title: Autosomal recessive transmission of MYBPC3 mutation results in malignant phenotype of hypertrophic cardiomyopathy.
abstract: BACKGROUND
  Hypertrophic cardiomyopathy (HCM) due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved.
  
  
  METHODS
  A pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls.
  
  
  RESULTS
  A novel missense mutation (c.1469G>T, p.Gly490Val) in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM.
  
  
  CONCLUSIONS
  Our data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.
authors.affiliation: Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yilu
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.forename: Yubao
authors.initials: Y
authors.lastname: Zou
authors.forename: Hongju
authors.initials: H
authors.lastname: Zhang
authors.forename: Chaowu
authors.initials: C
authors.lastname: Yan
authors.forename: Xinxing
authors.initials: X
authors.lastname: Feng
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jizheng
authors.initials: J
authors.lastname: Wang
authors.forename: Xianliang
authors.initials: X
authors.lastname: Zhou
authors.forename: Ferhaan
authors.initials: F
authors.lastname: Ahmad
authors.forename: Rutai
authors.initials: R
authors.lastname: Hui
authors.forename: Lei
authors.initials: L
authors.lastname: Song
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014463:Ultrasonography; D055815:Young Adult; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C