Case1: 5 week old female

DiseaseAssertion: Feeding problems and cyanosis. X-thorax showed a grossly enlarged heart

FamilyInfo: Family history of both parents was positive for HCM and sudden death

ParentalTesting: Initial echocardiography revealed no abnormalities in the 32-year-old mother, who was heterozygous for c.2373dup, nor in the 31-year-old father, heterozygous for c.2827C>T. ECG in the father showed mild repolarization abnormalities (ST elevation of 0.5 mm in V1, followed by a negative T in V1–V4). Re-evaluation after 7 years revealed moderate septal hypertrophy (HCM) with an interventricular septum of 14 mm in the mother, and interventricular septal measurements at the upper limit of the normal range (12 mm) in the father.

CasePresentingHPOs: HP:0001640, HP:0001639,

CaseHPOFreeText: Severe cardiomegaly and dilatation with a total weight of 115  g (normal weight at this age, 30  g). Right ventricular thickening was noted, especially of the posterior wall. The anterior wall of the left ventricle was severely thickened and showed abnormal trabeculation and multiple intertrabecular recesses as seen in noncompaction cardiomyopathy. Secundum ASD was confirmed. No other congenital malformations were found. Microscopic examination of cardiac tissue (Figure 1a) showed myofibrillar disarray in both the ventricular septum and the left ventricular wall. Hypertrophic myocytes with a diameter of 20–30 μm (normal 12  μm) and multiple vacuoles on electron microscopy suggested glycogenosis

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: Microscopic postmortem examination of heart muscle from patient 1. Hypertrophic myocytes with myofibrillar disarray typical of HCM due to sarcomeric protein variations were present, albeit without a significant amount of interstitial fibrosis (hematoxylin and eosin staining, magnification × 100). (b) Electron micrograph showing a large, irregular vacuole.

Variant: NC_000011.10:g.47337730dup, NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter)

ClinVar: 37039, 42619

CAID: CA013001, CA012139

gnomAD: 11-47356671-G-A, 11-47359280-A-AC

AdditionalInfo: NR

Case4: 6 week old female

DiseaseAssertion: dyspnea, hypotension, feeding difficulties, and failure to thrive

FamilyInfo: Her mother was diagnosed with postpartum HCM with diastolic dysfunction, confirmed by cardiac MRI, at age 26. Echocardiography of the father was normal; ECG showed a right bundle branch block. A paternal uncle of patient 4 had died aged 3 months of unknown cause

ParentalTesting: Both parents were heterozygous for c.2827C>T p.(Arg943*) nonsense mutation in MYBPC3

CasePresentingHPOs: HP:0001639

CaseHPOFreeText: Severe HCM with features of noncompaction, and severe diastolic and systolic left ventricular dysfunction (IVSd 11 mm, Z+10; LVPWd 10 mm, Z+10, FS 13% (LVID 17/20) and left ventricular mass 255 g/m2). A secundum ASD with a left–right shunt was also observed.

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: NR

Variant: NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter)

ClinVar: 37039

CAID: CA013001

gnomAD: 11-47356671-G-A

AdditionalInfo: NR

Case2: 4 week old male

DiseaseAssertion: Feeding problems in the first weeks of life and dyspnea and mild hypotonia were noticed at age 4 weeks.

FamilyInfo: NR

ParentalTesting: NR

CasePresentingHPOs: HP:0001640

CaseHPOFreeText: A grossly enlarged heart was observed on the X-thorax (heart–thorax ratio 0.8%) and low oxygen saturation blood levels were found. Echocardiography revealed moderately dilated ventricles with severe diastolic and systolic dysfunction. Hypertrabeculation with flow perfused intertrabecular recesses was present in both ventricles, including the apical walls (Figure 3). An apical muscular ventricular septal defect (VSD) was visualized, although deep recessal flow complicated interpretation of the images

CaseNotHPOs: NR

CaseNotHPOFreeText: NR

CasePreviousTesting: NR

Genotyping Method: NR

FunctionalAnalysis: NR

Variant: NC_000011.10:g.47337730dup, NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter)

ClinVar: 37039, 42619

CAID: CA013001, CA012139

gnomAD: 11-47356671-G-A, 11-47359280-A-AC

AdditionalInfo: NR