Screening of the four genes most commonly involved in hypertrophic cardiomyopathy.

Purpose: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease with a prevalence of 1:500 in the general population. The clinical presentation and natural history is heterogeneous, ranging from benign asymptomatic forms to more malignant expressions that may result in sudden or heart failure death. To date, over 455 mutations have been reported in 20 different genes encoding proteins of the cardiac sarcomere, proteins of the z-disc, protein of the intercalated discs. Pathogenic mutations in the β-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), troponin T (TNNT2) and troponin I (TNNI3) genes account for about 70% of the total. The aim of the present study was to perform a systematic screening of these genes in an Italian consecutive cohort of HCM patients. Methods: We analyzed a series of 82 patients (age: 33±17 years; 60 males, 43 index cases and 39 isolated cases) enrolled at a tertiary Center. The method involved PCR amplification of exons or exon segments of MYH7, MYBPC3, TNNT2, TNNI3 genes, denaturing high performance liquid chromatography of amplicons and direct sequencing. Results: In 24 (29%) of the 82 patients we identified 22 distinct mutations of which 16 were classified as novel (not found in a control series of 300 chromosomes). Nine (41%) mutations were identified in MYH7 gene, 7 (32%) in MYBPC3 gene, 4 (18%) TNNI3 gene and 2 (9%) in TNNT2 gene. Two patients carrying MYH7 (G407C) and MYPC3 (A364T) mutation suddenly died at young age; five patients with single mutation in MYH7 (I1207M), MYBPC3 (A364T e Q366X), TNNI3 (K207T) o TNNT2 (R94L) are transplanted at age 60, 12, 62, 28, and 59 yrs respectively. Moreover, we detected 3 patients carrying a double mutation: one young proband showing two mutations in the MYH7 gene suddenly died and one of two patients carrying one mutation in MYH7 and the other in MYBPC3 gene died of heart failure at young age. In 5 malignant families for SD and HFD with identification of causative mutation, genetic testing was performed in 17 first degree relatives. Of these, 4 affected familial members had the same mutations of index cases, 7 relatives were unaffected and not carriers and 6 affected familial didn't share the same mutation of proband. Conclusions: Mutation screening of the four genes most frequently involved in HCM is complex, expensive and pathogenic mutation was detected only in 30% of patients. Therefore, these results might have implications for genetic diagnosis strategy leading to improve genetic counselling and better clinical management in families with HCM.