Insight into the Natural History of Pathogenic Variant c.919-2A>G in the SLC26A4 Gene Involved in Hearing Loss: The Evidence for Its Common Origin in Southern Siberia (Russia)

Abstract

Pathogenic variants in the SLC26A4 gene leading to nonsyndromic recessive deafness (DFNB4), or Pendred syndrome, are some of the most common causes of hearing loss worldwide. Earlier, we found a high proportion of SLC26A4-related hearing loss with prevailing pathogenic variant c.919-2A>G (69.3% among all mutated SLC26A4 alleles that have been identified) in Tuvinian patients belonging to the indigenous Turkic-speaking Siberian people living in the Tyva Republic (Southern Siberia, Russia), which implies a founder effect in the accumulation of c.919-2A>G in Tuvinians. To evaluate a possible common origin of c.919-2A>G, we genotyped polymorphic STR and SNP markers, intragenic and flanking SLC26A4, in patients homozygous for c.919-2A>G and in healthy controls. The common STR and SNP haplotypes carrying c.919-2A>G were revealed, which convincingly indicates the origin of c.919-2A>G from a single ancestor, supporting a crucial role of the founder effect in the c.919-2A>G prevalence in Tuvinians. Comparison analysis with previously published data revealed the identity of the small SNP haplotype (~4.5 kb) in Tuvinian and Han Chinese carriers of c.919-2A>G, which suggests their common origin from founder chromosomes. We assume that c.919-2A>G could have originated in the geographically close territories of China or Tuva and subsequently spread to other regions of Asia. In addition, the time intervals of the c.919-2A>G occurrence in Tuvinians were roughly estimated.