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Two novel heterozygous truncating variants in NR4A2 identified in patients with neurodevelopmental disorder and brief literature review

Pathogenic variants in the nuclear receptor superfamily 4 group A member 2 (NR4A2) cause an autosomal dominant neurodevelopmental disorder with or without seizures. Here, we described two patients presenting with developmental delay, language impairment, and attention-deficit hyperactivity disorder....

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Autores principales: Song, Xiaozhen, Xu, Wuhen, Xiao, Man, Lu, Yanfen, Lan, Xiaoping, Tang, Xiaojun, Xu, Nanjie, Yu, Guangjun, Zhang, Hong, Wu, Shengnan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9383035/
https://www.ncbi.nlm.nih.gov/pubmed/35992907
http://dx.doi.org/10.3389/fnins.2022.956429
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author Song, Xiaozhen
Xu, Wuhen
Xiao, Man
Lu, Yanfen
Lan, Xiaoping
Tang, Xiaojun
Xu, Nanjie
Yu, Guangjun
Zhang, Hong
Wu, Shengnan
author_facet Song, Xiaozhen
Xu, Wuhen
Xiao, Man
Lu, Yanfen
Lan, Xiaoping
Tang, Xiaojun
Xu, Nanjie
Yu, Guangjun
Zhang, Hong
Wu, Shengnan
author_sort Song, Xiaozhen
collection PubMed
description Pathogenic variants in the nuclear receptor superfamily 4 group A member 2 (NR4A2) cause an autosomal dominant neurodevelopmental disorder with or without seizures. Here, we described two patients presenting with developmental delay, language impairment, and attention-deficit hyperactivity disorder. Trio-based whole exome sequencing revealed two novel heterozygous variants, c.1541-2A > C and c.915C > A, in NR4A2. Both variants were identified as de novo and confirmed by Sanger sequencing. In vitro functional analyses were performed to assess their effects on expression of mRNA or protein. The canonical splicing variant c.1541-2A > C caused aberrant splicing, leading to the retention of intron 7 and a truncated protein due to an early termination codon within intron 7 with decreased protein expression, while the variant c.915C > A was shown to result in a shorter protein with increased expression level unexpectedly. The clinical and genetic characteristics of the previously published patients were briefly reviewed for highlighting the potential link between mutations and phenotypes. Our research further confirms that NR4A2 is a disease-causing gene of neurodevelopmental disorders and suggests alterations in different domains of NR4A2 cause various severity of symptoms.
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spelling pubmed-93830352022-08-18 Two novel heterozygous truncating variants in NR4A2 identified in patients with neurodevelopmental disorder and brief literature review Song, Xiaozhen Xu, Wuhen Xiao, Man Lu, Yanfen Lan, Xiaoping Tang, Xiaojun Xu, Nanjie Yu, Guangjun Zhang, Hong Wu, Shengnan Front Neurosci Neuroscience Pathogenic variants in the nuclear receptor superfamily 4 group A member 2 (NR4A2) cause an autosomal dominant neurodevelopmental disorder with or without seizures. Here, we described two patients presenting with developmental delay, language impairment, and attention-deficit hyperactivity disorder. Trio-based whole exome sequencing revealed two novel heterozygous variants, c.1541-2A > C and c.915C > A, in NR4A2. Both variants were identified as de novo and confirmed by Sanger sequencing. In vitro functional analyses were performed to assess their effects on expression of mRNA or protein. The canonical splicing variant c.1541-2A > C caused aberrant splicing, leading to the retention of intron 7 and a truncated protein due to an early termination codon within intron 7 with decreased protein expression, while the variant c.915C > A was shown to result in a shorter protein with increased expression level unexpectedly. The clinical and genetic characteristics of the previously published patients were briefly reviewed for highlighting the potential link between mutations and phenotypes. Our research further confirms that NR4A2 is a disease-causing gene of neurodevelopmental disorders and suggests alterations in different domains of NR4A2 cause various severity of symptoms. Frontiers Media S.A. 2022-08-03 /pmc/articles/PMC9383035/ /pubmed/35992907 http://dx.doi.org/10.3389/fnins.2022.956429 Text en Copyright © 2022 Song, Xu, Xiao, Lu, Lan, Tang, Xu, Yu, Zhang and Wu. 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 Neuroscience
Song, Xiaozhen
Xu, Wuhen
Xiao, Man
Lu, Yanfen
Lan, Xiaoping
Tang, Xiaojun
Xu, Nanjie
Yu, Guangjun
Zhang, Hong
Wu, Shengnan
Two novel heterozygous truncating variants in NR4A2 identified in patients with neurodevelopmental disorder and brief literature review
title Two novel heterozygous truncating variants in NR4A2 identified in patients with neurodevelopmental disorder and brief literature review
title_full Two novel heterozygous truncating variants in NR4A2 identified in patients with neurodevelopmental disorder and brief literature review
title_fullStr Two novel heterozygous truncating variants in NR4A2 identified in patients with neurodevelopmental disorder and brief literature review
title_full_unstemmed Two novel heterozygous truncating variants in NR4A2 identified in patients with neurodevelopmental disorder and brief literature review
title_short Two novel heterozygous truncating variants in NR4A2 identified in patients with neurodevelopmental disorder and brief literature review
title_sort two novel heterozygous truncating variants in nr4a2 identified in patients with neurodevelopmental disorder and brief literature review
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9383035/
https://www.ncbi.nlm.nih.gov/pubmed/35992907
http://dx.doi.org/10.3389/fnins.2022.956429
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