A novel KCNQ4 gene variant (c.857A>G; p.Tyr286Cys) in an extended family with non-syndromic deafness 2A
A novel KCNQ4 gene variant (c.857A>G; p.Tyr286Cys) in an extended family with non-syndromic deafness 2A
复制标题
非综合征性耳聋大家族中的新型 KCNQ4 基因变异（c.857A>G；p.Tyr286Cys）2A
DOI：
10.3892/mmr.2021.12059
复制
发表时间：
2021-06-01
影响因子：
3.4
通讯作者：
Zha, Dingjun
中科院分区：
文献类型：
--
作者：
Li, Qiong;Liang, Pengfei;Zha, Dingjun
耳聋是人类最常见的感觉障碍之一;值得注意的是，>60%的耳聋病例归因于遗传因素。钾电压门控通道亚家族Q成员4（KCNQ 4）的变异体在病因学上与一种类型的进行性听力损失、耳聋非综合征型常染色体显性2A（DFNA 2A）相关。在本研究中，全外显子测序（WES）进行了一个五代中国家庭的46名成员的听力损失的三个成员。对11名家族成员进行纯音测听和桑格测序，以确定KCNQ 4基因的新变异是否与受影响的家族成员分离。此外，对野生型KCNQ 4蛋白及其变异体进行了进化保守性分析和蛋白质三级结构预测。该家族表现为常染色体显性遗传、进行性、语后、非综合征型感音神经性听力损失。在KCNQ 4通道的孔区域中的甘氨酸-酪氨酸-甘氨酸特征序列中鉴定了一种新的共分离杂合错义变体（c.857A>G; p.Tyr286Cys）。预测该变体导致KCNQ 4蛋白质中286位的酪氨酸至半胱氨酸取代。在位置286处的酪氨酸在不同物种中是很保守的。酪氨酸被半胱氨酸取代会影响孔区的结构，导致通道功能丧失。KCNQ 4基因是常染色体显性遗传性非综合征性听力损失患者中最常见的突变基因之一。综上所述，对于本研究中分析的家族，结合桑格测序进行WES，导致在KCNQ 4基因外显子6中检测到一种新的、潜在致病性变体（c.857 A>G; p.Tyr286 Cys）。本研究增加了在KCNQ 4基因中观察到的致病性变体的数量，这些发现可能有助于DFNA 2A的诊断和早期介入治疗的设计。
Deafness is one of the most common sensory disorders found in humans; notably, >60% of all cases of deafness have been attributed to genetic factors. Variants in potassium voltage-gated channel subfamily Q member 4 (KCNQ4) are etiologically linked to a type of progressive hearing loss, deafness non-syndromic autosomal dominant 2A (DFNA2A). In the present study, whole-exome sequencing (WES) was performed on three members of a five-generation Chinese family with 46 members with hearing loss. Pure tone audiometry and Sanger sequencing were performed for 11 family members to determine whether the novel variant in the KCNQ4 gene was segregated with the affected family members. In addition, evolutionary conservation analysis and computational tertiary structure protein prediction of the wild-type KCNQ4 protein and its variant were performed. The family exhibited autosomal dominant, progressive, post-lingual, non-syndromic sensorineural hearing loss. A novel co-segregating heterozygous missense variant (c.857A>G; p.Tyr286Cys) in the glycine-tyrosine-glycine signature sequence in the pore region of the KCNQ4 channel was identified. This variant was predicted to result in a tyrosine-to-cysteine substitution at position 286 in the KCNQ4 protein. The tyrosine at position 286 is well conserved across different species. The substitution of tyrosine with cysteine would affect the structure of the pore region, resulting in the loss of channel function. The KCNQ4 gene is one of the most common mutated genes observed in patients with autosomal dominant, non-syndromic hearing loss. Taken together, for the family analyzed in the present study, performing WES in conjunction with Sanger sequencing has led to the detection of a novel, potentially causative variant (c.857 A>G; p.Tyr286Cys) in exon 6 of the KCNQ4 gene. The present study has added to the number of pathogenic variants observed in the KCNQ4 gene, and the findings may prove to be useful for both the diagnosis of DFNA2A and in the design of early interventional therapies.