Epilepsy is one of the most common neurological diseases in children, characterized by recurrent seizures. While genetic factors play a significant role in various forms of epilepsy, such as developmental and epileptic encephalopathy (DEE) and idiopathic generalized epilepsy (IGE), the etiology of most patients remains unknown.
This research published in the Genes & Diseases journal by a team from Guangzhou Medical University, Shao Yang University, Guangdong General Hospital, the 900 Hospital of the Joint Service Support Force of the People’s Liberation Army of China, the Children’s Hospital of Shanxi and Peking University People’s Hospital determines the association between CSMD1 and generalized epilepsies.
Initially, a trio-based whole-exome sequencing approach was conducted on a cohort of 173 individuals diagnosed with generalized epilepsy. Four pairs of CSMD1 compound heterozygous variants were identified in four unrelated cases with IGE. Additionally, CSMD1 variants were identified in five DEE cases featured by generalized seizures from the matching platform, including two with de novo and three with compound heterozygous variants.
All identified variants were located in the functional domains of the CSMD1 protein and were predicted via bioinformatics tools to alter hydrogen bonding or reduce protein stability. Notably, DEE-associated variants were more damaging, closer in protein structure, and exhibited lower minor allele frequencies (MAF) than the IGE-associated variants, suggesting a minor allele frequency-phenotype severity correlation.
Gene expression analysis further revealed that CSMD1 was extensively expressed throughout the brain, particularly in the cortex. Importantly, the CSMD1 temporal expression pattern correlated with the disease onset and outcomes.
In conclusion, this study indicates that CSMD1 is associated with generalized epilepsies and is a novel causative gene of DEE. Overall, the findings of this research could pave the way for improved genetic testing for epilepsy and targeted interventions for affected individuals.
Reference
Title of Original Paper: CSMD1 as a causative gene of developmental and epileptic encephalopathy and generalized epilepsies
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2024.101473
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