High-throughput sequencing and better understanding of aetiological spectrum of Hypertrophic cardiomyopathy

Background and objective Hypertrophic cardiomyopathy (HCM) is one of the leading causes of sudden cardiac death in young adults, with a prevalence of 1/500 in the general population. HCM is a genetic disease usually related to a sarcomeric gene mutation. Despite advances in knowledge, elucidation of the genetic cause is reached in only 30–60% of cases with conventional Sanger sequencing and analysis of a limited number of genes (usually the five major sarcomeric genes). We hypothesized that high-throughput sequencing of a large panel of genes will allow a more comprehensive evaluation of the etiologic spectrum of HCM. Methods and results We used high-throughput sequencing technology, with a panel of 107 genes (all the various cardiomyopathies and arrhythmia genes) that we recently developed (Nimblegen capture then Illumina MiSeq sequencing), in a cohort of 97 unrelated patients with HCM. We detected 2740 variants including 99 variants that we classified as pathogenic using restrictive criteria. A pathogenic mutation was identified (i) in 31 patients (32% of cohort of patients) in the group of 5 conventional sarcomeric genes ( MYBPC3, MYH7, TNNT2, MYL2, TNNI3 ) including patients with multiple mutations, (ii) in 8 patients (8%) with a mutation in the group of additional sarcomeric genes (such as MYH6 ), (iii) in 4 patients (4%) with a mutation in the group of non-sarcomeric genes previously associated to HCM (such as GLA responsible for Fabry disease) and (iv) in additional patients with a mutation in new genes not yet reported in HCM (such as AKAP9 ). Conclusion High-throughput sequencing of a large panel of genes associated with hereditary heart diseases allowed us to determine the large genetic spectrum of HCM. We confirmed the prominent role of sarcomeric genes, highlighted the role of non-sarcomeric causes (some with specific therapeutics) and identified mutations in potential new genes responsible for the disease.