Targeted Sequencing of 242 Clinically Important Genes in the Russian Population From the Ivanovo Region

Abstract

We performed a targeted sequencing of 242 clinically important genes mostly associated with cardiovascular diseases in a representative population sample of 1,658 individuals from the Ivanovo region northeast of Moscow. Approximately 11% of 11,876 detected variants were not found in the Single Nucleotide Polymorphism Database (dbSNP) or reported earlier in the Russian population. Most novel variants were singletons and doubletons in our sample, and virtually no novel alleles presumably specific for the Russian population were able to reach the frequencies above 0.1–0.2%. The overwhelming majority (99.3%) of variants detected in this study in three or more copies were shared with other populations. We found two dominant and seven recessive known pathogenic variants with allele frequencies significantly increased compared to those in the gnomAD non-Finnish Europeans. Of the 242 targeted genes, 28 were in the list of 59 genes for which the American College of Medical Genetics and Genomics (ACMG) recommended the reporting of incidental findings. Based on the number of variants detected in the sequenced subset of ACMG59 genes, we approximated the prevalence of known pathogenic and novel or rare protein-truncating variants in the complete set of ACMG59 genes in the Ivanovo population at 1.4 and 2.8%, respectively. We analyzed the available clinical data and observed the incomplete penetrance of known pathogenic variants in the 28 ACMG59 genes: only 1 individual out of 12 with such variants had the phenotype most likely related to the variant. When known pathogenic and novel or rare protein-truncating variants were considered together, the overall rate of confirmed phenotypes was about 19%, with maximum in the subset of novel protein-truncating variants. We report three novel protein truncating variants in APOB and one in MYH7 observed in individuals with hypobetalipoproteinemia and hypertrophic cardiomyopathy, respectively. Our results provide a valuable reference for the clinical interpretation of gene sequencing in Russian and other populations.

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

“…Several previous studies focused on investigating the genome-wide variation of the Russian population. These include the pilot phase of the Genomes Russia project (Zhernakova et al 2020), an exome-based study of monogenic disease prevalence in 694 patients (Barbitoff et al 2019), and a targeted sequencing study of 242 known disease genes in 1,658 healthy individuals from the Ivanovo region (Ramensky et al 2021). In these works, several important aspects of the genome variation in Russian patients have been pinpointed.…”

“…In these works, several important aspects of the genome variation in Russian patients have been pinpointed. All of these studies, however, lack in the comprehensiveness of the analysis due to either low sample size (such as in the Genomes Russia project) or narrow set of analyzed genes (Ramensky et al 2021).…”

Management of biobanking for medical genetics research

“…В связи с этим всего за несколько лет количество научных проектов, проводимых в сотрудничестве с Биобанком, значительно увеличилось. Технологии биобанкирования и стандартизация всех этапов пробоподготовки и информационного сопровождения в виде баз данных позволяют проводить широкомасштабные генетические исследования [26][27][28][29]. Другой пример возрастающей важности биобанков как источника биообразцов необходимого количества и качества -это развитие протеомики, метаболомики, липидомики и других омикс-технологий, которые могут дать информацию о развитии и прогнозе заболеваний, а также о возможных реакциях на определенный образ жизни (питание и др.)…”

Editorial: Bioinformatics of Genome Regulation, Volume I

“…Zinchenko et al (2021) studied rare hereditary diseases in Russia. Ramensky et al (2021) discussed targeted sequencing of a set of clinically important genes associated with cardiovascular diseases. Gozman et al (2021) raised important actual problem of the role of genetic variance in disease severity in COVID-19 Patients.…”

“… Zinchenko et al (2021) studied rare hereditary diseases in Russia. Ramensky et al (2021) discussed targeted sequencing of a set of clinically important genes associated with cardiovascular diseases.…”