title: Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.
abstract: BACKGROUND
  Mutations in the gene for cardiac myosin-binding protein C account for approximately 15 percent of cases of familial hypertrophic cardiomyopathy. The spectrum of disease-causing mutations and the associated clinical features of these gene defects are unknown.
  
  
  METHODS
  DNA sequences encoding cardiac myosin-binding protein C were determined in unrelated patients with familial hypertrophic cardiomyopathy. Mutations were found in 16 probands, who had 574 family members at risk of inheriting these defects. The genotypes of these family members were determined, and the clinical status of 212 family members with mutations in the gene for cardiac myosin-binding protein C was assessed.
  
  
  RESULTS
  Twelve novel mutations were identified in probands from 16 families. Four were missense mutations; eight defects (insertions, deletions, and splice mutations) were predicted to truncate cardiac myosin-binding protein C. The clinical expression of either missense or truncation mutations was similar to that observed for other genetic causes of hypertrophic cardiomyopathy, but the age at onset of the disease differed markedly. Only 58 percent of adults under the age of 50 years who had a mutation in the cardiac myosin-binding protein C gene (68 of 117 patients) had cardiac hypertrophy; disease penetrance remained incomplete through the age of 60 years. Survival was generally better than that observed among patients with hypertrophic cardiomyopathy caused by other mutations in the genes for sarcomere proteins. Most deaths due to cardiac causes in these families occurred suddenly.
  
  
  CONCLUSIONS
  The clinical expression of mutations in the gene for cardiac myosin-binding protein C is often delayed until middle age or old age. Delayed expression of cardiac hypertrophy and a favorable clinical course may hinder recognition of the heritable nature of mutations in the cardiac myosin-binding protein C gene. Clinical screening in adult life may be warranted for members of families characterized by hypertrophic cardiomyopathy.
authors.affiliation: Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: H
authors.initials: H
authors.lastname: Niimura
authors.forename: L L
authors.initials: LL
authors.lastname: Bachinski
authors.forename: S
authors.initials: S
authors.lastname: Sangwatanaroj
authors.forename: H
authors.initials: H
authors.lastname: Watkins
authors.forename: A E
authors.initials: AE
authors.lastname: Chudley
authors.forename: W
authors.initials: W
authors.lastname: McKenna
authors.forename: A
authors.initials: A
authors.lastname: Kristinsson
authors.forename: R
authors.initials: R
authors.lastname: Roberts
authors.forename: M
authors.initials: M
authors.lastname: Sole
authors.forename: B J
authors.initials: BJ
authors.lastname: Maron
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: C E
authors.initials: CE
authors.lastname: Seidman
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000401:mortality; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009218:Myosins; D010375:Pedigree; D019683:Penetrance; D016019:Survival Analysis; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D009218:Myosins; D000099163:Myosin Binding Protein C