Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy

Objectives We studied the clinical and genetic features of hypertrophic car diomyopathy (HCM) caused by mutations in the myosin-binding protein C gene (MYBPC3) in 110 consecutive, unrelated patients and family members of Europ ean descent. Background Mutations in the MYBPC3 gene represent the cause of HCM in simil ar to 15% of familial cases. MYBPC3 mutations were reported to include main ly nonsense versus missense mutations and to be characterized by a delayed onset and benign clinical course of the disease in Japanese and French fami lies. We investigated the features that characterize MYBPC3 variants in a l arge, unrelated cohort of consecutive patients. Methods The MYBPC3 gene was screened by single-strand conformational polymo rphism analysis and sequencing. The clinical phenotypes were analyzed using rest and 24-h electrocardiography, electrophysiology, two-dimensional and Doppler echocardiography and angiography. Results We identified 13 mutations in the: MYBPC3 gene: one nonsense, four missense and three splicing mutations and five small deletions and insertio ns. Of these, 11 were novel, and two were probably founder mutations. Patie nts with MYBPC3 mutations presented a broad range of phenotypes. In general the 16 carriers of protein truncations had a tendency toward earlier disea se manifestations (33 +/- 13 vs. 48 +/-9 years; p = 0.06) and more frequent ly needed invasive procedures (septal ablation or cardioverter-defibrillato r implantation) compared with the 9 carriers of missense mutations or in-fr ame deletions (12/16 vs. 1/9 patients; p < 0.01). Conclusions Multiple mutations, which include missense, nonsense and splici ng mutations, as well as small deletions and insertions, occur in the MYBPC 3 gene. Protein truncation mutations seem to cause a more severe disease ph enotype than missense mutations or in-frame deletions. (J Am Coll Cardiol 2 001;38:322-30) (C) 2001 by the American College of Cardiology.