1. Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects
- Author
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Ingrid M.E. Frohn-Mulder, Yvonne M. Hoedemaekers, Michelle Michels, Michiel Dalinghaus, Johanna C. Herkert, Irenaeus F.M. de Coo, Arthur van den Wijngaard, Dennis Dooijes, Ronald R. de Krijger, Marja W. Wessels, MUMC+: DA KG Lab Centraal Lab (9), RS: CARIM - R2 - Cardiac function and failure, Genetica & Celbiologie, Klinische Genetica, Clinical Genetics, Pediatrics, Cell biology, Pathology, Cardiology, and Neurology
- Subjects
Heart Defects, Congenital ,Male ,Heterozygote ,Pathology ,medicine.medical_specialty ,DNA Mutational Analysis ,Cardiomyopathy ,SPLICE DONOR SITE ,Case Reports ,Gene mutation ,Biology ,Compound heterozygosity ,medicine.disease_cause ,PHENOTYPE ,Sudden death ,Article ,FAMILIAL HYPERTROPHIC CARDIOMYOPATHY ,Electrocardiography ,Fatal Outcome ,SUDDEN-DEATH ,Cardiomyopathy, Hypertrophic, Familial ,medicine ,Genetics ,Journal Article ,Humans ,Genetic Predisposition to Disease ,Genetics(clinical) ,Genetics (clinical) ,Mutation ,Heart septal defect ,Heart Septal Defects ,Homozygote ,Infant, Newborn ,Infant ,LEFT-VENTRICULAR NONCOMPACTION ,ADULTS ,medicine.disease ,PREVALENCE ,Echocardiography ,Failure to thrive ,BINDING-PROTEIN-C ,Left ventricular noncompaction ,Female ,SARCOMERE MUTATIONS ,medicine.symptom ,Carrier Proteins ,GENE-MUTATIONS - 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.2827C > T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C > T 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.
- Published
- 2015