RYR2 sequencing reveals novel missense mutations in a Kazakh idiopathic ventricular tachycardia study cohort

PLoS One. 2014 Jun 30;9(6):e101059. doi: 10.1371/journal.pone.0101059. eCollection 2014.


Channelopathies, caused by disturbed potassium or calcium ion management in cardiac myocytes are a major cause of heart failure and sudden cardiac death worldwide. The human ryanodine receptor 2 (RYR2) is one of the key players tightly regulating calcium efflux from the sarcoplasmic reticulum to the cytosol and found frequently mutated (<60%) in context of catecholaminergic polymorphic ventricular tachycardia (CPVT1). We tested 35 Kazakhstani patients with episodes of ventricular arrhythmia, two of those with classical CPVT characteristics and 33 patients with monomorphic idiopathic ventricular arrhythmia, for variants in the hot-spot regions of the RYR2 gene. This approach revealed two novel variants; one de-novo RYR2 mutation (c13892A>T; p.D4631V) in a CPVT patient and a novel rare variant (c5428G>C; p.V1810L) of uncertain significance in a patient with VT of idiopathic origin which we suggest represents a low-penetrance or susceptibility variant. In addition we identified a known variant previously associated with arrhythmogenic right ventricular dysplasia type2 (ARVD2). Combining sets of prediction scores and reference databases appeared fundamental to predict the pathogenic potential of novel and rare missense variants in populations where genotype data are rare.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Base Sequence
  • Cohort Studies
  • Electrocardiography
  • Female
  • Gene Expression
  • Humans
  • Kazakhstan
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Ryanodine Receptor Calcium Release Channel / genetics*
  • Sequence Analysis, DNA
  • Tachycardia, Ventricular / genetics*
  • Tachycardia, Ventricular / physiopathology


  • Ryanodine Receptor Calcium Release Channel

Grants and funding

This study was supported by a Grant -in-Aid from Ministry of Education and Science of the Republic of Kazakhstan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.