 34

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

PMID: 33899203

Gene: ABCA4

HGNC ID: 34

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.

PMID: 22863181

Gene: ABCA4

HGNC ID: 34

PMID: 33633436 Gene:ABCA4 HGNC:34

PMID: 38694055 Gene: ABCA4

PMID: 37510299 Gene: ABCA4 CAID: CA119132

PMID: 35243166

Gene: ABCA4

HGNC: 34

PMID: 10634626 Gene: ABCA4 HGNCID: HGNC:34

Fifty-two unrelated French patients referred to the Eye University Clinic of Creteil for unilateral or bilateral exudative AMD due to any type of choroidal neovascularization (well-defined, occult, or vascularized pigment epithelium detachment) were included in this study.

SSCP analysis in a control population, obtained from 90 unrelated French individuals without any complaint of visual impairment. Our control group was not age- or sex-matched, and no ophthalmological examination was performed for these individuals.

MonDO:

Case: DiseaseAssertion: Age-related macular degeneration FamilyInfo: CasePresentingHPOs: CaseHPOFreeText: CaseNOTHPOs: CaseNOTHPOFreeText: CasePreviousTesting:

GenotypingMethod: entire coding sequence of the ABCR gene using a combination of single-strand conformation polymorphism (SSCP) and direct sequence analysis of each exon

Variant: "ABCR" (ABCA4), p.Ser2255ile

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.

PMID: 18334942

Gene: ABCA4

HGNC ID: 34

Case#: patient 33, male, Spanish

DiseaseAssertion: STGD

FamilyInfo: Figure 1. Both parents and two siblings of the proband were heterozygous for ABCA4 c.5413A>G allele. Sister affected despite heterozygosity.

CasePresentingHPOs: HP:0007663, HP:0030786, HP:0007722

CaseHPOFreeText: myopia, astigmatism, opafication of posterior pole of lens, hyperpigmentation, a few central yellowish flecks, shallow peripheral scotomas in both eyes, full-field ERG response showed slightly reduced—but still within the normal range—amplitudes for rod, mixed cone-rod, cone single flash, and cone flicker, respectively.

CasePreviousTesting: n/a

GenotypingMethod: microarray

PreviouslyPublished: 11385708, 12442277

Variant: ABCA4 p.Asn1805Asp (c.5413A>G)

ClinVar: 99373 https://www.ncbi.nlm.nih.gov/clinvar/variation/99373/?term=%22ABCA4%22%5BGENE%5D+AND+%22p.Asn1805Asp%22%5BVARNAME%5D+AND+%22(c.5413A%3EG)%22%5BVARNAME%5D

gnomAD: 0.000009292 https://gnomad.broadinstitute.org/variant/1-94014590-T-C?dataset=gnomad_r4

PMID: 18334942

Gene: ABCA4

HGNCID: 34

Case#: patient 26, female, Spanish

DiseaseAssertion: early onset RP

FamilyInfo: Figure 1. One brother homozygous for ABCA4 c.5413A.G allele, parents and one brother heterozygous for ABCA4 c.5413A>G allele. All three brothers and father carriers of p.Cys948Tyr allele on the CRB1 gene. Mother heterozygous for p. Trp822ter (c.2465G>A)

CasePresentingHPOs: HP:0000662, HP:0001133, HP:0007663,

CaseHPOFreeText: hyperopia, astigmatism, nystagmus, roundish pigments distributed across entire retina including peripheral retina, posterior pole, and macular region, filiform constriction on retinal vessels.

CasePreviousTesting: N/A

GenotypingMethod: Microarray

PreviouslyPublished: 11385708, 12442277

Variant: ABCA4 p.Asn1805Asp (c.5413A>G)

ClinVar: 99373 https://www.ncbi.nlm.nih.gov/clinvar/variation/99373/?term=%22ABCA4%22%5BGENE%5D+AND+%22p.Asn1805Asp%22%5BVARNAME%5D+AND+%22(c.5413A%3EG)%22%5BVARNAME%5D

gnomAD: 0.000009292 https://gnomad.broadinstitute.org/variant/1-94014590-T-C?dataset=gnomad_r4

Patient 71674: Female, Swiss, 13 years old. bi-allelic variants in ABCA4, diagnosed with Retinal dystrophy DD: Retinitis pigmentosa

