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.

先天性听力障碍 (HI) 具有遗传异质性，使其基因诊断具有挑战性。研究新的 HI 基因和变体将增强我们对分子机制的理解并有助于基因诊断。我们使用来自加纳和巴基斯坦的两个大家庭受影响成员的 DNA 样本进行了外显子组测序和分析，分离了常染色体显性 (AD) 非综合征性 HI (NSHI)。使用计算机模拟方法，我们模拟并评估了可能的致病变异对蛋白质结构和功能的影响。我们在 SLC12A2 中发现了两个可能的致病变异， c.2935G >A:p.(E979K) 和 c.2939A>T:p.(E980V)，它们分别与加纳和巴基斯坦家族中的 NSHI 分离。SLC12A2编码对内耳内淋巴稳态至关重要的离子转运蛋白，最近有报道称其与综合征性和非综合征性 HI 有关。两种变体都映射到SLC12A2基因的可变剪接外显子 21 。外显子 21 编码 SLC12A2 细胞质尾部的 17 个残基，在物种间高度保守，优先在耳蜗组织中表达。对以往研究和我们当前数据的回顾表明，在 AD 非综合征性或综合征性 HI 的 10 个家族中，8 个 (80%) 在外显子 21 (48 bp) 的 17 个氨基酸残基区域内有变异，表明这alternate 域对内耳中的转运蛋白活动至关重要。SLC12A2的基因型谱得到扩展并参与ADNSHI中的 SLC12A2 得到确认。这些结果还证明了SLC12A2在不同人群（包括撒哈拉以南非洲人）的 ADNSHI 中发挥的作用。