Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss.
Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss.
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DOI：
10.1002/humu.23666
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发表时间：
2019-01
期刊：
影响因子：
3.9
通讯作者：
Riazuddin S
中科院分区：
文献类型：
--
作者：
Richard EM;Santos-Cortez RLP;Faridi R;Rehman AU;Lee K;Shahzad M;Acharya A;Khan AA;Imtiaz A;Chakchouk I;Takla C;Abbe I;Rafeeq M;Liaqat K;Chaudhry T;Bamshad MJ;Nickerson DA;University of Washington Center for Mendelian Genomics;Schrauwen I;Khan SN;Morell RJ;Zafar S;Ansar M;Ahmed ZM;Ahmad W;Riazuddin S;Friedman TB;Leal SM;Riazuddin S
在全世界68个与非综合征性常染色体隐性听力损失（HL）相关的基因中，有31个是通过巴基斯坦的近亲家系分离耳聋而发现的。在这项研究中，我们利用全基因组基因分型、Sanger和外显子组测序，鉴定了321个巴基斯坦家庭中41个先前报道的HL基因分离的163个DNA变异。其中，在29个基因中发现的71个（43.6%）变异是新的。正如对近亲家庭分离性疾病的遗传研究所预期的那样，大多数受影响个体（94.4%）是hl相关变异的纯合子，其他变异是复合杂合子。巴基斯坦人群中最常见的5个HL基因分别是SLC26A4、MYO7A、GJB2、CIB2和HGF。我们的研究提供了巴基斯坦家庭中HL的遗传病因概况，这将允许开发更有效的遗传诊断工具，帮助准确的遗传咨询和指导未来基因治疗的应用。这些发现在解释所有祖先中可能与HL相关的变异的致病性方面也很有价值。巴基斯坦人口及其研究人类遗传学的基础设施将继续对HL和其他遗传疾病的基因发现有价值。
Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 71 (43.6%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL-associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling and guide application of future gene-based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.
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