Tian Xinyuan, Zhang Chuan, Zhou Bingbo, Chen Xue, Feng Xuan, Zheng Lei, Wang Yupei, Hao Shengju, Hui Ling
School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China.
Center for Medical Genetics, Gansu Provincial Maternity and Child Health Hospital, Gansu Provincial Clinical Research Center for Birth Defects and Rare Diseases, Lanzhou, China.
Front Genet. 2022 Jul 22;13:938639. doi: 10.3389/fgene.2022.938639. eCollection 2022.
Dominant variants in the gap junction beta-2 () gene may lead to various degrees of syndromic hearing loss (SHL) which is manifest as sensorineural hearing impairment and hyperproliferative epidermal disorders, including palmoplantar keratoderma with deafness (PPKDFN). So far, only a few dominant variants causing PPKDFN have been discovered. Through the whole-exome sequencing (WES), a Chinese female patient with severe palmoplantar hyperkeratosis and delayed-onset hearing loss has been identified. She had a novel heterozygous variant, c.224G>C (p.R75P), in the gene, which was unreported previously. The proband's mother who had a mild phenotype was suggested the possibility of mosaicism by WES (∼120×), and the ultra-deep targeted sequencing (∼20,000×) was used for detecting low-level mosaic variants which provided accurate recurrence-risk estimates and genetic counseling. In addition, the analysis of protein structure indicated that the structural stability and permeability of the connexin 26 (Cx26) gap junction channel may be disrupted by the p.R75P variant. Through retrospective analysis, it is detected that the junction of extracellular region-1 (EC1) and transmembrane region-2 (TM2) is a variant hotspot for PPKDFN, such as p.R75. Our report reflects the important and effective diagnostic role of WES in PPKDFN and low-level mosaicism, expands the spectrum of the variant, and furthermore provides strong proof about the relevance between the p.R75P variant in and PPKDFN.
缝隙连接蛋白β-2（GJB2）基因的显性变异可能导致不同程度的综合征性听力损失（SHL），表现为感音神经性听力障碍和过度增殖性表皮疾病，包括伴耳聋的掌跖角化病（PPKDFN）。到目前为止，仅发现少数导致PPKDFN的显性变异。通过全外显子组测序（WES），鉴定出一名患有严重掌跖角化过度和迟发性听力损失的中国女性患者。她的GJB2基因中有一个新的杂合变异，c.224G>C（p.R75P），此前未被报道。先证者的母亲表现为轻度表型，WES（约120×）提示存在嵌合体的可能性，采用超深度靶向测序（约20,000×）检测低水平嵌合变异，以提供准确的复发风险评估和遗传咨询。此外，蛋白质结构分析表明，p.R75P变异可能会破坏连接蛋白26（Cx26）缝隙连接通道的结构稳定性和通透性。通过回顾性分析，检测到细胞外区域-1（EC1）和跨膜区域-2（TM2）的交界处是PPKDFN的一个变异热点，如p.R75。我们的报告反映了WES在PPKDFN和低水平嵌合体中的重要且有效的诊断作用，扩展了GJB2变异谱，并且进一步提供了关于GJB2基因中p.R75P变异与PPKDFN相关性的有力证据。
