Abstract 535: Screening Mutations of MYBPC3 in 114 Unrelated Patients With Hypertrophic Cardiomyopathy Using Targeted Capture and Next-Generation Sequencing

Abstract

Background and Purpose: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease and a major cause of sudden cardiac death. Mutations in the gene encoding the myosin binding protein C (MYBPC3) represent the cause of HCM in ~35% of all cases of HCM. However, genetic testing for MYBPC3 in clinic setting has been limited due to the cost and relatively time-consuming Sanger sequencing. Therefore, we developed a HCM gene diagnostic kit enabling ultra-low-cost candidate gene targeted resequencing in a large cohort. Methods: Clinical evaluations, electrocardiography and echocardiography data of all patients with HCM were collected in Anzhen Hospital, Beijing, from 2012 to 2013. Exomes were captured with MYBPC3-containing panel using biotinylatedoligo-probes and sequenced by Illumina HiSeq2000. Results: In a cohort of 114 patients with HCM, a total of 21 different mutations in the MYBPC3 gene, including 3 nonsense, 6 indels and 12 missense mutations, were identified from 29 patients. These patients were presented in a broad range of phenotypes with mean age of 36.6 ± 12.5 years at onset. Phenotype-genotype analyses showed that clinical manifestations (NYHA class 3~4) were more severe in the double-mutation group (n=3, 100%) as well as the premature termination codon (PTC) group (n=12, 50%), compared with the missense mutation group (n=14, 21.4%) (p=0.03). Interestingly, the p.Y842X mutation was detected in four unrelated cases (4/29, 13.79%) with severe phenotypes, such as syncope, arrhythmias, and history of receiving invasive therapies. Conclusions: We demonstrated that the power of targeted resequencing in a cohort of HCM patients, and found that MYBPC3 is a common HCM-causing gene in Chinese patients (~25.4%). We also confirmed that truncation mutations or double mutations in MYBPC3 could lead to relatively severe phenotypes, and propose that the p.Y842X mutation might be correlated with severe phenotypes in Chinese patients with HCM.