Unexpectedly low mutation rates in beta-myosin heavy chain and cardiac myosin binding protein genes in Italian patients with hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere-related genes have been implicated in HCM etiology, those encoding β-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high-performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n = 125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease.

Fig. 1

Schematic representation of homosapiens β-myosin heavy chain protein and the location of the novel mutations (n = 3) and non-synonymous SNP found in the 136 HCM patients analyzed. Red, missense mutations; black, silent mutation; blue, non-synonymous SNP.

Fig. 2

Schematic representation of the location of the novel mutations (n = 8) and the non-synonymous SNPs (n = 3) detected within cardiac myosin binding protein in the 136 HCM patients analyzed. Novel mutation 2905+1 (exon 25) is not shown. Red, missense mutations; purple, nonsense mutations producing stop codons; blue, non-synonymous SNPs.