Hearing impairment (HI) is a common disorder of sensorineural function with a highly heterogeneous genetic background. Although substantial progress has been made in the understanding of the genetic etiology of hereditary HI, many genes implicated in HI remain undiscovered. Via exome and Sanger sequencing of DNA samples obtained from consanguineous Pakistani families that segregate profound prelingual sensorineural HI, we identified rare homozygous missense variants in four genes (ADAMTS1, MPDZ, MVD, and SEZ6) that are likely the underlying cause of HI. Linkage analysis provided statistical evidence that these variants are associated with autosomal recessive nonsyndromic HI. In silico analysis of the mutant proteins encoded by these genes predicted structural, conformational or interaction changes. RNAseq data analysis revealed expression of these genes in the sensory epithelium of the mouse inner ear during embryonic, postnatal, and adult stages. Immunohistochemistry of the mouse cochlear tissue, further confirmed the expression of ADAMTS1, SEZ6, and MPDZ in the neurosensory hair cells of the organ of Corti, while MVD expression was more prominent in the spiral ganglion cells. Overall, supported by in silico mutant protein analysis, animal models, linkage analysis, and spatiotemporal expression profiling in the mouse inner ear, we propose four new candidate genes for HI and expand our understanding of the etiology of HI.

听力障碍（HI）是一种常见的感觉神经功能障碍，具有高度异质性的遗传背景。尽管在了解遗传性 HI 的遗传病因方面已经取得了实质性进展，但许多与 HI 相关的基因仍未被发现。通过对从分离出严重语前感音神经性 HI 的巴基斯坦近亲家庭获得的 DNA 样本进行外显子组和桑格测序，我们在四个基因（ ADAMTS1 、 MPDZ 、 MVD和SEZ6 ）中发现了罕见的纯合错义变异，这些基因可能是 HI 的根本原因。连锁分析提供了统计证据，表明这些变异与常染色体隐性遗传非综合征性 HI 相关。对这些基因编码的突变蛋白进行计算机分析，预测结构、构象或相互作用的变化。 RNAseq 数据分析揭示了这些基因在胚胎、出生后和成年阶段的小鼠内耳感觉上皮中的表达。小鼠耳蜗组织的免疫组化进一步证实ADAMTS1、SEZ6和MPDZ在柯蒂氏器感觉毛细胞中表达，而MVD在螺旋神经节细胞中表达更为突出。总体而言，在计算机突变蛋白分析、动物模型、连锁分析和小鼠内耳时空表达谱的支持下，我们提出了 HI 的四个新候选基因，并扩展了我们对 HI 病因学的理解。