RYR2 Sequencing Reveals Novel Missense Mutations in a Kazakh Idiopathic Ventricular Tachycardia Study Cohort

Abstract

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.

Patients with coronary heart disease, dilated cardiomyopathy and idiopathic ventricular tachycardia share overlapping patterns of pathogenic variation in cardiac risk genes

“…However, data from diverse, heterogeneous populations exposed to the same environmental conditions and similar lifestyles yield important information on natural genetic plasticity. Such data are fundamental to genetic epidemiology and are critical to dissect natural polymorphisms from pathogenic alterations ( Akilzhanova et al, 2014 ). Genome-wide data and linkage disequilibrium patterns are unavailable for Central Asian populations and are not represented in publicly available databases.…”

“…These can contribute to our understanding of critical mechanisms to provide the maximum benefit to the individual, especially before the early stages of pathogenesis. Classical CHD markers defined by the Framingham risk score (FRS), including age, cholesterol, smoking status, blood-pressure, and diabetes status are not predictive in a timely way ( Akilzhanova et al, 2014 ). Genetic risk loci have been reported for cell proliferation genes, inflammation and immunity related genes, cholesterol and lipid biogenesis genes, among others.…”

Role of risk stratification and genetics in sudden cardiac death

“…Increased sympathetic activities will quickly raise the heart rate, but due to reduced rectifying potassium channel activity, the necessary QT shortening is prevented. Catecholaminergic polymorphic ventricular tachycardia caused by a mutation in the cardiac ryanodine receptor D r a f t channel (RyR2) gene leading to calcium leakage from the sarcoplasmic reticulum of the cardiac myocyte has also been correlated with swimming-related SCD events of due to arrhythmia in children (Kenny and Martin 2011), SCD in young adults (Arakawa et al 2015), and idiopathic ventricular tachycardia in adults (Akilzhanova et al 2014). …”

Peer Review #1 of "Patients with coronary heart disease, dilated cardiomyopathy and idiopathic ventricular tachycardia share overlapping patterns of pathogenic variation in cardiac risk genes (v0.1)"

“…However, data from diverse, heterogeneous populations exposed to the same environmental conditions and similar lifestyles yield important information on natural genetic plasticity. Such data are fundamental to genetic epidemiology and are critical to dissect natural polymorphisms from pathogenic alterations [3]. Genome-wide data and linkage disequilibrium patterns are unavailable for Central Asian populations and are not represented in publicly available databases.…”

“…These can contribute to our understanding of critical mechanisms to provide the maximum benefit to the individual, especially before the early stages of pathogenesis. Classical CHD markers defined by the Framingham risk score (FRS), including age, cholesterol, smoking status, blood-pressure, and diabetes status are not predictive in a timely way [3]. Genetic risk loci have been reported for cell proliferation genes, inflammation and immunity related genes, cholesterol and lipid biogenesis genes, among others.…”