Targeted next-generation sequencing and parental genotyping in sporadic Chinese Han deaf patients
Targeted next-generation sequencing and parental genotyping in sporadic Chinese Han deaf patients
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中国汉族散发性耳聋患者的靶向二代测序和亲本基因分型
DOI：
10.1111/cge.13182
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发表时间：
2018-04-01
影响因子：
3.5
通讯作者：
Yang, T.
中科院分区：
文献类型：
--
作者：
He, L.;Pang, X.;Yang, T.
对靶向下一代测序（NGS）结果的解释对于在散发性耳聋患者中鉴定的变异可能具有挑战性。在本研究中，我们对44例散发性耳聋患者的143个致病相关基因进行了靶向NGS，并使用亲本基因分型来检测候选致病变异是否符合隐性或从头模式。在29个次要等位基因频率（MAF）小于0.005的隐性候选变体中，3对明显的复合杂合变体遗传自同一亲本等位基因，排除了它们的致病作用。此外，OTOA p.Gln293Arg变异体的非分离导致通过拷贝数变异分析在相对等位基因上发现OTOA的基因组微缺失。总体而言，13对隐性候选变异被认为是13例患者的病因。在MAF小于0.0005的28个显性候选变异中，没有一个是从头发生的，表明它们不是致病的。我们的研究结果显示，在散发性耳聋患者中靶向NGS可能会产生显着的假阳性率。父母基因分型是一个简单但有效的步骤，以尽量减少假阳性结果。我们的研究还表明，显性耳聋基因的新生变异可能不是散发性耳聋的常见原因。
The interpretation of the targeted next-generation sequencing (NGS) results can be challenging for variants identified in the sporadic deaf patients. In this study, we performed targeted NGS of 143 deafness-associated genes in 44 sporadic deaf patients and use parental genotyping to test whether the candidate pathogenic variants complied with recessive or de novo pattern. Of 29 recessive candidate variants with minor allele frequencies (MAFs) less than 0.005, 3 pairs of apparent compound heterozygous variants were inherited from the same parental allele, ruling out their pathogenic roles. In addition, non-segregation of an OTOA p.Gln293Arg variant led to the discovery of a genomic microdeletion of OTOA on the opposite allele by copy number variation analysis. Overall, 13 pairs of recessive candidate variants were deemed causative in 13 patients. Of the 28 dominant candidate variants with MAFs less than 0.0005, none occurred de novo, suggesting that they were not disease causing. Our results revealed that targeted NGS in sporadic deaf patients may generate a significant false-positive rate. Parental genotyping is a simple but effective step toward minimizing the false-positive results. Our study also showed that de novo variants in dominant deafness genes may not be a common cause for sporadic deafness.