TARGETED NEXT GENERATION SEQUENCING REVEALS NEW INSIGHTS INTO THE GENETIC BASIS OF INHERITED ARRHYTHMIA IN KAZAKHSTANI PATIENTS
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Date
2020
Authors
Akilzhanova, A.
Guelly, C.
Abilova, Zh.
Rakhimova, S.
Akhmetova, A.
Kairov, U.
Trajanoski, S.
Akilzhanova, G.
Kozhamkulov, U.
Abdrakhmanov, A.
Journal Title
Journal ISSN
Volume Title
Publisher
International conference "MODERN PERSPECTIVES FOR BIOMEDICAL SCIENCES: FROM BENCH TO BEDSIDEā; National Laboratory Astana
Abstract
Introduction:Ventricular arrhythmias are caused by mutations of ion channels and their interacting
proteins. Most arrhythmia syndromes are inherited in an autosomal dominant manner, such that
first-degree family members have a 50% chance of inheriting the disease. Identification of the mutation
allows for predictive genetic testing in other living family members. Variable penetrance is common in
all arrhythmia syndromes, the same mutation in the same family causing wide variation in phenotype.
This suggests that other factors such as genetic modifiers and environmental factors may influence the
phenotype.
Recent advances in genetic sequencing techniques and the potential of therapeutic intervention in patents
with inherited cardiac arrhythmias have garnered this group of disorders much attention in the
scientific community. The purpose of the study was to identify the mutational spectrum of ventricular
tachycardia (VT) in Kazakhstani patients.
Material and Methods: using predeveloped a targeted panel of 96 known cardiac disease genes, associated
with cardiomyopathy and arrhythmia we screened 92patients, diagnosed with VT and dilated
cardiomyopathy (VT DCM) or idiopathic VT (iVT).
Results. Targeted sequencing and stepwise filtering of the annotated variants identified a total of 307
unique variants in 74 genes totaling up in 456 variants for the overall study group. Variants included
one in/del variant, four splice-site variants and 451single-nucleotide variants (SNV) within the coding
exonic regions. Seven (0.15%) of the SNVs were unique stop-gain variants, three of those residing in the
TTN gene. 168 HGMD mutations (61unique) were observed in 37 genes. According to ACMG variants
were classified as 9 pathogenic (KCNJ2R218Q and TTN R5338X in iVT patients, KCNQ1c.477+1G>A, LMNA
Q353X, MYH7 F244L, TTN L17465X and W21011X, DSG2c.2334+1G>A, GAA W746C in VT DCM patients),
11likely pathogenic, 97 variants with uncertain significance and rest as benign were observed.
Conclusions: Individuals presenting with VT either secondary to DCM or of idiopathic etiology carry
multiple rare mutations and potentially pathogenic sequence variants in cardiac risk genes in a similar
pattern and at a comparable frequency. Further studies are needed to identify more mutations causing
VT in a larger cohort of patients.
Study was supported by a grant from the Ministry Education and Science, Republic of Kazakhstan
(AP05134683).
Description
Keywords
targeted NGS, ventricular tachycardia, novel mutations, genotype-phenotype correlations, Research Subject Categories::MEDICINE