Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families.
Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families.
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DOI：
10.1186/gb-2011-12-9-r89
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发表时间：
2011-09-14
期刊：
影响因子：
12.3
通讯作者：
Avraham KB
中科院分区：
文献类型：
--
作者：
Brownstein Z;Friedman LM;Shahin H;Oron-Karni V;Kol N;Abu Rayyan A;Parzefall T;Lev D;Shalev S;Frydman M;Davidov B;Shohat M;Rahile M;Lieberman S;Levy-Lahad E;Lee MK;Shomron N;King MC;Walsh T;Kanaan M;Avraham KB
鉴定负责医学上重要性状的基因是人类遗传学中的一个重大挑战。由于听力损失的遗传异质性，靶向DNA捕获和大规模平行测序是应对这一挑战的理想工具。我们的基因组分析对象是以色列犹太人和巴勒斯坦阿拉伯家庭，他们的听力损失在遗传方式和严重程度上各不相同。构建了定制的1.46 MB cRNA寡核苷酸设计，其含有246个负责人或小鼠耳聋的基因。从11个先证者制备双端文库，并对条形码多重样品进行测序以达到高覆盖深度。罕见的单碱基对和indel变体通过过滤dbSNP132和1000基因组计划中多态性的序列读数来鉴定。我们鉴定了CDH23、MYO15A、TECTA、TMC 1和WFS1中的有害突变。先证者的关键突变与听力损失共分离。对相关人群中的其他家庭进行筛查。TMC1 p.S647P被证明是一个创始等位基因，导致摩洛哥犹太人群体中34%的遗传性听力损失。在11个原始先证者及其家族中的6个中鉴定出关键突变，导致在另外20个先证者及其家族中鉴定出致病等位基因。将基因组分析整合到听力损失的早期临床诊断中将能够预测相关表型并促进康复。对这些基因编码的蛋白质进行表征将有助于理解听力损失的生物学机制。
Identification of genes responsible for medically important traits is a major challenge in human genetics. Due to the genetic heterogeneity of hearing loss, targeted DNA capture and massively parallel sequencing are ideal tools to address this challenge. Our subjects for genome analysis are Israeli Jewish and Palestinian Arab families with hearing loss that varies in mode of inheritance and severity. A custom 1.46 MB design of cRNA oligonucleotides was constructed containing 246 genes responsible for either human or mouse deafness. Paired-end libraries were prepared from 11 probands and bar-coded multiplexed samples were sequenced to high depth of coverage. Rare single base pair and indel variants were identified by filtering sequence reads against polymorphisms in dbSNP132 and the 1000 Genomes Project. We identified deleterious mutations in CDH23, MYO15A, TECTA, TMC1, and WFS1. Critical mutations of the probands co-segregated with hearing loss. Screening of additional families in a relevant population was performed. TMC1 p.S647P proved to be a founder allele, contributing to 34% of genetic hearing loss in the Moroccan Jewish population. Critical mutations were identified in 6 of the 11 original probands and their families, leading to the identification of causative alleles in 20 additional probands and their families. The integration of genomic analysis into early clinical diagnosis of hearing loss will enable prediction of related phenotypes and enhance rehabilitation. Characterization of the proteins encoded by these genes will enable an understanding of the biological mechanisms involved in hearing loss.
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DOI：
10.1177/000348941011901207
发表时间：
2010-12
期刊：
The Annals of otology, rhinology, and laryngology
影响因子：
--
作者：
Hildebrand MS;Kahrizi K;Bromhead CJ;Shearer AE;Webster JA;Khodaei H;Abtahi R;Bazazzadegan N;Babanejad M;Nikzat N;Kimberling WJ;Stephan D;Huygen PL;Bahlo M;Smith RJ;Najmabadi H
通讯作者：
Najmabadi H
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
3.6
作者：
Brownstein, Z;Ben-Yosef, T;Avraham, KB
通讯作者：
Avraham, KB
影响因子：
5.2
作者：
Shahin, Hashem;Walsh, Tom;Kanaan, Moien
通讯作者：
Kanaan, Moien
影响因子：
7
作者：
Li, Heng;Ruan, Jue;Durbin, Richard
通讯作者：
Durbin, Richard