Whole‐exome sequencing provides insights into monogenic disease prevalence in Northwest Russia

Abstract

BackgroundAllele frequency data from large exome and genome aggregation projects such as the Genome Aggregation Database (gnomAD) are of ultimate importance to the interpretation of medical resequencing data. However, allele frequencies might significantly differ in poorly studied populations that are underrepresented in large‐scale projects, such as the Russian population.MethodsIn this work, we leveraged our access to a large dataset of 694 exome samples to analyze genetic variation in the Northwest Russia. We compared the spectrum of genetic variants to the dbSNP build 151, and made estimates of ClinVar‐based autosomal recessive (AR) disease allele prevalence as compared to gnomAD r. 2.1.ResultsAn estimated 9.3% of discovered variants were not present in dbSNP. We report statistically significant overrepresentation of pathogenic variants for several Mendelian disorders, including phenylketonuria (PAH, rs5030858), Wilson's disease (ATP7B, rs76151636), factor VII deficiency (F7, rs36209567), kyphoscoliosis type of Ehlers‐Danlos syndrome (FKBP14, rs542489955), and several other recessive pathologies. We also make primary estimates of monogenic disease incidence in the population, with retinal dystrophy, cystic fibrosis, and phenylketonuria being the most frequent AR pathologies.ConclusionOur observations demonstrate the utility of population‐specific allele frequency data to the diagnosis of monogenic disorders using high‐throughput technologies.

Analysis of the Spectrum of ACE2 Variation Suggests a Possible Influence of Rare and Common Variants on Susceptibility to COVID-19 and Severity of Outcome

“…To characterize the spectrum of variants in the ACE2 gene in the Russian population, we analyzed an updated version of the WES dataset published previously ( Barbitoff et al, 2019 ) (see “Materials and Methods”). The raw dataset was composed of 1,359 samples.…”

“…An updated version of the Russian exome variant dataset ( Barbitoff et al, 2019 ) was used in this study. A total of 665 previously undescribed samples were added to the dataset, with most of the individuals being of European ethnicity (self-reported) and residents of the northwestern region of Russia.…”

“…For additional samples (not described in Barbitoff et al, 2019 ), library preparation and sequencing were performed as follows: DNA samples from the blood of all patients were isolated by phenol extraction. DNA concentration was determined using Quantus Fluorometer TM and QuantiFluor ® dsDNA System (Promega Corporation, Madison, WI, United States).…”

“…Bioinformatic analysis of the exome sequencing data was performed as described in Barbitoff et al (2019) . Only variants inside the ACE2 region (chrX:15,579,156-15,620,271) were considered in this analysis.…”

Next generation sequencing in sudden cardiac death (pilot study)

“…Поэтому без большого преувеличения можно сказать, что каждая статья по результатам исследования ВСС с помощью методов NGS представляет уникальные данные, сравнивать которые приходится очень осторожно, принимая во внимание вышеописанные различия. Остаются сложности анализа представителей русской популяции, связанные с их недостаточной представленностью в крупных проектах [39].…”