Chd2, encoding chromodomain helicase DNA-binding protein 2, is a member of the sucrose non-fermenting (SNF-2) protein family of epigenetic regulators. It is involved in chromatin remodeling, which is crucial for regulating gene expression, and has significant importance in neurodevelopment [1,4,6].

Pathogenic de novo mutations in Chd2 have been identified as causes of early-onset epileptic encephalopathy, abnormal brain function, and intellectual disability [1,3]. In pediatric glioma, depletion of Chd2 in H3.1K27M diffuse midline glioma (DMG) cells compromises cell viability, neuron-to-glioma synaptic connections, and neuron-induced proliferation both in vitro and in vivo, while also extending the survival of H3.1K27M DMG-bearing mice. Mechanistically, Chd2 coordinates with the transcription factor FOSL1 to control the expression of axon-guidance and synaptic genes in these cells [2]. In a cohort of patients with epileptic encephalopathies, de novo Chd2 mutations accounted for 1.2% of cases [3]. A variety of phenotypes are associated with Chd2 pathogenic variants, including severe global developmental delay, childhood-onset myoclonic epilepsy, and additional neuropsychiatric features such as autism, ADHD, and hyperactivity [4]. In adult patients with likely pathogenic or pathogenic Chd2 variants, 79% still have ongoing seizures, 71% have autism spectrum disorder, and higher seizure severity is associated with worse non-seizure outcomes [5].

In conclusion, Chd2 is essential for proper neurodevelopment and its dysregulation is associated with various neurodevelopmental disorders, especially epileptic encephalopathies and glioma-related pathologies. Research on Chd2, including through model-based studies, has provided valuable insights into its role in these disease conditions, highlighting its potential as a therapeutic target [1-3,6,8,9].

References:

1. Wilson, Marc-Michel, Henshall, David C, Byrne, Susan M, Brennan, Gary P. 2021. CHD2-Related CNS Pathologies. In International journal of molecular sciences, 22, . doi:10.3390/ijms22020588. https://pubmed.ncbi.nlm.nih.gov/33435571/

2. Zhang, Xu, Duan, Shoufu, Apostolou, Panagiota E, Gogos, Joseph A, Zhang, Zhiguo. . CHD2 Regulates Neuron-Glioma Interactions in Pediatric Glioma. In Cancer discovery, 14, 1732-1754. doi:10.1158/2159-8290.CD-23-0012. https://pubmed.ncbi.nlm.nih.gov/38767413/

3. Carvill, Gemma L, Heavin, Sinéad B, Yendle, Simone C, Scheffer, Ingrid E, Mefford, Heather C. 2013. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. In Nature genetics, 45, 825-30. doi:10.1038/ng.2646. https://pubmed.ncbi.nlm.nih.gov/23708187/

4. Clara-Hwang, Angela, Stefani, Stefani, Lau, Tracy, Striano, Pasquale, Efthymiou, Stephanie. 2024. Expanding the Mutational Landscape and Clinical Phenotype of CHD2-Related Encephalopathy. In Neurology. Genetics, 10, e200168. doi:10.1212/NXG.0000000000200168. https://pubmed.ncbi.nlm.nih.gov/39035822/

5. Rong, Marlene, Zulfiqar Ali, Quratulain, Aledo-Serrano, Angel, Bassett, Anne S, Andrade, Danielle M. 2024. Adult Phenotype of CHD2-Associated Disorders. In Neurology. Genetics, 10, e200194. doi:10.1212/NXG.0000000000200194. https://pubmed.ncbi.nlm.nih.gov/39601014/

6. Lamar, Kay-Marie J, Carvill, Gemma L. 2018. Chromatin Remodeling Proteins in Epilepsy: Lessons From CHD2-Associated Epilepsy. In Frontiers in molecular neuroscience, 11, 208. doi:10.3389/fnmol.2018.00208. https://pubmed.ncbi.nlm.nih.gov/29962935/