Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort.
Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort.
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DOI：
10.1038/gim.2015.89
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发表时间：
2016-04
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影响因子：
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通讯作者：
Tekin M
中科院分区：
文献类型：
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作者：
Bademci G;Foster J 2nd;Mahdieh N;Bonyadi M;Duman D;Cengiz FB;Menendez I;Diaz-Horta O;Shirkavand A;Zeinali S;Subasioglu A;Tokgoz-Yilmaz S;Huesca-Hernandez F;de la Luz Arenas-Sordo M;Dominguez-Aburto J;Hernandez-Zamora E;Montenegro P;Paredes R;Moreta G;Vinueza R;Villegas F;Mendoza-Benitez S;Guo S;Bozan N;Tos T;Incesulu A;Sennaroglu G;Blanton SH;Ozturkmen-Akay H;Yildirim-Baylan M;Tekin M
常染色体隐性遗传性非综合征性耳聋（ARNSD）的特点是高度的遗传异质性，有报道的突变在58个不同的基因。本研究旨在通过全外显子组测序（WES）检测多种族ARNSD队列中导致耳聋的变异。在排除了最常见的基因GJB 2突变后，我们对来自土耳其、伊朗、墨西哥、厄瓜多尔和波多黎各的160个ARNSD多重家族进行了WES，以筛查所有已知ARNSD基因的突变。我们在90个（56%）家庭中检测到ARNSD致病变异，其中54%以前从未报道过。已鉴定的突变位于31个已知的ARNSD基因中。最常见的突变基因是MYO15A（13%）、MYO7A（11%）、SLC26A4（10%）、TMPRSS3（9%）、TMC 1（8%）、ILDR1（6%）和CDH23（4%）。在多个具有共同单倍型的家庭中检测到9个突变，表明创始人效应。我们报告了一个大型的多种族队列与ARNSD中，所有已知的ARNSD基因的综合分析确定致病DNA变异的56%的家庭。在剩下的家族中，WES使我们能够在新基因中寻找致病变异，从而提高我们在更多家族中解释潜在病因的能力。
Autosomal recessive non-syndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity with reported mutations in 58 different genes. This study was designed to detect deafness causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES). After excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador and Puerto Rico to screen for mutations in all known ARNSD genes. We detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%) and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes suggesting founder effects. We report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.