Physiologically, the human and murine hearing systems are very similar, justifying the extensive use of mice in experimental models for hearing impairment (HI). About 340 murine HI genes have been reported; however, whether variants in all human-mouse ortholog genes contribute to HI has been rarely investigated. In humans, nearly 120 HI genes have been identified to date, with GJB2 and GJB6 variants accounting for half of congenital HI cases, of genetic origin, in populations of European and Asian ancestries, but not in most African populations. The contribution of variants in other known genes of HI among the populations of African ancestry is poorly studied and displays the lowest pick-up rate. We used whole exome sequencing (WES) to investigate pathogenic and likely pathogenic (PLP) variants in 34 novel human-mouse orthologs HI genes, in 40 individuals from Cameroon and South Africa diagnosed with non-syndromic hearing impairment (NSHI), and compared the data to WES data of 129 ethnically matched controls. In addition, protein modeling for selected PLP gene variants, gene enrichment, and network analyses were performed. A total of 4/38 murine genes, d6wsu163e, zfp719, grp152 and minar2, had no human orthologs. WES identified three rare PLP variants in 3/34 human-mouse orthologs genes in three unrelated Cameroonian patients, namely: OCM2, c.227G>C p.(Arg76Thr) and LRGI1, c.1657G>A p.(Gly533Arg) in a heterozygous state, and a PLP variant MCPH1, c.2311C>G p.(Pro771Ala) in a homozygous state. In silico functional analyses suggest that these human-mouse ortholog genes functionally co-expressed interactions with well-established HI genes: GJB2 and GJB6. The study found one homozygous variant in MCPH1, likely to explain HI in one patient, and suggests that human-mouse ortholog variants could contribute to the understanding of the physiology of hearing in humans.

Impact statement

Despite, human and murine hearing system being very similar, the contribution of variants in relevant mouse-ortholog genes to hearing impairment (HI) has not been fully investigated. The contribution of variants in the known non-syndromic hearing impairment (NSHI) genes among Africans is poorly studied, suggesting that the novel gene(s) and mutations are yet to be discovered in NSHI in the African populations. Using whole exome sequencing (WES), this study identified rare candidate pathogenic and likely pathogenic (PLP) variants in 3/34 novel human-mouse ortholog genes in 3/40 individuals, with one homozygous variant, MCPH1, c.2311C>G p.(Pro771Ala), likely to explain HI in one patient. In silico functional analyses suggest that these human-mouse ortholog genes could contribute to the understanding of the physiology of hearing in humans and thus the variants identified in those genes deserve additional investigations.

中文翻译：

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全外显子组测序在被诊断为非综合征性听力障碍的非洲个体中识别出新的人鼠直系同源基因中的罕见编码变体

在生理上，人类和鼠类的听力系统非常相似，这证明了在听力障碍 (HI) 实验模型中广泛使用小鼠是合理的。已报道了大约 340 个鼠 HI 基因；然而，很少有人研究是否所有人类小鼠直系同源基因的变异都会导致 HI。在人类中，迄今为止已鉴定出近 120 个 HI 基因，其中GJB2和GJB6在欧洲和亚洲血统的人群中，占遗传起源的先天性 HI 病例的一半，但在大多数非洲人群中不存在。其他已知 HI 基因的变异在非洲血统人群中的贡献研究很少，并且显示出最低的拾取率。我们使用全外显子组测序 (WES) 在喀麦隆和南非诊断为非综合征性听力障碍 (NSHI) 的 40 个个体中研究了 34 个新的人鼠直系同源物 HI 基因中的致病性和可能致病性 (PLP) 变异，并比较了129 名种族匹配对照的 WES 数据。此外，对选定的 PLP 基因变体、基因富集和网络分析进行了蛋白质建模。共4/38个鼠基因，d6wsu163e，zfp719, grp152和minar2,没有人类直系同源物。WES 在三名无关喀麦隆患者的 3/34 人鼠直系同源基因中鉴定出三种罕见的 PLP 变体，即：OCM2，c.227G>C p.(Arg76Thr) 和LRGI1，c.1657G>A p.(Gly533Arg)杂合状态和纯合状态的 PLP 变体MCPH1， c.2311C>G p.(Pro771Ala)。计算机功能分析表明，这些人-小鼠直系同源基因在功能上与公认的 HI 基因：GJB2和GJB6共表达相互作用。该研究在MCPH1中发现了一个纯合变体，可能解释了一名患者的 HI，并表明人鼠直系同源变异可能有助于理解人类听力的生理学。

影响陈述

尽管人类和小鼠的听力系统非常相似，但相关小鼠直系同源基因的变异对听力障碍 (HI) 的贡献尚未得到充分研究。对非洲人已知非综合征听力障碍 (NSHI) 基因变异的贡献研究很少，这表明在非洲人群的 NSHI 中尚未发现新基因和突变。使用全外显子组测序 (WES)，本研究在 3/40 个体的 3/34 个新型人鼠直系同源基因中鉴定了罕见的候选致病性和可能致病性 (PLP) 变异，其中一个纯合变异，MCPH1，c.2311C>G p .(Pro771Ala)，可能解释了一名患者的 HI。计算机功能分析表明，这些人鼠直系同源基因可能有助于理解人类听力的生理学，因此在这些基因中鉴定出的变异值得进一步研究。