# Comparative analysis of haplotypes carrying pathogenic variants c.1545T>G, c.2027T>A and c.919-2A>G of the SLC26A4 gene in patients with hearing loss from the Tyva Republic (Southern Siberia)

## TL;DR

This study analyzes genetic variants in the SLC26A4 gene linked to hearing loss in the Tyva Republic, showing how these variants are inherited from common ancestors.

## Contribution

The study identifies specific haplotypes associated with three SLC26A4 pathogenic variants in Tuvinian patients, supporting a founder effect in their prevalence.

## Key findings

- Each pathogenic variant in SLC26A4 has a distinct haplotype background inherited from different founder ancestors.
- The high prevalence of SLC26A4-related hearing loss in Tuva is attributed to a cumulative founder effect.
- Genotyping data from STRs and SNPs helped reconstruct haplotypes for the analyzed pathogenic variants.

## Abstract

Pathogenic variants in the SLC26A4 gene (OMIM #605646), leading to non-syndromic recessive hearing loss type 4 (DFNB4) and Pendred syndrome, significantly contribute to the etiology of hearing loss in many populations of the world. The spectrum and prevalence of different pathogenic SLC26A4 variants are characterized by wide ethnogeographical variability. A high frequency of some of them in certain regions of the world may indicate either their independent origin or be a consequence of the founder effect. The proportion of SLC26A4-associated hearing loss in Tuvinian patients (the Tyva Republic, Southern Siberia) is one of the highest in the world (28.2 %) and the vast majority of mutant SLC26A4 alleles are represented by three pathogenic variants c.919-2A>G, c.2027T>A and c.1545T>G (69.3, 17.5 and 8.0 %, respectively). Their overall carrier frequency in the Tuvinian population reaches 7.1 %. The accumulation of these variants in Tuvinian patients suggests a role of the founder effect in their prevalence in Tuva, which can be confirmed by the common genetic background (haplotypes) for each of them. For reconstruction of haplotypes in the carriers of variants c.1545T>G and c.2027T>A, the genotyping data of a panel of polymorphic genetic markers were used: five STRs (four of them flank the SLC26A4 gene at different distances and one is intragenic) and nine intragenic SNPs. Comparative analysis of the reconstructed haplotypes for c.1545T>G and c.2027T>A with previously obtained data on haplotypes for the c.919-2A>G variant showed that each of the analyzed variants has a specific (similar for all carriers of a particular variant) genetic background, apparently inherited from different “founder ancestors”. These data confirm the cumulative founder effect in the prevalence of pathogenic variants c.1545T>G, c.2027T>A, and c.919- 2A>G of the SLC26A4 gene in the indigenous population of the Tyva Republic. The obtained data are relevant both for predicting the prevalence of SLC26A4-caused hearing loss and for development of region-specific DNA diagnostics of inherited hearing loss in the Tyva Republic.