Identification and Functional Evaluation of Autosomal Recessive Nonsyndromic Hearing Impairment Genes in sub-Saharan Africans

非综合征性听力障碍（NSHI）是已知的最异质性的性状，有~170个定位位点和98个基因被鉴定。据推测，许多NSHI基因仍有待发现，因为许多不同的过程可能在内耳内发生故障并导致听力障碍。迄今为止，大多数NSHI基因鉴定研究都是在欧洲和亚洲确定的家族中进行的，在中东和印度次大陆的NSHI家族中发现的最多。为了获得NSHI所涉及的基因和变体的完整图片，需要在其他人群中进行基因鉴定，特别是撒哈拉以南非洲人。尽管有许多已鉴定的NSHI基因，但只有GJB 2和 GJB 6已在撒哈拉以南非洲进行了系统研究。在撒哈拉以南非洲的其他研究只报道了已知NSHI基因的新变异。此外，NSHI在非裔美国人中研究不足，并且对该人群中NSHI的遗传病因学知之甚少。因此，对撒哈拉以南非洲人和非洲裔美国人中NSHI-β致病变体的等位基因结构和频率知之甚少。我们使用OtoSCOPE测序阵列对来自喀麦隆的10个NSHI家族进行的初步研究表明，喀麦隆约30%的NSHI基因要么不存在于其他人群中，要么尚未被识别。然而，由于研究受试者确定的区域有限，30%的估计值可能较低。最近一项使用耳镜对51名听力受损的非裔美国人进行的研究表明，74%的研究对象在已知的NSHI基因中没有变异。我们估计NSHI基因中已知的致病性变异只能解释非裔美国人中约4.1%的ARNSHI，这是NSHI的最常见形式。为了鉴定对非洲血统个体重要的新的NSHI基因，我们将从南非（科萨血统）和喀麦隆收集125个分离早发性（<6岁）常染色体隐性NSHI的家族、500个早发性NSHI先证者和500个对照.这将是迄今为止在撒哈拉以南非洲进行的最大规模的NSHI研究。外显子组和全基因组测序，过滤方法和生物信息学评估将用于发现含有致病性NSHI变体的基因。这些基因将被功能和表达研究跟踪.在撒哈拉以南非洲人群中发现新的NSHI基因将使我们更好地了解听力障碍的遗传病因。提高对听觉过程至关重要的基因和蛋白质的知识将有助于开发用于NSHI早期诊断的治疗干预和遗传筛查方案。这项研究具有很高的公共卫生意义，特别是对少数民族人口，因为它将改善遗传筛查，并在未来预测人工耳蜗植入和治疗结果在撒哈拉以南非洲人，非洲裔美国人和西班牙裔美国人的非洲血统。

Nonsyndromic hearing impairment (NSHI) is the most heterogeneous trait known with ~170 mapped loci and 98 genes identified. It is hypothesized that many NSHI genes remain to be discovered due to the many different processes that can malfunction within the inner ear and cause hearing impairment. To date, most NSHI gene identification studies have been performed in families ascertained in Europe and Asia with the greatest number of findings in NSHI families from the Middle East and the Indian Subcontinent. In order to get a complete picture of the genes and variants involved in NSHI, gene identification needs to be performed in additional populations, in particular sub-­Saharan Africans. Despite many identified NSHI genes, only GJB2 and GJB6 have been systematically studied in sub-­Saharan Africans. Other studies in sub-­Saharan Africans have only reported novel variants in known NSHI genes. Additionally NSHI is understudied in African-­Americans and little is known about the genetic etiology of NSHI in this population. Therefore little is known about the allelic architecture and frequency of NSHI-­causal variants in sub-­Saharan Africans and African-­Americans. Our preliminary studies of 10 NSHI families from Cameroon using the OtoSCOPE sequencing array demonstrated that ~30% of NSHI genes in Cameroon are either not present in other populations or have yet to be identified. However this estimate of 30% may be low due to the limited region of study subject ascertainment. A recent study of 51 hearing impaired African-­Americans using OtoSCOPE demonstrated that 74% of the study subjects did not have a variant in a known NSHI gene. We estimate that known pathogenic variants in NSHI genes only explain ~4.1% of ARNSHI in African-­Americans, which is the most common form of NSHI. To identify novel NSHI genes that are important to individuals of African ancestry, we will collect 125 families that segregate early-­onset (<6 years of age) autosomal recessive NSHI, 500 early-­onset NSHI probands and 500 controls from South Africa (Xhosa ancestry) and Cameroon. This will be the largest study of NSHI to date in sub-­Saharan Africans. Exome and whole genome sequencing, filtering approaches and bioinformatic evaluation will be used to find genes containing pathogenic NSHI variants. These genes will be followed-­up with functional and expression studies. The identification of novel NSHI genes in the sub-­Saharan African population will give us a better insight into the genetic etiology of hearing impairment. Improved knowledge of genes and proteins that are essential to the auditory process will aid in the development of therapeutic interventions and genetic screening protocols for early diagnosis of NSHI. This study has high public health significance, in particular for minority populations, since it will improve genetic screening and in the future prediction of cochlear implant and treatment outcomes in sub-­Saharan Africans, African-­Americans and Hispanic-­Americans of African descent.