Identification of Two Rare Variants in Iranian Families With Familial Sudden Cardiac Death

TL;DR

This study identifies rare genetic variants in two Iranian families linked to sudden cardiac death, offering insights for genetic counseling.

Contribution

The study reports two rare heterozygous missense variants in RYR2 and SCN5A genes associated with cardiac channelopathies in Iranian families.

Findings

Rare heterozygous missense variants in RYR2 and SCN5A genes were identified in two Iranian families with sudden cardiac death.

The mutated residues in these genes are conserved across humans and primates, indicating their functional importance.

The findings confirm previous associations between these mutations and channelopathy pathogenesis.

Abstract

Cellular action potential is characterized by a particular sequence of depolarizing and repolarizing ion currents regulated by ion channels. Genetic mutations in these channels disrupt the essential movement of ions, such as Na+, Ca++, and K+, across the cell membrane, leading to dangerous arrhythmias and sudden cardiac death (SCD). Most cases of unexplained SCD are caused by pathogenic variants in genes linked to channelopathies and cardiomyopathy. Genetic investigations might aid in confirming the clinical diagnosis based solely on observations. Other advantages of genetic studies are clinical management of the patient, family screening, appropriate genetic counseling, and risk assessment for family members. This study was conducted to investigate the genetic cause of early‐onset SCD in two Iranian families. Whole‐exome sequencing was performed on the probands from each family, and the Illumina DRAGEN haplotype variant calling system was used to identify variants in each patient. Here, we identified rare heterozygous missense variants in the RYR2 and SCN5A genes, which are linked to cardiac channelopathies. Alignment studies reveal that the mutated residues are conserved across humans and primates, underscoring their crucial role in protein function. Previously reported associations between these mutations and channelopathy pathogenesis have been confirmed in the present study. This study provides valuable insights for genetic counseling of families with a history of sudden death.

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