Abstract
Congenital hearing impairment (HI) is genetically heterogeneous making its genetic diagnosis challenging. Investigation of novel HI genes and variants will enhance our understanding of the molecular mechanisms and to aid genetic diagnosis. We performed exome sequencing and analysis using DNA samples from affected members of two large families from Ghana and Pakistan, segregating autosomal-dominant (AD) non-syndromic HI (NSHI). Using in silico approaches, we modeled and evaluated the effect of the likely pathogenic variants on protein structure and function. We identified two likely pathogenic variants in SLC12A2, c.2935G>A:p.(E979K) and c.2939A>T:p.(E980V), which segregate with NSHI in a Ghanaian and Pakistani family, respectively. SLC12A2 encodes an ion transporter crucial in the homeostasis of the inner ear endolymph and has recently been reported to be implicated in syndromic and non-syndromic HI. Both variants were mapped to alternatively spliced exon 21 of the SLC12A2 gene. Exon 21 encodes for 17 residues in the cytoplasmatic tail of SLC12A2, is highly conserved between species, and preferentially expressed in cochlear tissues. A review of previous studies and our current data showed that out of ten families with either AD non-syndromic or syndromic HI, eight (80%) had variants within the 17 amino acid residue region of exon 21 (48 bp), suggesting that this alternate domain is critical to the transporter activity in the inner ear. The genotypic spectrum of SLC12A2 was expanded and the involvement of SLC12A2 in ADNSHI was confirmed. These results also demonstrate the role that SLC12A2 plays in ADNSHI in diverse populations including sub-Saharan Africans.
Highlights
Hearing impairment (HI) is the most common sensory human disorder [1]
HI genetics is highly heterogeneous [2]; to date, >120 genes have been implicated in non-syndromic HI (NSHI) [3]
Analysis Sanger sequencing was used to confirm and verify segregation of the identified SLC12A2 [NM_001046.2:c.2935G>A:p.(E979K) and c.2939A>T: Both the p.(E979K) and p.(E980V) variants were classified as likely pathogenic (Table S1) and lie adjacent in an intracellular area of the protein, which is highly conserved amongst species (Fig. 3A)
Summary
Hearing impairment (HI) is the most common sensory human disorder [1]. the characterization of HI is complex, it may be described as conductive, sensorineural, or mixed; syndromic or non-syndromic (NS); prelingual or post-lingual, progressive, or nonprogressive [2]. Pathogenic variants in the gap junction protein beta 2 (GJB2), encoding for connexin 26, remain the most common genetic cause of NSHI [4]. We used exome sequencing (ES) to identify pathogenic variants in SLC12A2 in two families, one Ghanaian and the other Pakistani, both segregating autosomal-dominant (AD) NSHI. The SLC12A are transmembrane proteins that mediate electroneutral transport of ions, influx and efflux of Na+, K+, and Cl− ions [8]. They regulate physiological function, including ion transport, modulate inhibitory synaptic transmission, and maintain and regulate cell volume [9]
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