Andreas Brodehl, Carsten Hain, Franziska Flottmann, Sandra Ratnavadivel, Anna Gärtner-Rommel, Bärbel Klauke, Jörn Kalinowski, Hermann Körperich, Jan Gummert, Lech Paluszkiewicz, Marcus-André Deutsch, Hendrik Milting
- Currently, little is known about the genetic background of restrictive cardiomyopathy (RCM). Herein, we screened an index patient with RCM in combination with atrial fibrillation using a next generation sequencing (NGS) approach and identified the heterozygous mutation \(\it DES\)-c.735G>C. As \(\it DES\)-c.735G>C affects the last base pair of exon-3, it is unknown whether putative missense or splice site mutations are caused. Therefore, we applied nanopore amplicon sequencing revealing the expression of a transcript without exon-3 in the explanted myocardial tissue of the index patient. Western blot analysis verified this finding at the protein level. In addition, we performed cell culture experiments revealing an abnormal cytoplasmic aggregation of the truncated desmin form (p.D214-E245del) but not of the missense variant (p.E245D). In conclusion, we show that \(\it DES\)-c.735G>C causes a splicing defect leading to exon-3 skipping of the \(\it DES\) gene. \(\it DES\)-c.735G>C can be classified as a pathogenic mutation associated with RCM and atrial fibrillation. In the future, this finding might have relevance for the genetic understanding of similar cases.
