Unique spectra of deafness-associated mutations in Mongolians provide insights into the genetic relationships among Eurasian populations

Abstract

Genetic factors are an important cause of idiopathic sensorineural hearing impairment (SNHI). From the epidemiological perspective, mutations of three deafness genes: GJB2, SLC26A4, and MT-RNR1, are much more prevalent than those of other genes worldwide. However, mutation spectra of common deafness genes differ remarkably across different populations. Here, we performed comprehensive genetic examination and haplotype analyses in 188 unrelated Mongolian families with idiopathic SNHI, and compared their mutation spectra and haplotypes to those of other European and Asian cohorts. We confirmed genetic diagnoses in 18 (9.6%) of the 188 families, including 13 with bi-allelic GJB2 mutations, three with bi-allelic SLC26A4 mutations, and two with homoplasmic MT-RNR1 m.1555A>G mutation. Moreover, mono-allelic mutations were identified in 17 families (9.0%), including 14 with mono-allelic GJB2 mutations and three with mono-allelic SLC26A4 mutations. Interestingly, three GJB2 mutations prevalent in other populations, including c.35delG in Caucasians, c.235delC in East Asians, and c.-23+1G>A in Southwest and South Asians, were simultaneously detected in Mongolian patients. Haplotype analyses further confirmed founder effects for each of the three mutations, indicating that each mutation derived from its ancestral origin independently. By demonstrating the unique spectra of deafness-associated mutations, our findings may have important clinical and scientific implications for refining the molecular diagnostics of SNHI in Mongolian patients, and for elucidating the genetic relationships among Eurasian populations.

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

“…Taking into account the complexity of ethnic history of Tuvinians, it remains unclear, who actually were the c.516G>C founders—different ancient Turkic- or Mongolic-speaking groups or other aboriginal peoples who lived there. The introduction of c.516G>C into Tuva territory with migration flows of ancient Mongolic-speaking groups is not consistent with the finding of c.516G>C in only one deaf patient from Mongolia [ 14 , 59 ] as well as with its absence in Mongolian patients living in China [ 60 , 61 ]. It is known that several nomadic Tuvinian groups roamed in the past across the territories of Tuva and Mongolia had remained in Mongolia when Tuva was separated from Mongolia to become under Russian protectorate after the breakup of the Qing Empire in 1911–1912 [ 54 , 55 ].…”

“…The proportion of the splice donor site mutation c.-23+1G>A reaches 27.6% of all mutant GJB2 alleles in Tuvinian deaf patients [ 41 ] and 14.8% in Altaian patients [ 42 ]. Splice donor site GJB2 variant c.-23+1G>A has been detected among deaf patients of different origin around the world [ 14 , 22 , 59 , 62 , 63 , 64 , 65 , 66 , 67 ]. The extremely high prevalence of c.-23+1G>A (up to 92.2% of all mutant GJB2 alleles found in patients and carrier frequency reaching of 10.2%) observed in Yakuts, indigenous Turkic-speaking people living in the subarctic region of Russia (the Sakha Republic, Eastern Siberia), was explained by the founder effect in an isolated population and a probable selective advantage for the c.-23+1G>A heterozygotes in severe subarctic climate [ 22 , 67 , 68 ].…”

“…The extremely high prevalence of c.-23+1G>A (up to 92.2% of all mutant GJB2 alleles found in patients and carrier frequency reaching of 10.2%) observed in Yakuts, indigenous Turkic-speaking people living in the subarctic region of Russia (the Sakha Republic, Eastern Siberia), was explained by the founder effect in an isolated population and a probable selective advantage for the c.-23+1G>A heterozygotes in severe subarctic climate [ 22 , 67 , 68 ]. The c.-23+1G>A is also the most common mutation in deaf Mongolian patients from Mongolia [ 14 , 59 ].…”

“…To our knowledge, the haplotypes bearing c.-23+1G>A were analyzed only in a few studies [ 14 , 22 , 59 , 69 ]. Tekin et al (2010) suggested diverse origins of c.-23+1G>A based on multiple c.-23+1G>A-associated haplotypes found in comparative analysis of seven Mongolian and three Anatolian Turkish c.-23+1G>A homozygous patients [ 59 ].…”

“…Specific ethno-geographic prevalence patterns were found for many of them [ 3 , 4 , 5 ]. For instance, variant c.35delG (p.Gly12Valfs*2) is prevalent in deaf patients of Caucasian origin [ 3 , 6 ]; c.235delC (p.Leu79Cysfs*3) is common in some Asian populations [ 4 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]; c.167delT (p.Leu56Argfs*26) is frequent in Ashkenazi Jews [ 15 , 16 ]; c.427C>T (p.Arg143Trp) is specific for population of Ghana (West Africa) and Peru (South America) [ 17 , 18 ]; c.71G>A (p.Trp24*) is widely spread in Indians and European Gypsies [ 19 , 20 , 21 ]; c.109G>A (p.Val37Ile) prevails in populations of Southeast Asia [ 5 ]; the splice donor variant c.-23+1G>A was found in many populations worldwide but extremely high prevalence of c.-23+1G>A was detected among Yakuts (Eastern Siberia, Russia) [ 22 ]; c.131G>A (p.Trp44*) was found with high frequency among descendants of ancestral Mayan population in Guatemala [ 23 ].…”