Case#: 7-year-old boy

DiseaseAssertion: Atrial flutter (AFL), sick sinus syndrome (SSS), Brugada syndrome (BrS)

FamilyInfo: Family history of sudden death in maternal grandfather at age 30 years. Family testing identified the same SCN5A variant in the proband's mother and sister. The mother was asymptomatic but had a coved type ST elevation in V1 lead recorded at the 3rd intercostal position (Fig. 1e) and remained free of cardiac events until age 37 years. His sister's ECG was normal, and she remained free of cardiac events for 10 months

ParentalTesting: Mother was found to have the same LOF variant

CasePresentingHPOs: HP:0004749, HP:0011712, HP:0011704, HP:0011654

CaseHPOFreeText: AFL detected on ECG with right bundle branch block but no history of arrhythmia, congenital heart disease, or cardiomyopathy. Post-RFCA, patient had sinus arrest lasting up to 7s, leading to diagnosis of sick sinus syndrome (SSS). Post-ablation ECG following a second RFCA revealed Brugada-type patterns, raising suspicion of Brugada syndrome (BrS) which eventually lead to a diagnosis.

CaseNotHPOs: HP:0001638, HP:0001279, HP:0011675

CaseNotHPOFreeText: Cardiomyopathy, syncope, arrhythmia

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: NR

Variant: c.2678G > A p.Arg893His

ClinVar: 67749

CAID: CA016396

gnomAD: https://gnomad.broadinstitute.org/variant/3-38585800-C-T?dataset=gnomad_r4 (v4.1.0 GrpMax FAF: 0.000003390 (European non-Finnish) )

Case#: 55-year-old man

DiseaseAssertion: single coronary artery (SCA) and presented with dilated cardiomyopathy (DCM)

FamilyInfo: Unremarkable

ParentalTesting: NR

CasePresentingHPOs: HP:0002094, HP:0031352, HP:0001638, HP:0001644, HP:0010741

CaseHPOFreeText: chest tightness and dyspnoea after activity lasting for 2 months. CTCA showed congenital absence of the right coronary artery. TTE revealed enlargement of the left heart and cardiomyopathy. CMR revealed DCM. oedema of both lower limbs. Laboratory data in Table 1.

CaseNotHPOs: NR

CaseNotHPOFreeText: Stenosis

CasePreviousTesting: See NGS results in Supplementary Table 1

Genotyping Method: Genetic screening (NGS results in Supplementary Table 1) with confirmation by Sanger

FunctionalAnalysis: NR

Variant: c.1858C>T (p.Arg620Cys)

ClinVar: 67694

CAID: CA015449

gnomAD: v4.1.0 GrpMax FAF: 0.00002033 (European non-Finnish)

AdditionalInfo: The patient also has APOA5:c.990_993delAACA (p. Asp332Valfs*5) (P/LP in ClinVar with 2 stars)