Selection of Diagnostically Significant Regions of the SLC26A4 Gene Involved in Hearing Loss

Abstract

Screening pathogenic variants in the SLC26A4 gene is an important part of molecular genetic testing for hearing loss (HL) since they are one of the common causes of hereditary HL in many populations. However, a large size of the SLC26A4 gene (20 coding exons) predetermines the difficulties of its complete mutational analysis, especially in large samples of patients. In addition, the regional or ethno-specific prevalence of SLC26A4 pathogenic variants has not yet been fully elucidated, except variants c.919-2A>G and c.2168A>G (p.His723Arg), which have been proven to be most common in Asian populations. We explored the distribution of currently known pathogenic and likely pathogenic (PLP) variants across the SLC26A4 gene sequence presented in the Deafness Variation Database for the selection of potential diagnostically important parts of this gene. As a result of this bioinformatic analysis, we found that molecular testing ten SLC26A4 exons (4, 6, 10, 11, 13−17 and 19) with flanking intronic regions can provide a diagnostic rate of 61.9% for all PLP variants in the SLC26A4 gene. The primary sequencing of these SLC26A4 regions may be applied as an initial effective diagnostic testing in samples of patients of unknown ethnicity or as a subsequent step after the targeted testing of already-known ethno- or region-specific pathogenic SLC26A4 variants.

Keywords: SLC26A4; bioinformatic analysis; hearing loss; molecular testing; pathogenic variants; pendrin.

Figure 1

The proportions of different SLC26A4 variants (P, LP, VUS, LB and B). (a) Different types of variants in the entire SLC26A4 gene sequence. (b) Different types of variants in the SLC26A4 coding region. (c) Different types of variants in the SLC26A4 intronic regions.

Figure 2

The distribution of PLP variants located in the SLC26A4 coding region according to their molecular consequences.

Figure 3

The PLP variation rates in the SLC26A4 coding exons. The exons with the variation rates above the threshold (median = 21.39) are colored.

Figure 4

Distribution of PLP variants located in the SLC26A4 intronic regions. *—variant c.1342-2_1343dup (splice region variant /intron variant) was included; **—variant c.164+2_164+5delinsGAGG (“splice donor variant/intron variant”) was included.

Figure 5

The regions of the SLC26A4 gene sequence with the highest diagnostic value. The exons with high rates of the PLP variants with adjacent intronic regions are marked in orange color and highlighted with a dotted line. The most common PLP variants (n = 42, see in text and Table S2) are shown above the bars. Seven variants with both relatively high MAFs (>0.05%) and high mutation rates in patients are shown in red.