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NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Archetypal disease-causing mutations are cysteine-affecting variants within the 34 epidermal growth factor-like repeat (EGFr...

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Autores principales: Hu, Yacen, Sun, Qiying, Zhou, Yafang, Yi, Fang, Tang, Haiyun, Yao, Lingyan, Tian, Yun, Xie, Nina, Luo, Mengchuan, Wang, Zhiqin, Liao, Xinxin, Xu, Hongwei, Zhou, Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320595/
https://www.ncbi.nlm.nih.gov/pubmed/34335700
http://dx.doi.org/10.3389/fgene.2021.705284
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author Hu, Yacen
Sun, Qiying
Zhou, Yafang
Yi, Fang
Tang, Haiyun
Yao, Lingyan
Tian, Yun
Xie, Nina
Luo, Mengchuan
Wang, Zhiqin
Liao, Xinxin
Xu, Hongwei
Zhou, Lin
author_facet Hu, Yacen
Sun, Qiying
Zhou, Yafang
Yi, Fang
Tang, Haiyun
Yao, Lingyan
Tian, Yun
Xie, Nina
Luo, Mengchuan
Wang, Zhiqin
Liao, Xinxin
Xu, Hongwei
Zhou, Lin
author_sort Hu, Yacen
collection PubMed
description Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Archetypal disease-causing mutations are cysteine-affecting variants within the 34 epidermal growth factor-like repeat (EGFr) region of the Notch3 extracellular subunit. Cysteine-sparing variants and variants outside the EGFr coding region associated with CADASIL phenotype have been reported. However, the linkage between untypical variants and CADASIL is unclear. In this study, we investigated the spectrum of NOTCH3 variants in a cohort of 38 probands from unrelated families diagnosed as CADASIL. All coding exons of the NOTCH3 gene were analyzed, and clinical data were retrospectively studied. We identified 23 different NOTCH3 variants including 14 cysteine-affecting pathogenic variants, five cysteine-sparing pathogenic variants, two reported cysteine-sparing variants of unknown significance (VUS), and two novel VUS outside EGFr region. In retrospective studies of clinical data, we found that patients carrying cysteine-sparing pathogenic variants showed later symptom onset (51.36 ± 7.06 vs. 44.96 ± 8.82, p = 0.023) and milder temporal lobe involvement (1.50 ± 1.74 vs. 3.11 ± 2.32, p = 0.027) than patients carrying cysteine-affecting pathogenic variants. Our findings suggested that untypical variants comprise a significant part of NOTCH3 variants and may be associated with a distinctive phenotype.
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spelling pubmed-83205952021-07-30 NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients Hu, Yacen Sun, Qiying Zhou, Yafang Yi, Fang Tang, Haiyun Yao, Lingyan Tian, Yun Xie, Nina Luo, Mengchuan Wang, Zhiqin Liao, Xinxin Xu, Hongwei Zhou, Lin Front Genet Genetics Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Archetypal disease-causing mutations are cysteine-affecting variants within the 34 epidermal growth factor-like repeat (EGFr) region of the Notch3 extracellular subunit. Cysteine-sparing variants and variants outside the EGFr coding region associated with CADASIL phenotype have been reported. However, the linkage between untypical variants and CADASIL is unclear. In this study, we investigated the spectrum of NOTCH3 variants in a cohort of 38 probands from unrelated families diagnosed as CADASIL. All coding exons of the NOTCH3 gene were analyzed, and clinical data were retrospectively studied. We identified 23 different NOTCH3 variants including 14 cysteine-affecting pathogenic variants, five cysteine-sparing pathogenic variants, two reported cysteine-sparing variants of unknown significance (VUS), and two novel VUS outside EGFr region. In retrospective studies of clinical data, we found that patients carrying cysteine-sparing pathogenic variants showed later symptom onset (51.36 ± 7.06 vs. 44.96 ± 8.82, p = 0.023) and milder temporal lobe involvement (1.50 ± 1.74 vs. 3.11 ± 2.32, p = 0.027) than patients carrying cysteine-affecting pathogenic variants. Our findings suggested that untypical variants comprise a significant part of NOTCH3 variants and may be associated with a distinctive phenotype. Frontiers Media S.A. 2021-07-15 /pmc/articles/PMC8320595/ /pubmed/34335700 http://dx.doi.org/10.3389/fgene.2021.705284 Text en Copyright © 2021 Hu, Sun, Zhou, Yi, Tang, Yao, Tian, Xie, Luo, Wang, Liao, Xu and Zhou. 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
Hu, Yacen
Sun, Qiying
Zhou, Yafang
Yi, Fang
Tang, Haiyun
Yao, Lingyan
Tian, Yun
Xie, Nina
Luo, Mengchuan
Wang, Zhiqin
Liao, Xinxin
Xu, Hongwei
Zhou, Lin
NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients
title NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients
title_full NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients
title_fullStr NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients
title_full_unstemmed NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients
title_short NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients
title_sort notch3 variants and genotype-phenotype features in chinese cadasil patients
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320595/
https://www.ncbi.nlm.nih.gov/pubmed/34335700
http://dx.doi.org/10.3389/fgene.2021.705284
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