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 cardiomyopathy (HCM) caused by mutations in the myosin-binding protein C gene (MYBPC3) in 110 consecutive, unrelated patients and family members of European descent. Background Mutations in the MYBPC3 gene represent the cause of HCM in similar to 15% of familial cases. MYBPC3 mutations were reported to include mainly nonsense versus missense mutations and to be characterized by a delayed onset and benign clinical course of the disease in Japanese and French families. We investigated the features that characterize MYBPC3 variants in a large, unrelated cohort of consecutive patients. Methods The MYBPC3 gene was screened by single-strand conformational polymorphism 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 insertions. Of these, 11 were novel, and two were probably founder mutations. Patients with MYBPC3 mutations presented a broad range of phenotypes. In general the 16 carriers of protein truncations had a tendency toward earlier disease manifestations (33 +/- 13 vs. 48 +/-9 years; p = 0.06) and more frequently needed invasive procedures (septal ablation or cardioverter-defibrillator implantation) compared with the 9 carriers of missense mutations or in-frame deletions (12/16 vs. 1/9 patients; p < 0.01). Conclusions Multiple mutations, which include missense, nonsense and splicing mutations, as well as small deletions and insertions, occur in the MYBPC3 gene. Protein truncation mutations seem to cause a more severe disease phenotype than missense mutations or in-frame deletions. (J Am Coll Cardiol 2001;38:322-30) (C) 2001 by the American College of Cardiology.