European Heart Journal Advance Access originally published online on March 15, 2005
European Heart Journal 2005 26(8):794-803; doi:10.1093/eurheartj/ehi193
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Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene
1INSERM Unité 621, IFR14, CIB Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75013 Paris, France
2Département de Génétique, Cytogénétique et Embryologie, Groupe hospitalier Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75013 Paris, France
3Département de Cardiologie, Groupe hospitalier Pitié-Salpêtrière, 47–83 Bd de l'Hôpital, 75013 Paris, France
4Cardiology Department, University Hospital, Antwerp, Belgium
5University of Ottawa Heart Institute, Ottawa, Canada
Received 13 September 2004; revised 25 January 2005; accepted 3 February 2005; online publish-ahead-of-print 15 March 2005.
* Corresponding author. Tel: +33 1 42 17 68 10; fax: +33 1 42 17 68 00. E-mail address: villard{at}chups.jussieu.fr
See page 751 for the editorial comment on this article (doi:10.1093/eurheartj/ehi208)
Aims Familial dilated cardiomyopathy (FDCM) is associated with mutations in more than 10 genes, but genes mutation frequencies and associated clinical features remain largely unknown. Here, we performed a mutation analysis of four genes involved in FDCM in a population of idiopathic DCM.
Methods and results A SSCP and sequencing mutation screening of all the exons coding for beta myosin heavy chain (MYH7 gene), cardiac T troponin (TNNT2 gene), phospholamban (PLN gene), and the cardio-specific exon of metavinculin (VCL gene) were performed in 96 independent patients (54 familial and 42 sporadic). It led to the identification of eight heterozygous mutations, seven new ones in MYH7, and the already described R141W mutation in TNNT2. MYH7 mutations (in five familial and two sporadic cases) substitute residues located either in the head (I201T, T412N, A550V) or tail domains (T1019N, R1193S, E1426K, R1634S) of the protein. DCM was not associated with skeletal myopathy or conduction defects in any patients. Contrasting clinical features were observed between MYH7 and TNNT2 mutations carriers. In MYH7 vs. TNNT2, mean age at diagnosis was late (P<0.03), penetrance was incomplete in adults (56 vs. 100%), and mean age at major cardiac event was higher (P<0.04).
Conclusion We have identified seven mutations in MYH7, one in TNNT2, and none in PLN or in the VCL cardio-specific exon. MYH7 appears as the most frequently mutated gene in our FDCM population (
10%), and mutation carriers present with delayed onset, in contrast to TNNT2.
Key Words: Genetics • Cardiomyopathy • Mutation • Troponin • Myosin
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