Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

Abstract

Familial hypertrophic cardiomyopathy (HCM) is usually caused by autosomal dominant pathogenic mutations in genes encoding sarcomeric or sarcomere-associated cardiac muscle proteins. The disease mainly affects adults, although young children with severe HCM have also been reported. We describe four unrelated neonates with lethal cardiomyopathy, and performed molecular studies to identify the genetic defect. We also present a literature overview of reported patients with compound heterozygous or homozygous pathogenic MYBPC3 mutations and describe their clinical characteristics. All four children presented with feeding difficulties, failure to thrive, and dyspnea. They died from cardiac failure before age 13 weeks. Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded. All of them had septal defects. Two patients were compound heterozygotes for the pathogenic c.2373dup p. (Trp792fs) and c.2827C4T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C4T mutations. All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n = 21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life. In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy. In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients.

Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy

“…30 Mechanisms responsible for this apparent phenotypic overlap with other cardiomyopathies are incompletely understood.…”

“…Of note, in both animal models 56,57 and some of the case reports with double radical MYBPC3 mutations, [29][30][31] severe systolic dysfunction and ventricular dilatation were described as were signs of noncompaction. 30 Mechanisms responsible for this apparent phenotypic overlap with other cardiomyopathies are incompletely understood.…”

Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification

“…The remaining cardiac gene variants represent a subset associated with factors such as digenic inheritance, low penetrance, population specific variation, or potential role as disease modifiers, causing their classification to be conservative, even with significant occurrences of the variant in the control population. 16,17 Nine of the 12 (75%) Lynch syndrome variants with an ExAC frequency exceeding the MPAF were in the PMS2 gene. Analysis of variants in PMS2 is challenging owing to the presence of numerous pseudogenes with high homology that preclude unequivocal differentiation between true variants versus those originating in the pseudogenes.…”

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

“…5 In this study, a significantly poor outcome was observed in a minority of young NCCM and DCM patients, partly explained by homozygous and compound heterozygous mutations. 39 Because MYBPC3 founder mutations are truncating mutations leading to haploinsufficiency, 8 compound heterozygous or homozygous mutations would theoretically result in human MYBPC3 knockouts (no functional MYBPC3 protein), leading to severe HF at a young age. 39 The likelihood of compound heterozygotes or homozygotes in countries with founder mutations is increased.…”

“…39 Because MYBPC3 founder mutations are truncating mutations leading to haploinsufficiency, 8 compound heterozygous or homozygous mutations would theoretically result in human MYBPC3 knockouts (no functional MYBPC3 protein), leading to severe HF at a young age. 39 The likelihood of compound heterozygotes or homozygotes in countries with founder mutations is increased. 5 The finding of NCCM and DCM in the FG+ population and within 1 family supports previous suggestions that the various cardiomyopathies are part of a cardiomyopathy spectrum with similar pathogenesis.…”