Figure 3: Segregation analysis performed on family samples GenotypingMethod: Whole exome sequencing performed on HiSeq2000 and NextSeq500 (252 genes)

Multiple Variants: VPS13B NM_017890.4:c.897 8A>G:p.Asn2993Ser Heterozygous CM041280

PCDH15 NM_001142763.1:c. 4329_4337del:p.Pro 1446_Pro1448del Heterozygous

DHX38 NM_014003.3:c.366 2C>T:p.Thr1221Met Heterozygous

USH1G NM_173477.4:c.310 A>G:p.Met104Val Heterozygous

PMID: 36833411

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)

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

PMID: 10874631

Gene: ABCA4

HGNC ID: 34

Case#: patient 34, female

DiseaseAssertion: RP19

FamilyInfo: paternal first cousin with STGD, healthy father heterozygous for 1938-1 G>A splice mutation, mother homozygous for normal allele

CasePresentingHPOs: HP:0000662, HP:0007663, HP:0007737, HP:0001133

CaseHPOFreeText: choriocapillaris atrophy, severe concentric reduction of the visual field, abrogation of rod function

Genotyping Method: PRISMTM Ready Reaction Sequencing Kit on an automatic fluorometric DNA sequencer

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.1938-1G>A

ClinVar: 99106 https://www.ncbi.nlm.nih.gov/clinvar/variation/99106/?term=%22ABCA4%22%5BGENE%5D+AND+%22(c.1938-1G%3EA)%22%5BVARNAME%5D

gnomAD: 0.000002488 https://gnomad.broadinstitute.org/variant/1-94060760-C-T?dataset=gnomad_r4

PMID: 10874631

Gene: ABCA4

HGNC ID: 34

Case#: patient 34, female

DiseaseAssertion: STGD

FamilyInfo: paternal first cousin with RP19, healthy father heterozygous for 1938-1 G>A splice mutation

CasePresentingHPOs: HP:0007663, HP:0000608, HP:0000603,

CaseHPOFreeText: yellowish flecks

Genotyping Method: PRISMTM Ready Reaction Sequencing Kit on an automatic fluorometric DNA sequencer

PreviouslyPublished: N/A

Variant: NM_000350.3(ABCA4):c.1938-1G>A

ClinVar: 99106 https://www.ncbi.nlm.nih.gov/clinvar/variation/99106/?term=%22ABCA4%22%5BGENE%5D+AND+%22(c.1938-1G%3EA)%22%5BVARNAME%5D

gnomAD: 0.000002488 https://gnomad.broadinstitute.org/variant/1-94060760-C-T?dataset=gnomad_r4

PMID: 22661473

Gene: ABCA4

HGNCID: HGNC:34

Stage I disease was characterized by central macular atrophy with parafoveal or perifoveal flecks. Where flecks were more numerous and extended anterior to the vascular arcades and/or nasal to the optic disc, then patients were classified as having stage II disease. Although partial resorption of flecks may be present in this stage, more complete resorption of flecks was indicative of stage III disease with choriocapillaris atrophy also within the macula. Widespread RPE and chorioretinal atrophy throughout the fundus defined stage IV disease.27 Based on this classification system, the patients in our study were subdivided into 2 groups, that is those with milder disease (stage I or II) and those with more severe disease (stage III or IV) phenotypes.

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: 25922843 Gene: ABCA4 HGNCID: HGNC:34

PMID: 34008801

Gene: ABCA4

HGNC ID: 34

PMID: 28726568

Gene: ABCA4

HGNC ID: 34

PMID: 35112029

Gene: ABCA4

HGNCID: HGNC:34

PMID: 26527198

Gene: ABCA4

HGNCID: HGNC:34

PMID: 40401218

Gene: ABCA4

HGNC ID: 34

PMID:328843395

Gene: ABCA4

HGNC ID: 34

PMID: 31819343

Gene: ABCA4

HGNC ID: 34

PMID: 40465261

Gene: ABCA4

HGNC ID: 34

PMID: 34679498

Gene: ABCA4

HGNC ID: 34

PMID:18854780

Gene: ABCA4

HGNC ID: 78

Disease: Stargardt

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