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

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