Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss.
Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss.
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DOI：
10.1007/s00439-016-1648-8
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发表时间：
2016-04
期刊：
影响因子：
5.3
通讯作者：
Smith RJH
中科院分区：
文献类型：
--
作者：
Sloan-Heggen CM;Bierer AO;Shearer AE;Kolbe DL;Nishimura CJ;Frees KL;Ephraim SS;Shibata SB;Booth KT;Campbell CA;Ranum PT;Weaver AE;Black-Ziegelbein EA;Wang D;Azaiez H;Smith RJH
听力损失是人类最常见的感觉缺陷，每500个新生儿中就有1个受到影响。由于其遗传异质性，以前尚未在大型多种族队列中完成全面的诊断测试。为了确定遗传对非综合征性听力损失的总体贡献，我们对1119例顺序累积的患者进行了全面的临床基因检测，包括靶向基因组富集和大规模平行测序。没有患者因表型、遗传或既往检测而被排除。在440例（39%）患者中，检测结果确定了听力损失的潜在遗传原因。在49个基因中发现致病变异，包括错义变异（49%）、大拷贝数变化（18%）、小插入和缺失（18%）、无义变异（8%）、剪接位点改变（6%）和启动子变异（< 1%）。根据表型，诊断率差异很大，对于有听力损失家族史或先天性对称性听力损失的患者，诊断率最高。相关基因谱显示出广泛的种族差异。这些发现支持通过发展循证听力损失诊断算法更有效地利用医疗资源。本文的在线版本（doi:10.1007/s00439-016-1648-8）包含补充材料，仅供授权用户使用。
Hearing loss is the most common sensory deficit in humans, affecting 1 in 500 newborns. Due to its genetic heterogeneity, comprehensive diagnostic testing has not previously been completed in a large multiethnic cohort. To determine the aggregate contribution inheritance makes to non-syndromic hearing loss, we performed comprehensive clinical genetic testing with targeted genomic enrichment and massively parallel sequencing on 1119 sequentially accrued patients. No patient was excluded based on phenotype, inheritance or previous testing. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 patients (39 %). Pathogenic variants were found in 49 genes and included missense variants (49 %), large copy number changes (18 %), small insertions and deletions (18 %), nonsense variants (8 %), splice-site alterations (6 %), and promoter variants (<1 %). The diagnostic rate varied considerably based on phenotype and was highest for patients with a positive family history of hearing loss or when the loss was congenital and symmetric. The spectrum of implicated genes showed wide ethnic variability. These findings support the more efficient utilization of medical resources through the development of evidence-based algorithms for the diagnosis of hearing loss. The online version of this article (doi:10.1007/s00439-016-1648-8) contains supplementary material, which is available to authorized users.