Recurrent de novo WFS1 pathogenic variants in Chinese sporadic patients with nonsyndromic sensorineural hearing loss
Recurrent de novo WFS1 pathogenic variants in Chinese sporadic patients with nonsyndromic sensorineural hearing loss
复制标题
中国散发性非综合征性感音神经性听力损失患者中复发性新发WFS1致病变异
DOI：
10.1002/mgg3.1367
复制
发表时间：
2020-06-22
影响因子：
2
通讯作者：
Wang, Qiuju
中科院分区：
文献类型：
--
作者：
Guan, Jing;Wang, Hongyang;Wang, Qiuju
遗传性听力损失（HL）在表型特征、遗传方式和致病基因突变方面具有异质性。遗传变异对散发性HL的贡献仍在很大程度上扩大。无论是隐性或从头显性变异可能会导致一个明显的散发发生HL。为了寻找这些变异体，我们招募了128例散发性非综合征感觉神经性HL（NSHL）患者，并在这些无关的三联体家族中进行靶向耳聋多基因测序，以阐明其分子基础。方法我们分析了来自128个无亲缘关系的双侧感觉神经性HL家系的384名成员（先证者及其双亲），这些家系中既往筛查未发现GJB 2、SLC 26 A4和MT-RNR 1基因突变。我们使用靶向基因组富集平台同时捕获127个已知耳聋基因的外显子、剪接位点和紧邻内含子序列。桑格测序用于确定先证者和他们的两个父母分离的候选基因中的致病变异。结果在5个家系中发现了2个WFS 1基因外显子8的杂合突变：c.2051C>T（p.A684V）和c.2590G>A（p.E864K）。3.9%（5/128）的散发性HL患者存在两种新的WFS 1突变。我们发现5例患者中有4例有相同的p.A684V新突变，他们的听力图显示对称的双侧和深度感音神经性听力障碍在所有频率，但只有p.E864K新突变的先证者表现出明显的双侧中度低中频感音神经性HL。我们的数据表明，这个WFS1p.A684V很可能是一个从头突变热点。结论3.9%（5/128）的散发性NSHL是由新WFS 1突变引起的。我们的数据表明，p.E864K突变是首次发现的，p.A684V突变可能是WFS 1的突变热点。这是第一个研究，强调WFS 1基因的两个新的突变已被指示分类不同的听力障碍表型。此外，新发p.A684V是在中国散发性儿童NSHL人群中发现的WFS 1突变热点，我们的研究也为具有明显显性致病性变异的散发病例的无症状父母测序的必要性提供了指导。
Background Hereditary hearing loss (HL) is heterogeneous in terms of their phenotypic features, modes of inheritance, and causative gene mutations. The contribution of genetic variants to sporadic HL remains largely expanding. Either recessive or de novo dominant variants could result in an apparently sporadic occurrence of HL. In an attempt to find such variants we recruited 128 Chinese patients with sporadic nonsyndromic sensorineural HL (NSHL) and performed targeted deafness multigene sequencing in these unrelated trios-families to elucidate the molecular basis. Methods We analyzed a total of 384 available members (probands and their two parents) from 128 unrelated Chinese families presenting with bilateral sensorineural HL, in which previous screening had found no mutations with theGJB2,SLC26A4, andMT-RNR1genes. We used a targeted genomic enrichment platform to simultaneously capture exons, splicing sites, and immediate flanking intron sequences of 127 known deafness genes. Sanger sequencing was used to identify probands and their two parents segregating causative variants in the candidate gene. Results We observed that two heterozygous de novoWFS1mutations in exon 8: c.2051C>T (p.A684V) and c.2590G>A (p.E864K) in five families. The two de novoWFS1mutations were found in 3.9% (5/128) of sporadic HL patients. We found that four of the five patients had the same de novo p.A684V mutation, and their audiograms showed symmetrical bilateral and profound sensorineural hearing impairments at all frequencies, but only the proband with de novo p.E864K mutation demonstrated significantly bilateral moderate low-mid frequency sensorineural HL. Our data suggest that thisWFS1p.A684V is likely to be a de novo mutational hot spot. Conclusions We found 3.9% (5/128) of sporadic NSHL is caused by de novoWFS1mutations. Our data provide that the de novo p.E864K mutation is first identified and de novo p.A684V mutation is likely to be a mutational hot spot inWFS1. It is the first study to highlight thatWFS1gene with the two de novo mutations has been indicated to classify the distinct hearing impairment phenotypes. Furthermore, de novo p.A684V serves as aWFS1mutational hot spot that was found in the Chinese population with sporadic childhood NSHL, and our study also provides pointers toward the necessity for sequencing of asymptomatic parents of a sporadic case with an apparent dominant pathogenic variant.