Updated carrier rates for c.35delG (GJB2) associated with hearing loss in Russia and common c.35delG haplotypes in Siberia

Abstract

BackgroundMutations in GJB2 gene are a major causes of deafness and their spectrum and prevalence are specific for various populations. The well-known mutation c.35delG is more frequent in populations of Caucasian origin. Data on the c.35delG prevalence in Russia are mainly restricted to the European part of this country. We aimed to estimate the carrier frequency of c.35delG in Western Siberia and thereby update current data on the c.35delG prevalence in Russia. According to a generally accepted hypothesis, c.35delG originated from a common ancestor in the Middle East or the Mediterranean ~ 10,000–14,000 years ago and spread throughout Europe with Neolithic migrations. To test the c.35delG common origin hypothesis, we have reconstructed haplotypes bearing c.35delG and evaluated the approximate age of c.35delG in Siberia.MethodsThe carrier frequency of c.35delG was estimated in 122 unrelated hearing individuals living in Western Siberia. For reconstruction of haplotypes bearing c.35delG, polymorphic D13S141, D13S175, D13S1853 flanking the GJB2 gene, and intragenic rs3751385 were genotyped in deaf patients homozygous for c.35delG (n = 24) and in unrelated healthy individuals negative for c.35delG (n = 67) living in Siberia.ResultsWe present updated carrier rates for c.35delG in Russia complemented by new data on c.35delG carrier frequency in Russians living in Western Siberia (4.1%). Two common D13S141-c.35delG-D13S175-D13S1853 haplotypes, 126-c.35delG-105-202 and 124-c.35delG-105-202, were reconstructed in the c.35delG homozygotes from Siberia. Moreover, identical allelic composition of the two most frequent c.35delG haplotypes restricted by D13S141 and D13S175 was established in geographically remote regions: Siberia and Volga-Ural region (Russia) and Belarus (Eastern Europe).ConclusionsDistribution of the c.35delG carrier frequency in Russia is characterized by pronounced ethno-geographic specificity with a downward trend from west to east. Comparative analysis of the c.35delG haplotypes supports a common origin of c.35delG in some regions of Russia (Volga-Ural region and Siberia) and in Eastern Europe (Belarus). A rough estimation of the c.35delG age in Siberia (about 4800 to 8100 years ago) probably reflects the early formation stages of the modern European population (including the European part of the contemporary territory of Russia) since the settlement of Siberia by Russians started only at the end of sixteenth century.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0650-5) contains supplementary material, which is available to authorized users.

High Rates of Three Common GJB2 Mutations c.516G>C, c.-23+1G>A, c.235delC in Deaf Patients from Southern Siberia Are Due to the Founder Effect

“…In some cases, analysis of genetic background of these mutations allowed to elucidate their approximate age and a presumable region of origin. The key role of the founder effect in prevalence of mutation c.35delG was established in numerous studies by analysis of the c.35delG-bearing haplotypes: this mutation first appeared approximately 10000–14000 years ago in the Middle East and/or the Mediterranean and then spread by human migrations throughout Europe and worldwide [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. The conservation of haplotype bearing mutation c.167delT found in Ashkenazi Jews suggests a single origin of this mutation which began to spread since a presumed Ashkenazi population bottleneck [ 15 , 16 ].…”

Analysis of GJB2 Gene Mutations in 1330 Deafness Cases of Major Ethnic Groups in Northwest China

“…Multiple studies on the Caucasian ethnic background have shown that c.35delG is a hotspot mutation in this group, representing an ancestral mutation in Caucasians. 15 , 18 - 20 In our study, all ethnic groups were found to harbor c.35delG, the mutation rate of c.35delG in Kazakh deaf patients with a Caucasian majority was significantly higher than that in Uygur patients with Caucasian and Mongolian integration ( P < .001), and the mutation rate in patients of Uygur nationality was significantly higher than that in patients of Han nationality with a Mongolian majority ( P < .001). This also verifies that c.35delG is a founder mutation in Caucasians and shows that all ethnic groups have a Caucasian background.…”

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

“…Unfortunately, both genotyping methods failed to achieve full genotyping precision. For example, analysis using the TaqMan custom panel did not reveal any carriers of the GJB2 variant rs80338939 (ESSE-Vologda and BCS), which is most common among Russian patients with SNHL [ 23 , 38 ]; thus, we suggested the incorrect work of the assay (assay ID ANEPWEH). This variant was detected using the NGS custom panel with AF of 1.74% (ESSE-Ivanovo).…”