RBM20 is a candidate gene for hypertrophic cardiomyopathy.

Abstract Background The genetic basis of a considerable fraction of hypertrophic cardiomyopathy (HCM) cases remains unknown. Whether the gene encoding RNA Binding Motif Protein 20 (RBM20) is implicated in HCM and the correlation of clinical characteristics of RBM20 heterozygotes with HCM remain unresolved. We aimed to investigate the association between RBM20 variants and HCM. Methods We compared rare variants in the RBM20 gene by exome sequencing in 793 HCM patients and 414 healthy controls. Based on a case-control approach, we used SKAT-O to explore whether RBM20 is associated with HCM. The genetic distribution of RBM20 rare variants was then compared between HCM heterozygotes and dilated cardiomyopathy (DCM) heterozygotes. Clinical features and prognosis of RBM20 heterozygotes were compared with non-heterozygotes. Results Gene-based association analysis implicated RBM20 as a susceptibility gene for developing HCM. Patients with RBM20 variants displayed a higher prevalence of sudden cardiac arrest (SCA) (6.7% vs. 0.9%, p = 0.001), increased sudden cardiac death (SCD) risk factor counts and impaired left ventricle systolic function. Further survival analysis revealed that RBM20 heterozygotes had higher incidences of resuscitated cardiac arrest, recurrent non-sustained ventricular tachycardia and malignant arrhythmias. Mendelian randomization suggested that RBM20 expression in left ventricle was causally associated with HCM and DCM with opposite effects. Conclusions This study identified RBM20 as a potential causal gene of HCM. RBM20 variants are associated with increased risk for SCA in HCM.