title: Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.
abstract: BACKGROUND
  Hypertrophic cardiomyopathy is an autosomal-dominant disorder in which 10 genes and numerous mutations have been reported. The aim of the present study was to perform a systematic screening of these genes in a large population, to evaluate the distribution of the disease genes, and to determine the best molecular strategy in clinical practice.
  
  
  RESULTS
  The entire coding sequences of 9 genes (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, TPM1, ACTC, andTNNC1) were analyzed in 197 unrelated index cases with familial or sporadic hypertrophic cardiomyopathy. Disease-causing mutations were identified in 124 index patients ( approximately 63%), and 97 different mutations, including 60 novel ones, were identified. The cardiac myosin-binding protein C (MYBPC3) and beta-myosin heavy chain (MYH7) genes accounted for 82% of families with identified mutations (42% and 40%, respectively). Distribution of the genes varied according to the prognosis (P=0.036). Moreover, a mutation was found in 15 of 25 index cases with "sporadic" hypertrophic cardiomyopathy (60%). Finally, 6 families had patients with more than one mutation, and phenotype analyses suggested a gene dose effect in these compound-heterozygous, double-heterozygous, or homozygous patients.
  
  
  CONCLUSIONS
  These results might have implications for genetic diagnosis strategy and, subsequently, for genetic counseling. First, on the basis of this experience, the screening of already known mutations is not helpful. The analysis should start by testing MYBPC3 and MYH7 and then focus on TNNI3, TNNT2, and MYL2. Second, in particularly severe phenotypes, several mutations should be searched. Finally, sporadic cases can be successfully screened.
authors.affiliation: UF de Cardiogénétique et Myogénétique, Service de Biochimie B, Hôpital de la Salpêtrière, 47 Bld de l'Hôpital, 75651 Paris Cedex 13, France. pascale.richard@psl.ap-hop-paris.fr
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.forename: Philippe
authors.initials: P
authors.lastname: Charron
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.forename: Céline
authors.initials: C
authors.lastname: Ledeuil
authors.forename: Theary
authors.initials: T
authors.lastname: Cheav
authors.forename: Claire
authors.initials: C
authors.lastname: Pichereau
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Benaiche
authors.forename: Richard
authors.initials: R
authors.lastname: Isnard
authors.forename: Olivier
authors.initials: O
authors.lastname: Dubourg
authors.forename: Marc
authors.initials: M
authors.lastname: Burban
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gueffet
authors.forename: Alain
authors.initials: A
authors.lastname: Millaire
authors.forename: Michel
authors.initials: M
authors.lastname: Desnos
authors.forename: Ketty
authors.initials: K
authors.lastname: Schwartz
authors.forename: Bernard
authors.initials: B
authors.lastname: Hainque
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
mesh_terms: D024741:Cardiomyopathy, Hypertrophic, Familial / Q000175:diagnosis* / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics; D011379:Prognosis; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D018995:Myosin Heavy Chains; D000099163:Myosin Binding Protein C