Identification of a novel pathogenic variant in in an Iranian family with long QT syndrome 2 by whole-exome sequencing.

Background: Long QT syndrome (LQTS) is a lethal cardiac condition. However, the clinical implementation of genetic testing has now made LQTS eminently treatable. Next-generation sequencing has remarkable potential for both clinical diagnostics and research of LQTS. Here, we investigated the genetic etiology in an LQTS-suspected Iranian pedigree by whole-exome sequencing and collected all variants with consensus based on publications.

Methods: WES was performed on the proband of this pedigree to reveal the underlying cause of sudden cardiac death (SCD). The variant found was validated and segregated by polymerase chain reaction and Sanger sequencing. Based on the literature review, variants were retrospectively analyzed to identify pathogenic variants, likely pathogenic variants, and variants of uncertain significance by using different prediction tools.

Results: WES identified an autosomal dominant nonsense variant, c.1425C>A: p.Tyr475Ter, in the gene, which appeared to be the most likely cause of LQTS in this pedigree. Moreover, our comprehensive literature review yielded 511 variants in association with the LQTS phenotype, with c.3002G>A (CADD Phred=49) being the most pathogenic variant.

Conclusions: Variants in the gene are considered a major cause of LQTS worldwide. The detected c.1425C>A is a novel variant to be reported from Iran for the first time. This result indicates the importance of screening in a pedigree with SCD cases.