Ramensky Vasily E, Ershova Alexandra I, Zaicenoka Marija, Kiseleva Anna V, Zharikova Anastasia A, Vyatkin Yuri V, Sotnikova Evgeniia A, Efimova Irina A, Divashuk Mikhail G, Kurilova Olga V, Skirko Olga P, Muromtseva Galina A, Belova Olga A, Rachkova Svetlana A, Pokrovskaya Maria S, Shalnova Svetlana A, Meshkov Alexey N, Drapkina Oxana M
National Medical Research Center for Therapy and Preventive Medicine, Moscow, Russia.
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
Front Genet. 2021 Oct 7;12:709419. doi: 10.3389/fgene.2021.709419. eCollection 2021.
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 and one in 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.
我们对来自莫斯科东北部伊万诺沃地区的1658名个体的代表性人群样本中的242个主要与心血管疾病相关的临床重要基因进行了靶向测序。在检测到的11876个变异中，约11%未在单核苷酸多态性数据库（dbSNP）中发现，或此前未在俄罗斯人群中报道过。我们样本中的大多数新变异都是单例和双例，实际上没有可能特定于俄罗斯人群的新等位基因频率能够达到0.1 - 0.2%以上。在本研究中检测到的三个或更多拷贝的变异绝大多数（99.3%）与其他人群共享。我们发现了两个显性和七个隐性已知致病变异，其等位基因频率与gnomAD非芬兰欧洲人相比显著增加。在242个靶向基因中，有28个在59个基因列表中，美国医学遗传学与基因组学学会（ACMG）建议报告这些基因的偶然发现。根据在ACMG59基因测序子集中检测到的变异数量，我们估计伊万诺沃人群中ACMG59基因全集中已知致病和新的或罕见的蛋白质截短变异的患病率分别为1.4%和2.8%。我们分析了可用的临床数据，观察到28个ACMG59基因中已知致病变异的不完全外显率：12名携带此类变异的个体中只有1人具有最可能与该变异相关的表型。当将已知致病和新的或罕见的蛋白质截短变异一起考虑时，确诊表型的总体发生率约为19%，在新的蛋白质截短变异子集中最高。我们分别在低β脂蛋白血症和肥厚型心肌病患者中报告了三个新的蛋白质截短变异和一个新的蛋白质截短变异。我们的结果为俄罗斯和其他人群基因测序的临床解释提供了有价值的参考。
