PATHOGENIC MUTATIONS IN HRYR2 GENE OF KAZAKHSTANI PATIENTS WITH VENTRICULAR TACHYCARDIA
Introduction: Ventricular tachycardia (VT) is the key factor of morbidity and mortality worldwide, resulting in sudden cardiac death and making it challenging issue within public health. Currently, VT associations with mutations in the hRYR2 gene involved in the process of calcium release in cardiomyocytes were identified. Hence it is highly important to study the contribution of genetic variations of the hRYR2 gene for formation of susceptibility to VT among the population of Kazakhstan.
Purpose: to study mutations in the hRYR2 gene in patients with ventricular tachycardia and their family members.
Materials and methods: This study was designed as a cohort study. Genetic variants of the hRYR2 gene were screened in 35 VT patients, 2 of them with catecholaminergic polymorphic ventricular tachycardia (CPVT) and 33 patients with idiopathic VT. When mutations were detected, the genetic analysis was also performed for the patient's relatives with mutations identified. The target regions of the hRYR2 gene, including the most important 45 exons, were amplified by PCR and directly sequenced using the DNA analyser 3730xL.
Data analysis was carried out using the programs SeqScape 2.7, SeqAnalysis 2.5, etc. Statistical calculations - studies of genetic variants and allele frequencies were carried out. Allele and genotype frequencies were compared between patients, their relatives and control groups, and in silico models were used to predict the clinical significance of a genetic variant.
Outcomes: New mutations were found in a patient with CPVT (c.A13892T; p.D4631V) and in one patient with VT (c.G5428C; p.V1810L). Both variants are located in phylogenetically conserved regions of the hRYR2 gene and they are clinically significant, pathological. In addition, c.C7511T mutation (p.T2504M) was found in one patient with VT previously associated with arrhythmogenic right ventricular dysplasia (ARVD). This variant is located in the phylogenetically conserved region of the hRYR2 gene and is also pathological (score according to MutationTaster D (0.99) and PolyPhenII D (0.99)).
Conclusions: Screening for mutations in cardiac ryanodine receptor gene hRYR2 type 2 in patients with VT has revealed clinically significant mutations, which made it possible to improve the treatment of these patients and offer the screening of these variants in close relatives. This research will be useful for Kazakhstani patients with ventricular arrhythmias in assessment of required genetic screening and reliable genetic counseling in order to predict and prevent the sudden cardiac death and differential diagnosis of arrhythmia.
Zhannur M. Abilova ¹*, https://orcid.org/0000-0001-9671-4574
Christian Gully², Makhabbat S. Bekbosynova³,
Ainur Zh. Akhmetoa¹, http:// orcid.org/0000-0002-5557-3338
Saule Y. Rakhimova¹, https://orcid.org/0000-0002-8245-2400
Ainur R. Akilzhanova¹, http://orcid.org/0000-0001-6161-8355
¹ Center for Life Science, «National Laboratory Astana, Nazarbayev University,
Nur-Sultan city, Republic of Kazakhstan;
² Medical Research Center, Medical University of Graz, Graz, Austria;
³ National Research Cardiac Surgery, Nur-Sultan city, Republic of Kazakhstan.
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Abilova Zh.M., Gully Ch., Bekbosynova M.S., Akhmetoa A.Zh., Rakhimova S.Y., Akilzhanova A.R. Pathogenic mutations in hRYR2 gene of kazakhstani patients with ventricular tachycardia // Nauka i Zdravookhranenie [Science & Healthcare]. 2020, (Vol.22) 4, pp. 60-70. doi 10.34689/SH.2020.22.4.06Related publications:
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