title: 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.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.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Marja W
authors.initials: MW
authors.lastname: Wessels
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Herkert
authors.affiliation: Department of Pediatric Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Frohn-Mulder
authors.affiliation: Department of Pediatric Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Dalinghaus
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Arthur
authors.initials: A
authors.lastname: van den Wijngaard
authors.affiliation: Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.affiliation: Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Michelle
authors.initials: M
authors.lastname: Michels
authors.affiliation: Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Irenaeus Fm
authors.initials: IF
authors.lastname: de Coo
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Hoedemaekers
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Dooijes
mesh_terms: D024741:Cardiomyopathy, Hypertrophic, Familial / Q000175:diagnosis / Q000235:genetics*; D002352:Carrier Proteins; D004252:DNA Mutational Analysis; D004452:Echocardiography; D004562:Electrocardiography; D017809:Fatal Outcome; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics; D006343:Heart Septal Defects / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C