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.

非综合性听力障碍（NSHI）是最异构的特征，鉴定出约170个映射基因座和98个基因。假设许多NSHI基因仍然有待发现，这是由于许多不同的过程可能在内耳内部发生故障并导致听力障碍。迄今为止，在欧洲和亚洲确定的家庭中，大多数NSHI基因识别研究都进行了，其中来自中东和印度次大陆的NSHI家族的发现数量最多。为了完整地了解NSHI涉及的基因和变体，需要在其他人群中，尤其是撒哈拉以南非洲人进行基因鉴定。尽管有许多NSHI基因，但只有GJB2和 GJB6在撒哈拉以南非洲人中进行了系统的研究。撒哈拉以南非洲人的其他研究仅报道了已知的NSHI基因中的新型变异。此外，在非裔美国人中可以理解NSHI，对该人群的NSHI遗传病因知之甚少。因此，对撒哈拉以南非洲人和非裔美国人的NSHI-CAUSAL变体的等位基因建筑和频率知之甚少。我们对使用耳镜测序阵列对喀麦隆的10个NSHI家族的初步研究表明，喀麦隆中约有30％的NSHI基因在其他人群中不存在，或者尚未确定。但是，由于研究学科确定区域有限，该30％的估计值可能很低。一项对使用耳镜的51个听力障碍者的研究障碍者的研究表明，该研究受试者的74％在已知的NSHI基因中没有变体。我们估计，NSHI基因中已知的病原变异仅解释了非裔美国人的Arnshi的约4.1％，这是NSHI最常见的形式。为了确定对非洲血统很重要的新型NSHI基因，我们将收集125个家庭，这些家庭将早期发作（<6岁）的常染色体隐性nshi，500个早期发作的NSHI Probands和500个来自南非（Xhosa Ancestry）和摄影师的家庭。这将是迄今为止在撒哈拉以南非洲人的NSHI最大的研究。外显子和整个基因组测序，过滤方法和生物信息学评估将用于查找含有致病性NSHI变体的基因。这些基因将进行功能和表达研究。在撒哈拉以南非洲人口中新型NSHI基因的鉴定将使我们更好地了解听力障碍的遗传病因。改善对听觉过程至关重要的基因和蛋白质的知识将有助于发展热干预措施和基因筛查方案，以早期诊断NSHI。这项研究具有很高的公共卫生意义，特别是对于少数群体，因为它将改善伊斯兰教非洲人，非裔美国人和非洲血统的西班牙裔美国人的人工耳蜗植入物和治疗结果的未来预测。