The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy

Abstract

A major cause of heart failure is cardiomyopathies, with dilated cardiomyopathy (DCM) as the most common form. Over 40 genes are linked to DCM, among them <i>TTN</i> and <i>RBM20</i>. Next Generation Sequencing in clinical DCM cohorts revealed truncating variants in <i>TTN</i> (<i>TTN</i>tv), accounting for up to 25% of familial DCM cases. Mutations in the cardiac splicing factor RNA binding motif protein 20 (<i>RBM20</i>) are also known to be associated with severe cardiomyopathies. <i>TTN</i> is one of the major <i>RBM20</i> splicing targets. Most of the pathogenic <i>RBM20</i> mutations are localized in the highly conserved arginine serine rich domain (RS), leading to a cytoplasmic mislocalization of mutant <i>RBM20</i>. Here, we present a patient with an early onset DCM carrying a combination of (likely) pathogenic <i>TTN</i> and <i>RBM20</i> mutations. We show that the splicing of <i>RBM20</i> target genes is affected in the mutation carrier. Furthermore, we reveal <i>RBM20</i> haploinsufficiency presumably caused by the frameshift mutation in <i>RBM20</i>.