Next generation sequencing in sudden cardiac death (pilot study)

Abstract

Aim. To search for causal mutations in candidate genes responsible for the development of sudden cardiac death (SCD) in men who died under the age of 45.Material and methods. The SCD group (n=37) was formed using the criteria the World Health Organization and the European Society of Cardiology. Autopsy material was collected from men who died suddenly outside medical institutions and underwent forensic medical examination according to the standard protocol. Autopsy revealed no morphological changes that could explain sudden death. The mean age was 32,4±6,4 years. Genomic DNA was isolated from myocardial tissue using phenol-chloroform extraction. Clinical exome sequencing was performed. At first, we analyzed the results of sequencing of 24 genes, mutations in which lead to cardiovascular diseases associated with an increased risk of SCD: KCNQ1, KCNH2, SCN5A, AKAP9, ANK2, CACNA1C, CALM1, CALM2, CAV3, KCNE1, KNCJNE2, KCNE2, SCN4B, SNTA1, MYH2, APOB, KCNA5, TGFB3, NEB, PDX1, FLNC, PLEC, KCND3.Results. Of 37 samples, we revealed 13 probable pathogenic missense mutations in 9 samples (24,3%). Of 13 probable pathogenic variants, 5 were new.Conclusion. This pilot study provides following conclusions: it is necessary to continue molecular autopsy research in Russia; to increase the effectiveness of detecting causal mutations, it is necessary to reduce the age of patients with SCD included in the study; studying the families of deceased; cooperation of experienced specialists — forensic pathologist, laboratory geneticist, cardiologist.

Expanding the Russian allele frequency reference via cross-laboratory data integration: insights from 7,452 exome samples

“…Finally, a very recent study by Ramensky et al included 1,658 healthy controls; unfortunately, this study was based on a targeted sequencing of a small number of genes (242) (Ramensky et al, 2021). Despite the aforementioned limitations, data obtained in previous analyses have already been used for interpretation of clinical significance of variants (Glotov et al 2019; Maksimov et al 2020) and population genetics analyses (e.g., (Shikov et al 2020; Pinheiro, Sperb-Ludwig, and Schwartz 2021)). Exome-based allele frequencies have been included into several databases, including a database of BRCA1/BRCA2 gene mutations (https://oncobrca.ru/).…”

Role of genetic research in the prevention of life-threatening rhythm and cardiac conduction disorders in young people

“…у близких родственников пациента. Новые возможности для более детальной генетической диагностики у лиц, предрасположенных к развитию фатальных аритмий, несут высокопроизводительные технологии секвенирования [13,15,19,25]. Так, на сегодняшний день NGS технологии, в т.ч.…”

“…Так, на сегодняшний день NGS технологии, в т.ч. полноэкзомное секвенирование, позволяют исследовать панель нарушений ритма сердца, включающую в себя 40 генов, а также их мутаций, связанных с развитием LQTS, синдрома Бругада, SQTS, CPVT [10,16,25,26].…”