Guo Yingyuan, Hao Yanru, Zhang Dejun, Xu Hongen, Yu Duojiao, Lv Jingmao, Fu Zeming, Han Shuang, Guo Fang, Bai Jie, Guan Guofang
Department of Otolaryngology, The Second Hospital of Jilin University, Changchun, China.
Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China.
Transl Pediatr. 2021 Feb;10(2):378-387. doi: 10.21037/tp-20-435.
X-linked deafness-4 (DFNX4) caused by the functional loss of the gene is one form of nonsyndromic hearing loss with postlingual onset. This study aimed to investigate the cause of X-linked inherited sensorineural nonsyndromic hearing loss in a four-generation Chinese family and to explain the reason for extremely different hearing phenotypes between the proband and other family members.
Whole-exome sequencing (WES) and co-segregation analysis were used to identify the pathogenic variants. Furthermore, methylation differences among the androgen receptor genes were utilized to investigate whether the severe phenotype of the proband is related to X-chromosome inactivation (Xi).
We described in detail the clinical characteristics of the family and identified a novel missense mutation (c.262C>G: p.Gln88Glu) in by WES. This variant was co-segregated with the postlingual hearing loss phenotype and was absent in 300 normal controls. Also, we found that the proband, a 4-year-old female, carries two new compound heterozygous mutations (c.9259G>A: p.Val3087Ile and c.8576G>A: p.Arg2859His) in the gene, but to date without any other symptoms except profound sensorineural hearing loss. Additionally, analysis of X-chromosome inactivation indicated moderate skewing in the proband, which is probably related to the heterogeneity of clinical characteristics.
This is the first study to report a missense mutation of in a Chinese family. Our findings have enriched the mutation and phenotypic spectrum of the gene.
由该基因功能丧失引起的X连锁遗传性耳聋4型（DFNX4）是一种非综合征性听力损失，发病于语言发育之后。本研究旨在调查一个四代中国家系中X连锁遗传性感音神经性非综合征性听力损失的病因，并解释先证者与其他家庭成员听力表型差异极大的原因。
采用全外显子组测序（WES）和共分离分析来鉴定致病变异。此外，利用雄激素受体基因之间的甲基化差异来研究先证者的严重表型是否与X染色体失活（Xi）有关。
我们详细描述了该家系的临床特征，并通过WES鉴定出该基因中的一个新的错义突变（c.262C>G：p.Gln88Glu）。该变异与语言发育后的听力损失表型共分离，在300名正常对照中未出现。此外，我们发现先证者，一名4岁女性，在该基因中携带两个新的复合杂合突变（c.9259G>A：p.Val3087Ile和c.8576G>A：p.Arg2859His），但迄今为止除了严重的感音神经性听力损失外没有任何其他症状。此外，X染色体失活分析表明先证者存在中度偏斜，这可能与临床特征的异质性有关。
这是首次报道中国家系中该基因错义突变的研究。我们的发现丰富了该基因的突变和表型谱。
