Hearing Impairment Genetics Studies in Africa (HI-GENES Africa)

高基因非洲项目摘要/摘要 尽管已鉴定出大量基因，但仅对GJB2和GJB6进行了系统研究 在撒哈拉以南非洲人中，NSHI因果变异的流行率接近于零，我们估计 在非裔美国人中，已知的NSHI基因只能解释约4.1%的常染色体隐性(AR)NSHI。在 目前的项目名为HI-基因非洲，指的是非洲的听力障碍遗传学研究，我们 建议使用全基因组测序(WES)，研究迄今为止撒哈拉以南地区最大的样本 来自喀麦隆、马里、加纳和南非的非洲人以语言前ARNSHI识别小说 NSHI基因，并更好地了解非洲人群中NSHI的遗传病因。 目的1)确定来自喀麦隆、马里、加纳、 还有南非。我们将确定125个分离早发性(&lt；6岁)ARNSHI的家庭。 对于每个家庭，将确定多个受影响的成员(每个家庭至少有两个)和未受影响的成员。 此外，500名患有早发性HI的先证者(&lt；6岁)有强烈的ARNSHI证据 将会被确定。先证者和家属将由临床和医生仔细评估 听力测试，以排除由于感染性和耳毒性暴露引起的综合征HI和HI。 目的2)生成下一代听障家庭成员序列数据。为 每个家族，我们将外显子序列(包括线粒体基因组)样本，从两个受影响的 家庭成员，以及在父母和至少一个未受影响的兄弟姐妹中分离的后续变异 和一个对照的未受影响的人口。根据以往的经验，我们预计大约5%的家庭 (n=~8)使用外显子组测序无法识别原因变异，原因是阅读深度不足或 变异体位于非编码区。这些家族将通过生成完整的基因组序列进行后续研究 (WGS)数据，也有助于识别拷贝数变体。 目的3)分析序列数据，寻找新的NSHI基因。使用不同的孟德尔工具 我们将对已识别的变异进行注释，并分析罕见的变异(等位基因频率&lt；0.005 ExAC数据库和来自喀麦隆、马里、加纳和南非的测序数据)。 使用多种工具的生物信息学评估将被用来预测哪些变异是有害的。 罕见的破坏性变异的分离将在家庭中进行测试。考虑到样本量很大，存在非常大的 在多个家族中发现多个新的NSHI基因的可能性很高。 高基因非洲具有很高的公共卫生意义，特别是对少数群体来说，因为它 将改进基因筛查，并在未来预测人工耳蜗术和治疗结果 撒哈拉以南非洲人、非洲裔美国人和非裔西班牙裔美国人。

HI-GENES Africa Project Summary/Abstract Despite a large number of identified genes, only GJB2 and GJB6 have been systematically studied in sub-Saharan Africans, for which prevalence of NSHI-causal variants is close to zero and we estimate known NSHI genes only explain ~4.1% of autosomal recessive (AR) NSHI in African-Americans. In the current project called HI-GENES Africa, referring to Hearing Impairment Genetics Studies in Africa, we propose to use Whole genome sequencing (WES), to study to date, the largest sample of sub-Saharan Africans from Cameroon, Mali, Ghana, and South Africa with prelingual ARNSHI in order to identify novel NSHI genes and to better understand the genetic etiology of NSHI in African populations. Aim 1) Ascertain families and probands with early-onset NSHI from Cameroon, Mali, Ghana, and South Africa. We will ascertain 125 families that segregate early-onset (<6 years of age) ARNSHI. For each family multiple affected (at least two per family) and unaffected members will be ascertained. Additionally, 500 probands with early-onset HI (<6 years of age) with strong evidence of having ARNSHI will be ascertained. The probands and family members will be carefully evaluated by clinical and audiometric testing to rule out syndromic HI and HI due to infectious and ototoxic exposures. Aim 2) Generate next generation sequence data on hearing-impaired family members. For each family, we will exome-sequence (including the mitochondrial genome) samples, from two affected family members, and follow up variants segregating in their parents and at least one non-affected sibling and a control non- affected population. We anticipate from previous experience that for ~5% of the families (n=~8) a causal variant will not be identified using exome sequencing, due to insufficient read depth or variant is in non-coding region. These families will be followed-up by generating whole genome sequence (WGS) data that also help to identify copy number variants. Aim 3) Analyze sequence data to identify novel NSHI genes. Using Variant Mendelian Tools we will annotate the identified variants and analyze rare variants (allele frequency<0.005 according to the ExAC database and sequencing data from Cameroon, Mali, Ghana, and South Africa Controls). Bioinformatic evaluation using multiple tools will be used to predict which variants are deleterious. Segregation of rare damaging variants will be tested in families. Given the large sample size there is a very high probability of identifying a number of novel NSHI genes in multiple families. HI-GENES Africa 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.