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: 10238026
• 负责人: SUZANNE M LEAL
• 金额: $ 57.47万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238026
• 关键词: 6 year old; Affect; African; African American; 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）是已知的异质性最大的性状，有大约170个定位位点和98个基因。据推测，由于许多不同的过程可能在内耳内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族中进行的，在中东和印度次大陆的NSHI家族中发现的结果最多。为了全面了解NSHI中涉及的基因和变异，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。尽管已经发现了许多NSHI基因，但只有GJB2和