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Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings

BACKGROUND: Joubert syndrome (JS) is a rare genetic disorder, which can be defined by brain stem malformation, cerebellar vermis hypoplasia, and consequent “molar tooth sign” (MTS). JS always shares variety of phenotypes in development defects. With the development of next-generation sequencing, doz...

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Autores principales: Wang, Xiang, Zhang, Zhu, Zhang, Xueguang, Shen, Ying, Liu, Hongqian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325267/
https://www.ncbi.nlm.nih.gov/pubmed/32600475
http://dx.doi.org/10.1186/s40246-020-00274-4
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author Wang, Xiang
Zhang, Zhu
Zhang, Xueguang
Shen, Ying
Liu, Hongqian
author_facet Wang, Xiang
Zhang, Zhu
Zhang, Xueguang
Shen, Ying
Liu, Hongqian
author_sort Wang, Xiang
collection PubMed
description BACKGROUND: Joubert syndrome (JS) is a rare genetic disorder, which can be defined by brain stem malformation, cerebellar vermis hypoplasia, and consequent “molar tooth sign” (MTS). JS always shares variety of phenotypes in development defects. With the development of next-generation sequencing, dozens of causative genes have been identified to JS so far. Here, we investigated two male siblings with JS and uncovered a novel pathogenesis through combined methods. RESULTS: The siblings shared similar features of nystagmus, disorders of intellectual development, typical MTS, and abnormal morphology in fourth ventricle. Whole-exome sequencing (WES) and chromosome comparative genomic hybridization (CGH) were then performed on the proband. Strikingly, a maternal inherited nonsense variant (NM_025114.3: c.5953G>T [p.E1985*]) in CEP290 gene and a paternal inherited deletion in 12q21.32 including exons 1 to 10 of CEP290 gene were identified in the two affected siblings. We further confirmed the two variants by in vitro experiments: quantitative PCR and PCR sequencing. CONCLUSIONS: In this study, we first reported a novel causative mechanism of Joubert syndrome: a copy number variation (CNV) combined with a single-nucleotide variant in CEP290 gene, which can be helpful in the genetic diagnosis of this disease.
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spelling pubmed-73252672020-06-30 Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings Wang, Xiang Zhang, Zhu Zhang, Xueguang Shen, Ying Liu, Hongqian Hum Genomics Primary Research BACKGROUND: Joubert syndrome (JS) is a rare genetic disorder, which can be defined by brain stem malformation, cerebellar vermis hypoplasia, and consequent “molar tooth sign” (MTS). JS always shares variety of phenotypes in development defects. With the development of next-generation sequencing, dozens of causative genes have been identified to JS so far. Here, we investigated two male siblings with JS and uncovered a novel pathogenesis through combined methods. RESULTS: The siblings shared similar features of nystagmus, disorders of intellectual development, typical MTS, and abnormal morphology in fourth ventricle. Whole-exome sequencing (WES) and chromosome comparative genomic hybridization (CGH) were then performed on the proband. Strikingly, a maternal inherited nonsense variant (NM_025114.3: c.5953G>T [p.E1985*]) in CEP290 gene and a paternal inherited deletion in 12q21.32 including exons 1 to 10 of CEP290 gene were identified in the two affected siblings. We further confirmed the two variants by in vitro experiments: quantitative PCR and PCR sequencing. CONCLUSIONS: In this study, we first reported a novel causative mechanism of Joubert syndrome: a copy number variation (CNV) combined with a single-nucleotide variant in CEP290 gene, which can be helpful in the genetic diagnosis of this disease. BioMed Central 2020-06-29 /pmc/articles/PMC7325267/ /pubmed/32600475 http://dx.doi.org/10.1186/s40246-020-00274-4 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Primary Research
Wang, Xiang
Zhang, Zhu
Zhang, Xueguang
Shen, Ying
Liu, Hongqian
Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings
title Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings
title_full Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings
title_fullStr Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings
title_full_unstemmed Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings
title_short Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings
title_sort novel biallelic loss-of-function variants in cep290 cause joubert syndrome in two siblings
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325267/
https://www.ncbi.nlm.nih.gov/pubmed/32600475
http://dx.doi.org/10.1186/s40246-020-00274-4
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