Whole-Exome Sequencing Identified a Novel Variant (C.405_422+39del) in DSP Gene in an Iranian Pedigree with Familial Dilated Cardiomyopathy.

Mohammad Keramatipour,Yeganeh Eshaghkhani,Parisa Nourmohammadi,Arezoo Mohamadifar,Arezou Karamzade,Mostafa Asadollahi,Zahra Golchehre,Mohammad Reza Saberi ,Ahmad Amin ,Mehdi Taghizadeh

doi:10.52547/rbmb.10.2.280

Abstract

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 45% 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. Whole-exome sequencing (WES) was exploited for a 27-year-old heart-transplanted female as the proband, and the derived data were filtered using the standard pipelines. A 57-nucleotide deletion (c.405_422+39del) in the desmoplakin gene (DSP) (NM_004415.4) 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. It seems that the detected variant induces intron retention, resulting in a premature stop codon in intron 3 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.

Highlights

Dilated cardiomyopathy (DCM) is a serious myocardial disorder in which myocardium becomes weak and stretched, so that systolic function becomes impaired because of the enlargement and insufficient contraction of ventricles, a condition that leads to heart failure, arrhythmia, and sudden death [1,2,3]
Taking advantage of wholeexon sequencing (WES) technology and gene annotation, a novel small deletion variant (c.405_422+39del) was detected in desmoplakin gene (DSP) that may underlie the pathogenesis of DCM, and the results were validated by Sanger sequencing
To reveal the disease-causing genetic variant(s), the genomic DNA obtained from the proband was investigated by Whole-exome sequencing (WES)

Summary

Introduction

Dilated cardiomyopathy (DCM) is a serious myocardial disorder in which myocardium becomes weak and stretched, so that systolic function becomes impaired because of the enlargement and insufficient contraction of ventricles, a condition that leads to heart failure, arrhythmia, and sudden death [1,2,3]. It is shown that genetic variations in more than 50 genes encoding constituents of the cytoskeleton, sarcomere, nuclear membrane, and mitochondrial proteins can cause DCM, indicating considerable genetic heterogeneity in genetic cases of DCM [911]. 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. Conclusions: It seems that the detected variant induces intron retention, resulting in a premature stop codon in intron 3 of DSP leading to production of a truncated, nonfunctional protein. 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

Methods

Results

Conclusion