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Identification of two novel variants of the BCL11B gene in two Chinese pedigrees associated with neurodevelopmental disorders

OBJECTIVE: According to a recent report, the mutation of transcription factor gene BCL11B is associated with the development of neurodevelopmental disorders and immune deficiency. By analyzing both clinical features and genetic variations, this study aims to reveal the genetic etiology of four patie...

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Autores principales: Che, Fengyu, Tie, Xiaoling, Lei, Hong, Zhang, Xi, Duan, Mingyue, Zhang, Liyu, Yang, Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9513357/
https://www.ncbi.nlm.nih.gov/pubmed/36176959
http://dx.doi.org/10.3389/fnmol.2022.927357
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author Che, Fengyu
Tie, Xiaoling
Lei, Hong
Zhang, Xi
Duan, Mingyue
Zhang, Liyu
Yang, Ying
author_facet Che, Fengyu
Tie, Xiaoling
Lei, Hong
Zhang, Xi
Duan, Mingyue
Zhang, Liyu
Yang, Ying
author_sort Che, Fengyu
collection PubMed
description OBJECTIVE: According to a recent report, the mutation of transcription factor gene BCL11B is associated with the development of neurodevelopmental disorders and immune deficiency. By analyzing both clinical features and genetic variations, this study aims to reveal the genetic etiology of four patients with neurodevelopmental disorders from two unrelated Chinese pedigrees. METHODS: From the 4 cases, the clinical data were collected. The potential pathogenic gene variations were analyzed by means of based-trio whole exome sequencing (Trio-WES) and then validated through Sanger sequencing in their respective pedigrees. Furthermore, both the in vitro minigene assay and the NMD assay were performed to evaluate the impact of splicing and frameshift variants. RESULTS: The 4 patients displayed mild-to-severe intellectual developmental disorder, which was accompanied by speech delay, dysmorphic facies, and serious caries. In addition, the extended phenotype of developmental regression was observed in the proband from Family 1, which has been unreported previously. Molecular analysis was conducted to identify two novel heterozygous variants in the BCL11B gene: a maternal splicing variant c.427 + 1G > A in Family 1 and a de novo frameshift variant c.2461_2462insGAGCCACACCGGCG (p.Glu821Glyfs*28) in Family 2. As revealed by the in vitro minigene assay, the c.427 + 1G > A variant activated a new cryptic splice site. As confirmed by an overexpression assay, there was no significant difference in the level of mRNA and protein expression between the mutate-BCL11B (p.Glu821Glyfs*28) and the wild type. It confirms that p.Glu821Glyfs*28 variant could be an NMD escaping variant. CONCLUSION: The extended phenotype of BCL11B-related disorders is reported in this study to reveal the clinical and genetic heterogeneity of the disease. The study starts by identifying a splicing variant and a novel frameshift variant of the BCL11B gene, thus confirming its aberrant translation. The findings of this study expand the mutation spectrum of the genetic BCL11B gene, which not only improves the understanding of the associated neurodevelopmental disorders from a clinical perspective but also provides guidance on diagnosis and genetic counseling for patients.
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spelling pubmed-95133572022-09-28 Identification of two novel variants of the BCL11B gene in two Chinese pedigrees associated with neurodevelopmental disorders Che, Fengyu Tie, Xiaoling Lei, Hong Zhang, Xi Duan, Mingyue Zhang, Liyu Yang, Ying Front Mol Neurosci Molecular Neuroscience OBJECTIVE: According to a recent report, the mutation of transcription factor gene BCL11B is associated with the development of neurodevelopmental disorders and immune deficiency. By analyzing both clinical features and genetic variations, this study aims to reveal the genetic etiology of four patients with neurodevelopmental disorders from two unrelated Chinese pedigrees. METHODS: From the 4 cases, the clinical data were collected. The potential pathogenic gene variations were analyzed by means of based-trio whole exome sequencing (Trio-WES) and then validated through Sanger sequencing in their respective pedigrees. Furthermore, both the in vitro minigene assay and the NMD assay were performed to evaluate the impact of splicing and frameshift variants. RESULTS: The 4 patients displayed mild-to-severe intellectual developmental disorder, which was accompanied by speech delay, dysmorphic facies, and serious caries. In addition, the extended phenotype of developmental regression was observed in the proband from Family 1, which has been unreported previously. Molecular analysis was conducted to identify two novel heterozygous variants in the BCL11B gene: a maternal splicing variant c.427 + 1G > A in Family 1 and a de novo frameshift variant c.2461_2462insGAGCCACACCGGCG (p.Glu821Glyfs*28) in Family 2. As revealed by the in vitro minigene assay, the c.427 + 1G > A variant activated a new cryptic splice site. As confirmed by an overexpression assay, there was no significant difference in the level of mRNA and protein expression between the mutate-BCL11B (p.Glu821Glyfs*28) and the wild type. It confirms that p.Glu821Glyfs*28 variant could be an NMD escaping variant. CONCLUSION: The extended phenotype of BCL11B-related disorders is reported in this study to reveal the clinical and genetic heterogeneity of the disease. The study starts by identifying a splicing variant and a novel frameshift variant of the BCL11B gene, thus confirming its aberrant translation. The findings of this study expand the mutation spectrum of the genetic BCL11B gene, which not only improves the understanding of the associated neurodevelopmental disorders from a clinical perspective but also provides guidance on diagnosis and genetic counseling for patients. Frontiers Media S.A. 2022-09-13 /pmc/articles/PMC9513357/ /pubmed/36176959 http://dx.doi.org/10.3389/fnmol.2022.927357 Text en Copyright © 2022 Che, Tie, Lei, Zhang, Duan, Zhang and Yang. 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 Molecular Neuroscience
Che, Fengyu
Tie, Xiaoling
Lei, Hong
Zhang, Xi
Duan, Mingyue
Zhang, Liyu
Yang, Ying
Identification of two novel variants of the BCL11B gene in two Chinese pedigrees associated with neurodevelopmental disorders
title Identification of two novel variants of the BCL11B gene in two Chinese pedigrees associated with neurodevelopmental disorders
title_full Identification of two novel variants of the BCL11B gene in two Chinese pedigrees associated with neurodevelopmental disorders
title_fullStr Identification of two novel variants of the BCL11B gene in two Chinese pedigrees associated with neurodevelopmental disorders
title_full_unstemmed Identification of two novel variants of the BCL11B gene in two Chinese pedigrees associated with neurodevelopmental disorders
title_short Identification of two novel variants of the BCL11B gene in two Chinese pedigrees associated with neurodevelopmental disorders
title_sort identification of two novel variants of the bcl11b gene in two chinese pedigrees associated with neurodevelopmental disorders
topic Molecular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9513357/
https://www.ncbi.nlm.nih.gov/pubmed/36176959
http://dx.doi.org/10.3389/fnmol.2022.927357
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