Genomic analysis of a heterogeneous Mendelian phenotype: multiple novel alleles for inherited hearing loss in the Palestinian population.
Genomic analysis of a heterogeneous Mendelian phenotype: multiple novel alleles for inherited hearing loss in the Palestinian population.
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DOI：
10.1186/1479-7364-2-4-203
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发表时间：
2006-01
期刊：
影响因子：
4.5
通讯作者：
Kanaan M
中科院分区：
文献类型：
--
作者：
Walsh T;Abu Rayan A;Abu Sa'ed J;Shahin H;Shepshelovich J;Lee MK;Hirschberg K;Tekin M;Salhab W;Avraham KB;King MC;Kanaan M
隐性遗传表型在巴勒斯坦人口中很常见，这是由于大家庭婚姻的历史传统，特别是在与世隔绝的村庄。为了描述这一人群中遗传性听力损失的遗传学特征，我们与约旦河西岸的聋人学校合作，识别出有语前、双侧、重度到深度听力损失的儿童，这些儿童不是由于感染、创伤或其他已知环境暴露所致。在登记的156个家庭中，17个家庭(11%)的听力损失是由GJB2(连接蛋白26)突变引起的，与其他人群相比，GJB2相关耳聋的比例较小。为了估计在这个人群中有多少不同的基因可能导致听力损失，我们评估了10个家系与所有36个已知的人类常染色体耳聋相关基因的连锁，在信息丰富的亲属中的任何链接位置对听力相关基因进行了全序列测定。4个家系含有4个新等位基因：TMPRSS3(988ΔA=352top)、耳癌蛋白(1067A>；T=D356V)和垂蛋白(716T>；A=V239D和1001G>；T=346top)。在每个家庭中，所有受影响的个体都是关键突变的纯合子。每个等位基因都是队列中的一个或几个家族特有的；没有一个是普遍存在的。由于突变与耳聋相关的流行病学测试对于这些罕见的等位基因是不可行的，我们使用功能和生物信息学方法来评估它们的后果。在其他六个家庭中，听力损失与任何已知基因都没有关联，这表明这些家庭拥有导致这种表型的新基因。我们得出结论，遗传性听力损失在这个群体中具有高度的异质性，在这种情况下，大多数大家族都是遗传隔离的。我们还得出结论，在这个群体中，与其他地方一样，导致听力损失的基因也是相同的，因此，在这些家族中发现的基因向世界各地的听力损失遗传学提供了信息。
Recessively inherited phenotypes are frequent in the Palestinian population, as the result of a historical tradition of marriages within extended kindreds, particularly in isolated villages. In order to characterise the genetics of inherited hearing loss in this population, we worked with West Bank schools for the deaf to identify children with prelingual, bilateral, severe to profound hearing loss not attributable to infection, trauma or other known environmental exposure. Of 156 families enrolled, hearing loss in 17 families (11 per cent) was due to mutations in GJB2 (connexin 26), a smaller fraction of GJB2-associated deafness than in other populations. In order to estimate how many different genes might be responsible for hearing loss in this population, we evaluated ten families for linkage to all 36 known human autosomal deafness-related genes, fully sequencing hearing-related genes at any linked sites in informative relatives. Four families harboured four novel alleles of TMPRSS3 (988ΔA = 352stop), otoancorin (1067A >T = D356V) and pendrin (716T > A = V239D and 1001G > T = 346stop). In each family, all affected individuals were homozygous for the critical mutation. Each allele was specific to one or a few families in the cohort; none were widespread. Since epidemiological tests of association of mutations with deafness were not feasible for such rare alleles, we used functional and bioinformatics approaches to evaluate their consequences. In six other families, hearing loss was not linked to any known gene, suggesting that these families harbour novel genes responsible for this phenotype. We conclude that inherited hearing loss is highly heterogeneous in this population, with most extended families acting as genetic isolates in this context. We also conclude that the same genes are responsible for hearing loss in this population as elsewhere, so that gene discovery in these families informs the genetics of hearing loss worldwide.