Comprehensive genetic testing with ethnic-specific filtering by allele frequency in a Japanese hearing-loss population.
Comprehensive genetic testing with ethnic-specific filtering by allele frequency in a Japanese hearing-loss population.
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DOI：
10.1111/cge.12677
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发表时间：
2016-04
影响因子：
3.5
通讯作者：
Smith RJH
中科院分区：
文献类型：
--
作者：
Moteki H;Azaiez H;Booth KT;Shearer AE;Sloan CM;Kolbe DL;Nishio S;Hattori M;Usami S;Smith RJH
大规模平行测序（TGE+MPS）靶向基因组富集的最新进展使非综合征性听力损失（NSHL）的全面基因检测成为可能。通过桑格测序排除了GJB 2和MT-RNR 1（1555 A>G）变异体致病突变的NSHL受试者后，我们对日本194例推定为NSHL的先证者完成了TGE+MPS。我们使用了公开的次要等位基因频率（MAF）数据集和种族特异性MAF过滤对200名正常听力日本对照的内部数据库。种族特异性MAF过滤使我们能够将203种变异重新分类为常见变异，否则在非日本种族中注释为罕见或新变异。这一步骤最大限度地减少了假阳性结果，并改进了对已鉴定变体的注释。在27%的先证者中确定了致病变异，显性、隐性和散发性NSHL的解决率分别为35%、35%和19%。MYO 15 A和CDH 23的突变跟随GJB 2作为隐性NSHL的常见原因; STRC中的拷贝数变异是轻度至中度NSHL的主要原因。通过等位基因频率进行种族特异性过滤对于优化遗传数据的解释至关重要。
Recent advances in targeted genomic enrichment with massively parallel sequencing (TGE+MPS) have made comprehensive genetic testing for non-syndromic hearing loss (NSHL) possible. After excluding NSHL subjects with causative mutations in GJB2 and the MT-RNR1 (1555A>G) variant by Sanger sequencing, we completed TGE+MPS on 194 probands with presumed NSHL identified across Japan. We used both publicly available minor allele frequency (MAF) datasets and ethnic-specific MAF filtering against an in-house database of 200 normal-hearing Japanese controls. Ethnic-specific MAF filtering allowed us to re-categorize as common 203 variants otherwise annotated as rare or novel in non-Japanese ethnicities. This step minimizes false-positive results and improves the annotation of identified variants. Causative variants were identified in 27% of probands with solve rates of 35%, 35% and 19% for dominant, recessive and sporadic NSHL, respectively. Mutations in MYO15A and CDH23 follow GJB2 as the frequent causes of recessive NSHL; copy number variations in STRC are a major cause of mild-to-moderate NSHL. Ethnic-specific filtering by allele frequency is essential to optimize the interpretation of genetic data.