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

Abstract

The frequency of a genetic variant in a population is crucially important for accurate interpretation of known and novel variant effects in medical genetics. Recently, several large allele frequency databases, such as Genome Aggregation Database (gnomAD), have been created to serve as a global reference for such studies. However, frequencies of many rare alleles vary dramatically between populations, and population-specific allele frequency can be more informative than the global one. Many countries and regions (including Russia) remain poorly studied from the genetic perspective. Here, we report the first successful attempt to integrate genetic information between major medical genetic laboratories in Russia. We construct an expanded reference set of genetic variants by analyzing 6,096 exome samples collected in two major Russian cities of Moscow and St. Petersburg. An approximately tenfold increase in sample size compared to previous studies allowed us to identify genetically distinct clusters of individuals within an admixed population of Russia. We show that up to 18 known pathogenic variants are overrepresented in Russia compared to other European countries. We also identify several dozen high-impact variants that are present in healthy donors despite either being annotated as pathogenic in ClinVar or falling within genes associated with autosomal dominant disorders. The constructed database of genetic variant frequencies in Russia has been made available to the medical genetics community through a variant browser available at http://ruseq.ru.

Identification of Pathogenic Variant Burden and Selection of Optimal Diagnostic Method Is a Way to Improve Carrier Screening for Autosomal Recessive Diseases

“…In general, our data agree with previously published studies where differences between the Russian and European populations were shown for some rare variants [ 9 , 10 ]. It was shown previously that CFTRdele2,3 variant (hg19::chr7:117138367-117159446del) has Slavic origin with the highest frequency among CF patients of 6.4% in Czechia (5.8% in Russia) [ 39 ].…”

“…Furthermore, we performed a comparison of the obtained AF with those from recently published data for the Russian population [ 6 , 10 ]. There were no statistically significant differences in AF between our results and these two population studies, which is consistent with a close ethnic composition of studied groups of samples.…”

“…In addition, we compared our AF results to those in the known data for the Russian population, where available [ 6 , 10 ]. A total of six CFTR variants had AF for the Russian population ( n = 1324) in the study by Petrova et al [ 6 ]—rs121908751 (E92K), rs397508686 (L138ins), rs113993960 (F508del), rs121908776 (1677delTA), rs77010898 (W1282X), and hg19::chr7:117138367-117159446 (CFTRdele2,3).…”

“…There are no carrier screening programs in Russia, and the majority of the available panels [ 4 , 5 , 6 ] detect only a few variants most common for the disease. Besides there are only a limited number of studies with Russian population-based allele frequency (AF) data [ 6 , 7 , 8 , 9 , 10 ].…”

A Case of Severe Left-Ventricular Noncompaction Associated with Splicing Altering Variant in the FHOD3 Gene

“…As a result, both in the patient and his sister, we found a variant in the FHOD3 gene (chr18:36652930 G>A) affecting the canonical donor splice site after exon 12 of cardiospecific isoform (NM_001281740.3: c.1646+1G>A). This variant was absent from the gnomAD population database as well as from the recently emerged open database of genetic variation in Russian population “RuSeq” [ 20 ], but it was recently reported by Semsarian et al [ 21 ] in their HCM study. It also had a ClinVar entry describing it as a variant of uncertain significance (VUS) [ 22 ] in HCM without further details.…”