A child cohort study from South Italy enlarges the genetic spectrum of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most frequently autosomal dominant cardiomyopathy (1:500 of the general population) and the most common cause of sudden cardiac death in the young. HCM frequently goes undiagnosed until the appearance of overt signs and symptoms, thereby delaying prophylactic and therapeutic measures. Genetic screening detects mutations in about 70% of adult HCM patients. This study comprised 39 independent patients paediatric with clinical diagnosis of HCM. Patients underwent a complete cardiologic evaluation. To determine the molecular epidemiology of HCM genetic traits in our patients we tested for mutations 8 sarcomeric genes. All exons, including the splicing sites, and 5’ and 3’ UTR regions of MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL2, MYL3 and ACTC genes were amplified by PCR using novel primers. Mutations were identified in 57% of patients with familial HCM and in 22% of patients with presumed sporadic HCM. The most frequent gene altered in the genotyped patients was MYH7, which was mutated in 23% of cases. Genes MYBPC3, TNNT2 and TPM1 were altered in 10.2%, 5.1% and 2.1% of cases. Among 12 mutations identified, 8 were novel: p.M539L, p.R1045H, p.D1652Y in gene MYH7; p.V906G, c.3627+2 T>A in gene MYBCP3; p.V95M, p.R104H in gene TNNT2; and p.D58H in gene TPM1. Screening of 64 available relatives revealed that 27 had mutations; 11 of these individuals had no signs or symptoms suggestive of HCM. This study, besides characterizing the spectrum of mutations in a childhood population, and revealing an even greater genetic heterogeneity than formerly recognized, may increase genotype-phenotype correlations, and thus may help to identify asymptomatic candidates for early preventive or therapeutic measures