Familial hypertrophic cardiomyopathy (FHC) is inherited as an autosomal dominant disease with a prevalence of about 1 in 500 and is characterized by unexplained hypertrophy of the heart muscle. The hypertrophy predominantly involves the interventricular septum, although any localization within the myocardium may appear. Eventually, about 10% of the patients exhibit progressive wall thinning with dilation of the left ventricle. Typical morphological changes include myocyte hypertrophy with myocytic fiber disarray surrounding areas of increased connective tissue. Clinically, the condition ranges from an asymptomatic course to incidents of dizziness and syncopes, chest pain, and symptoms of heart failure. FHC is also a major cause of sudden cardiac death among young, otherwise healthy athletes (1
). Our understanding of the pathophysiological basis of the disease has increased dramatically during the last decade, not in the least because of genetic investigations. Disease-causing mutations have been described in 7 different genes, all encoding sarcomeric polypeptides. Therefore, FHC is assumed to be a disease of the heart sarcomere. The current hypothesis suggests that FHC is caused by impaired contractile performance of the sarcomere, leading to a compensatory hypertrophy of the heart (2
). More than 100 mutations have been reported, and missense mutations are the most prevalent type of change within the following genes encoding the polypeptides given in parentheses: MYH7
(β-myosin heavy chain), TNNI3
(troponin I), TNNT2
(troponin T), TPM1
(myosin-binding protein C), MYL2
(regulatory myosin light chain), and MYL3
(essential myosin light chain) (4
). Furthermore, a disease locus on chromosome 7 has been linked to FHC, but the gene remains to be identified (5
). Despite the numerous disease loci, it has not been possible to reveal mutations in the known disease genes in a substantial part of FHC families. In recent studies of French and Asian populations, it was possible to identify mutations in only 57% of the FHC cases (6
). These results indicate that not all FHC genes have been identified yet.
The present study reports on the investigation of a large FHC family, leading to the identification of a novel disease gene.