Anna Gärtner-Rommel, Julia Bloebaum, Andreas Brodehl, Bärbel Klauke, Katharina Sielemann, Astrid Kassner, Henrik Fox, Michiel Morshuis, Jens Tiesmeier, Uwe Schulz, Ralph Knöll, Jan Gummert, Hendrik Milting
- 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 \(\it TTN\) and \(\it RBM20\). Next Generation Sequencing in clinical DCM cohorts revealed truncating variants in \(\it TTN\) (\(\it TTN\)tv), accounting for up to 25% of familial DCM cases. Mutations in the cardiac splicing factor RNA binding motif protein 20 (\(\it RBM20\)) are also known to be associated with severe cardiomyopathies. \(\it TTN\) is one of the major \(\it RBM20\) splicing targets. Most of the pathogenic \(\it RBM20\) mutations are localized in the highly conserved arginine serine rich domain (RS), leading to a cytoplasmic mislocalization of mutant \(\it RBM20\). Here, we present a patient with an early onset DCM carrying a combination of (likely) pathogenic \(\it TTN\) and \(\it RBM20\) mutations. We show that the splicing of \(\it RBM20\) target genes is affected in the mutation carrier. Furthermore, we reveal \(\it RBM20\) haploinsufficiency presumably caused by the frameshift mutation in \(\it RBM20\).
