The etiological spectrum of hypertrophic cardiomypathies (HCM) is wide and some rare causes are largely underdiagnosed.

Our aim is to assess the impact of the next generation sequencing (NGS) for the diagnosis of two rare genetic diseases: Fabry disease and hereditary transthyretin amyloidosis (GLA & TTR genes) in a population with HCM.

We analysed 300 independent patients with HCM through a next generation sequencing (NGS) strategy using a panel of 107 genes involved in hereditary cardiomyopathies. The sequencing was performed by liquid-based capture of targeted areas (Nimblegen®) using HiSeq2500 device (Illumina®). The data were specifically reanalysed for this study, adjusting rules for pathogenicity interpretation based on ACMG guidelines and considering some high variant frequencies in these two genes.

We studied 300 patients, 217 males & 83 females, mean age of 46 years. The NGS resulted in the identification of 266 variants (all classes included) in the 2 genes of interest (GLA: 189 variants, TTR: 77 variants). Further analysis led us to identify 4 causal mutations (pathogenic or probably pathogenic): 3 in GLA (p.Arg118Cys, p.Val269Ala, p.Ala143Thr) and one in TTR (p.Val142Ile). Fabry disease or amyloidosis were not diagnosed before NGS analysis. In the cohort, the prevalence was 1.3% for Fabry disease and 0.3% for ATTR.

NGS using a large panel is able to identify rare causes of HCM which were not previously suspected. The observed prevalences are comparable to those reported in the literature for the Fabry disease but are lower than those reported for the ATTR which could be due to the relatively young age of the patients in our analysed cohort. Our results support a systematic NGS screening with a large panel including GLA and TTR genes in patients referred for HCM. This screening is especially important as patients carrying Fabry or ATTR diseases may benefit from new specific therapies.