Whole Exome Sequencing Reveals a Large Genetic Heterogeneity and Revisits the Causes of Hypertrophic Cardiomyopathy

ypertrophic cardiomyopathy (HCM), the most common hereditary heart disease, is autosomal dominant with incomplete penetrance and variability. Heterozygous mutations in 5 sarcomeric genes (MYBPC3, MYH7, TNNT2, TNNI3, and MYL2), estimated to account for 50% to 70% of HCM cases, are routinely screened for diagnosis, genetic counseling, predictive testing, and targeted follow-up of mutation carriers. 1 Secondary HCM cases caused by Fabry disease and transthyretin hereditary amyloidosis, which require specific therapies, remain underdiagnosed. 2 The HYPERGEN study evaluated the diagnostic value of whole exome sequencing (WES) in HCM compared with targeted sequencing of the 5 sarcomeric genes. Two hundred unrelated patients with newly diagnosed isolated HCM were enrolled in 5 French centers (Marseille, Bordeaux, Paris, Dijon, and Rennes). An institutional review committee approved the study. All subjects gave informed consent for genetic studies. HCM echocardiographic diagnosis was considered definite in presence of left ventricular hypertrophy (maximal wall thickness 15 mm in sporadic or >13 mm in familial cases) without dilatation or any other cardiac or systemic disease. The patient cohort included 132 men and 68 women (mean age, 55 years; range, 19-91; 86.5% above 40; 66% sporadic cases).