ORIGINAL RESEARCH article
Front. Genet.
Sec. Genetics of Common and Rare Diseases
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1590292
This article is part of the Research TopicDecoding Complexity: Genomic, Epigenomic, and Environmental Dynamics in Developmental and Neurogenetic DisordersView all 5 articles
Combined Molecular characterization and Dopa-Responsive treatment in two patients with NR4A2-Associated Intellectual Developmental Disorder
Provisionally accepted
- Taiyuan Children's Medical Center, Taiyuan, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Pathogenic variants in NR4A2 are associated with neurodevelopmental disorders including intellectual developmental disorder with language impairment and early-onset dopa-responsive dystonia-parkinsonism (IDLDP). Here we report two pediatric NR4A2-related cases presenting with global developmental delay, speech impairment, and intellectual disability. Comprehensive genetic investigations including whole-exome sequencing revealed a de novo missense variant (c.994G>C, p.Val332Leu) in NR4A2 and a 2q23.3-q24.2 deletion encompassing NR4A2.Functional validation via RNA sequencing revealed that the missense variant induces pathogenic exon 4 skipping through aberrant splicing. Both patients exhibited marked clinical improvements in linguistic competence and motor function following levodopa therapy, initiated after confirmation of dopaminergic responsiveness. A systematic review of 19 reported NR4A2-related cases revealed substantial phenotypic heterogeneity, with three of them demonstrating favorable responses to dopaminergic treatment. Our findings underscore the diagnostic value of integrating molecular profiling with functional RNA analysis to resolve complex neurogenetic disorders.Levodopa therapy shows therapeutic potential for NR4A2-deficient patients with dopa-responsive features, especially in linguistic improvement. This study expands the understanding of NR4A2-associated pathogenesis and provides insights for the precision management of related neurodevelopmental conditions.
Keywords: NR4A2 gene1, Intellectual developmental disorder2, Dopa-responsive dystonia-parkinsonism3, whole-exome sequencing4, RNA sequencing5, L-DOPA treatment6
Received: 09 Mar 2025; Accepted: 28 Aug 2025.
Copyright: © 2025 Liang, Li and Deng. 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) or licensor 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.
* Correspondence: Yang Deng, Taiyuan Children's Medical Center, Taiyuan, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.