Molecular characterization of a large MYBPC3 rearrangement in a cohort of 100 unrelated patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), a common and clinically heterogeneous disease characterized by unexplained ventricular myocardial hypertrophy and a high risk of sudden cardiac death, is mostly caused by mutations in MYH7 and MYBPC3 genes. As 70% of MYBPC3 mutations introduce a premature termination codon, the purpose of the current study was to report the prevalence of large MYBPC3 rearrangements. A large French cohort of 100 HCM patients, for whom no putatively causative point mutations were identified previously in the most prevalent HCM-causing genes, was investigated using an MLPA methodology. One HCM patient was identified to carry a large MYBPC3 rearrangement (<1%). This patient presents a 3505-bp deletion, which begins in the intron 27 and ends 485 bp after the MYBPC3 stop codon (g.47309385_47312889del). It was originated by recombination of a 296 bp AluSz sequence located in intron 27 and a 300 bp AluSx sequence located immediately downstream of exon 35. This study allowed the characterization of the first large MYBPC3 deletion reported in the literature. However, it appears that MLPA strategy, that moderates the identification of large MYBPC3 rearrangements, might confirm a clinical diagnosis only in a small number of patients (<1%).