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

撒哈拉以南非洲人常染色体隐性非综合征性听力障碍基因的鉴定和功能评估

• 批准号: 10468748
• 负责人: SUZANNE M LEAL
• 金额: $ 57.08万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468748
• 关键词: 6 year old; Affect; African; African American population; African ancestry; Age; Alleles; American; Architecture; Asia; Auditory; Bioinformatics; Cameroon; Child; Cochlear Implants; Cognitive; Copy Number Polymorphism; Country; Data; Data Analyses; Databases; Diagnosis; Diagnostic; Early Diagnosis; East Indian; Eligibility Determination; Emotional; Europe; Evaluation; Family; Family Study; Family history of; Family member; Frequencies; Future; GJB2 gene; GJB6 gene; Gene Frequency; Gene Proteins; Genes; Genetic Predisposition to Disease; Genetic Screening; Genetic study; Genome; Genotype; Hearing; Hearing Tests; Hispanic Americans; Individual; Intervention; Knowledge; Labyrinth; Language Development; Maps; Methods; Middle East; Minority Groups; Modality; Modeling; Otoscopes; Pathogenicity; Population; Prevalence; Probability; Process; Public Health; Quality Control; Reporting; Sample Size; Sampling; Sensory; South Africa; Speech Development; Study Subject; Syndrome; Testing; Therapeutic Intervention; Treatment outcome; Untranslated RNA; Variant; causal variant; early onset; early screening; exome; exome sequencing; experience; follow-up; genetic variant; genome sequencing; hearing impairment; hereditary hearing loss; improved; insight; member; mitochondrial genome; next generation sequence data; novel; ototoxicity; proband; rare variant; research clinical testing; segregation; social; therapeutic development; therapy development; tool; trait; treatment strategy; whole genome

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.

非综合征性听力障碍 (NSHI) 是已知的最具异质性的性状，已确定约 170 个定位基因座和 98 个基因。据推测，由于许多不同的过程可能导致内耳发生故障并导致听力障碍，因此许多 NSHI 基因仍有待发现。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庭中进行的，其中来自中东和印度次大陆的 NSHI 家庭的发现数量最多。为了全面了解 NSHI 所涉及的基因和变异，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。尽管已鉴定出许多 NSHI 基因，但只有 GJB2 和 GJB6 已在撒哈拉以南非洲地区进行了系统研究。其他针对撒哈拉以南非洲人的研究仅报告了已知 NSHI 基因的新变异。此外，对非裔美国人的 NSHI 的研究还不够，并且对该人群中 NSHI 的遗传病因知之甚少。因此，人们对撒哈拉以南非洲人和非裔美国人中 NSHI 因果变异的等位基因结构和频率知之甚少。我们使用 OtoSCOPE 测序芯片对喀麦隆 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，由于研究对象确定的区域有限，30% 的估计值可能较低。最近使用 OtoSCOPE 对 51 名听力受损的非洲裔美国人进行的一项研究表明，74% 的研究对象在已知的 NSHI 基因中不存在变异。我们估计 NSHI 基因中已知的致病性变异只能解释大约 4.1% 的非裔美国人 ARNSHI，这是 NSHI 最常见的形式。为了鉴定对非洲血统个体重要的新型 NSHI 基因，我们将收集 125 个分离早发（<6 岁）常染色体隐性 NSHI 的家族、500 个早发 NSHI 先证者和来自南非（科萨血统）和喀麦隆的 500 个对照。这将是迄今为止针对撒哈拉以南非洲人进行的最大规模的 NSHI 研究。外显子组和全基因组测序、过滤方法和生物信息评估将用于寻找含有致病性 NSHI 变异的基因。这些基因将进行功能和表达研究。在撒哈拉以南非洲人群中鉴定出新的 NSHI 基因将使我们更好地了解听力障碍的遗传病因。提高对听觉过程所必需的基因和蛋白质的了解将有助于制定 NSHI 早期诊断的治疗干预措施和基因筛查方案。这项研究具有很高的公共卫生意义，特别是对于少数群体而言，因为它将改善撒哈拉以南非洲人、非裔美国人和非洲裔西班牙裔美国人的基因筛查以及未来人工耳蜗植入和治疗结果的预测。