Whole-Exome Sequencing Identified a Novel Variant (C.۴۰۵_۴۲۲+۳۹del) in DSP Gene in an Iranian Pedigree with Familial Dilated Cardiomyopathy

Background: Dilated cardiomyopathy (DCM) is a progressive heart condition characterized by left ventricular chamber enlargement associated with systolic heart failure and prolonged action potential duration. Genetic variations in genes that encode cytoskeleton, sarcomere, and nuclear envelope proteins are responsible for ۴۵% of cases. In our study, we focused on a pedigree with familial DCM to decipher the potential genetic cause(s) in affected members developing arrhythmia, end-stage heart failure, and sudden death. Methods: Whole-exome sequencing (WES) was exploited for a ۲۷-year-old heart-transplanted female as the proband, and the derived data were filtered using the standard pipelines. Results: A ۵۷-nucleotide deletion (c.۴۰۵_۴۲۲+۳۹del) in the desmoplakin gene (DSP) (NM_۰۰۴۴۱۵.۴) was identified as a novel pathogenic variant. Familial segregation analysis indicated that this variant is present in clinically affected members and absent in unaffected members. Conclusions: It seems that the detected variant induces intron retention, resulting in a premature stop codon in intron ۳ of DSP leading to production of a truncated, nonfunctional protein. Additionally, it can trigger a nonsense-mediated mRNA decay pathway associated with inhibition of protein production. The present study results illustrated that a novel deletion in DSP can cause DCM in an Iranian family.

کلیدواژه ها:

Desmoplakin ، Dilated cardiomyopathy ، Pathogenic variant ، Whole exome sequencing.