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

Abstract

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 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Desmoplakin; Dilated cardiomyopathy; Pathogenic variant; Whole exome sequencing.

Fig. 1

The DCM-affected family pedigree. Members are identified by generations and numbers. The arrow appoints the family proband (IV: 9). In this pedigree, white symbols represent unaffected members; red and blue symbols represent affected; squares represent males, and circles females; parallel lines indicate the consanguineous marriage.

Fig. 2

Identification and molecular validation of c.405_422+39del variant in the patient and her family members. A) Result of electrophoresing PCR products of the proband (IV: 9), III: 2, IV: 7, IV: 10, IV: 5, III: 5, and negative control (NTC) on 1.5% gel agarose. The LDR lane contains ladder 100bp+3kb. Columns with two bands represent the heterozygous deletion. (B) The sequencing chromatograms indicate a disrupted base reading pattern after position G nucleotide (the blue vertical line) in the proband (IV: 9) and IV: 7, IV: 10, III: 5.

Fig. 3

The consequence of identified deletion. (A) Normal splicing. During normal splicing, Intron 3 is removed, and exon sequences are translated into the corresponding amino acids in a correct reading frame. (B) Intron retention scenario. The identified variant (c.405_422+39del) deletes 57 nucleotides from the genomic DNA, of which 18 nucleotides are located in exon 3, and 39 nucleotides remain in intron 3. Deletion of the normal splicing donor site led to intron 3 retention and subsequently this variant, resulting in a premature stop codon.