title: Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome.
abstract: BACKGROUND
  Small selected cohort studies suggest that mutations in the cardiac myosin binding protein-C (MYBPC3) gene cause late-onset, clinically benign hypertrophic cardiomyopathy (HCM). The aim of this study was to test this hypothesis in a large series of families with HCM associated with MYBPC3 mutations.
  
  
  RESULTS
  The initial study population comprised 57 probands with 42 mutations (26 [61.9%] novel) in MYBPC3. Missense mutations (15, 45.6%) were the most frequent, and multiple mutations occurred in 4 (7.0%) probands. Another 110 mutation carriers were identified during familial evaluation; 38 were clinically affected with left ventricular hypertrophy ≥13 mm. Disease penetrance was, therefore, incomplete (56.9% in all mutation carriers, 34.5% in relatives), related to age (38.4% <40 versus 68.6% ≥40 years, P<0.001), and was greater in males than females (65.1% versus 48.1%, P=0.03). In 9 families (25 individuals) with the R502W mutation, there was marked heterogeneity in age at diagnosis (5 to 80 years), pattern of hypertrophy (11 none, 9 asymmetrical, 3 concentric, 1 apical, 1 eccentric), and prognosis (premature sudden death in 2 individuals compared with survival to advanced age in 6 individuals). During follow up of 7.9+/-4.5 years, in 82 clinically affected individuals the annual risk of sudden death and all cause mortality was 0.46% and 0.93% per year, respectively.
  
  
  CONCLUSIONS
  Disease expression in families with HCM related to MYBPC3 mutations shows marked heterogeneity with incomplete, age-related, and gender specific penetrance. Importantly, complex genetic status is observed and should be considered when mutation analysis and cascade screening is used in the evaluation of at risk family members.
authors.affiliation: Inherited Cardiovascular Disease Unit, The Heart Hospital, London, United Kingdom.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Page
authors.forename: Stavros
authors.initials: S
authors.lastname: Kounas
authors.forename: Petros
authors.initials: P
authors.lastname: Syrris
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.forename: Rune
authors.initials: R
authors.lastname: Frank-Hansen
authors.forename: Paal Skytt
authors.initials: PS
authors.lastname: Andersen
authors.forename: Perry M
authors.initials: PM
authors.lastname: Elliott
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D019683:Penetrance; D012737:Sex Factors; D055815:Young Adult; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C