The frequent variant A57F in the GNE gene in patients from Russia has Finno-Ugric Mari origin

Abstract

Introduction: GNE-myopathy is a distal myopathy with adult-onset and initial involvement of anterior leg compartment. A founder effect has been demonstrated for some patients from several large cohorts in different countries.

Methods: In this study, we investigated the allele frequency of the c.169_170delinsTT (p.(Ala57Phe)) variant in the GNE gene (NM_001128227.3) among different ethnic populations (Mari, Tatar, and Bashkir) and estimated the age of the mutation's spread event.

Results: The c.169_170delinsTT variant in the GNE gene was detected in the Mari population with an allele frequency of 0.003788 but was not found in the Tatar or Bashkir populations. The disease incidence is estimated to be 1.43 (95% CI: 0.00092-43.78) per 100,000 in the Mari population. According to our study, the estimated age of the mutation's spread is 160.46 years (95% CI: 45.55-244.14).

Discussion: By comparing the information gathered with historical data on migration patterns in the Middle Volga region and estimating the age of the variant's dissemination, we propose hypotheses regarding its origin and the pathways through which it spread. In the current context of increased rate of interethnic marriages, investigating the spread of common pathogenic variants from historically isolated populations is important for molecular genetic diagnosis. This approach aids in optimizing diagnostic processes and reducing the diagnostic odyssey for patients.

Keywords: Bashkir; Finno-Ugric people; GNE; Mari; Nonaka myopathy; distal myopathy; founder effect; frequent variant.

FIGURE 1

Places of birth of patients with GNEM caused by the c.169_170delinsTT variant in a homozygous state or compound heterozygous state with other variants on the map. The enlarged area shown in the map is the Mari El Republic. The Volzhsky district is highlighted as the place of origin for patients 1.1, 1.2, 1.3, and 6.1. Additionally, the ancestors of patient 4.1, who now resides in Yoshkar-Ola, also originated from the Volzhsky district. Colored arrows indicate the historical trajectory of Mari migration in 16–19 centuries. Created with mapchart.net.

FIGURE 2

Lanes: 1—pUC19 DNA/Mspl (HpaII) Marker; 2—unrestricted PCR-fragment (357 bp); 3, 4—two products after restriction indicating WT/WT (189 bp, 168 bp); 5—three products after restriction indicating mut/mut (168 bp, 122 bp, 67 bp); 6—four products after restriction indicating WT/mut (189 bp, 168 bp, 122 bp, 67 bp).

FIGURE 3

Genetic analysis of GNEM in Mari population in UCSC Genome Browser: ideogram of human chromosome 9 (a); detailed view of regions of homozygosity in patients (depicted in black bars) and NCBI RefSeq HGMD subset of human genes (blue) (b); detailed view of GNE gene structure (in dark blue) with NM_001128227.3: c.169_170delinsTT variant location (magenta) (c).