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Case Report: A Novel GJB2 Missense Variant Inherited From the Low-Level Mosaic Mother in a Chinese Female With Palmoplantar Keratoderma With Deafness

Dominant variants in the gap junction beta-2 (GJB2) 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 GJB2 do...

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Autores principales: Tian, Xinyuan, Zhang, Chuan, Zhou, Bingbo, Chen, Xue, Feng, Xuan, Zheng, Lei, Wang, Yupei, Hao, Shengju, Hui, Ling
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354265/
https://www.ncbi.nlm.nih.gov/pubmed/35938034
http://dx.doi.org/10.3389/fgene.2022.938639
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author Tian, Xinyuan
Zhang, Chuan
Zhou, Bingbo
Chen, Xue
Feng, Xuan
Zheng, Lei
Wang, Yupei
Hao, Shengju
Hui, Ling
author_facet Tian, Xinyuan
Zhang, Chuan
Zhou, Bingbo
Chen, Xue
Feng, Xuan
Zheng, Lei
Wang, Yupei
Hao, Shengju
Hui, Ling
author_sort Tian, Xinyuan
collection PubMed
description Dominant variants in the gap junction beta-2 (GJB2) 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 GJB2 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 GJB2 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 GJB2 variant, and furthermore provides strong proof about the relevance between the p.R75P variant in GJB2 and PPKDFN.
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spelling pubmed-93542652022-08-06 Case Report: A Novel GJB2 Missense Variant Inherited From the Low-Level Mosaic Mother in a Chinese Female With Palmoplantar Keratoderma With Deafness Tian, Xinyuan Zhang, Chuan Zhou, Bingbo Chen, Xue Feng, Xuan Zheng, Lei Wang, Yupei Hao, Shengju Hui, Ling Front Genet Genetics Dominant variants in the gap junction beta-2 (GJB2) 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 GJB2 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 GJB2 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 GJB2 variant, and furthermore provides strong proof about the relevance between the p.R75P variant in GJB2 and PPKDFN. Frontiers Media S.A. 2022-07-22 /pmc/articles/PMC9354265/ /pubmed/35938034 http://dx.doi.org/10.3389/fgene.2022.938639 Text en Copyright © 2022 Tian, Zhang, Zhou, Chen, Feng, Zheng, Wang, Hao and Hui. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Tian, Xinyuan
Zhang, Chuan
Zhou, Bingbo
Chen, Xue
Feng, Xuan
Zheng, Lei
Wang, Yupei
Hao, Shengju
Hui, Ling
Case Report: A Novel GJB2 Missense Variant Inherited From the Low-Level Mosaic Mother in a Chinese Female With Palmoplantar Keratoderma With Deafness
title Case Report: A Novel GJB2 Missense Variant Inherited From the Low-Level Mosaic Mother in a Chinese Female With Palmoplantar Keratoderma With Deafness
title_full Case Report: A Novel GJB2 Missense Variant Inherited From the Low-Level Mosaic Mother in a Chinese Female With Palmoplantar Keratoderma With Deafness
title_fullStr Case Report: A Novel GJB2 Missense Variant Inherited From the Low-Level Mosaic Mother in a Chinese Female With Palmoplantar Keratoderma With Deafness
title_full_unstemmed Case Report: A Novel GJB2 Missense Variant Inherited From the Low-Level Mosaic Mother in a Chinese Female With Palmoplantar Keratoderma With Deafness
title_short Case Report: A Novel GJB2 Missense Variant Inherited From the Low-Level Mosaic Mother in a Chinese Female With Palmoplantar Keratoderma With Deafness
title_sort case report: a novel gjb2 missense variant inherited from the low-level mosaic mother in a chinese female with palmoplantar keratoderma with deafness
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354265/
https://www.ncbi.nlm.nih.gov/pubmed/35938034
http://dx.doi.org/10.3389/fgene.2022.938639
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