CCDC22 variants caused X-linked focal epilepsy and focal cortical dysplasia.

CCDC22 gene Focal cortical dysplasia Focal epilepsy Phenotypic variation

Journal

Seizure
ISSN: 1532-2688
Titre abrégé: Seizure
Pays: England
ID NLM: 9306979

Informations de publication

Date de publication:
12 Oct 2024
Historique:
received: 20 08 2024
revised: 09 10 2024
accepted: 12 10 2024
medline: 20 10 2024
pubmed: 20 10 2024
entrez: 19 10 2024
Statut: aheadofprint

Résumé

The CCDC22 gene plays vital roles in regulating the NF-κB pathway, an essential pathway for neuroinflammation, neurodevelopment, and epileptogenesis. Previously, variants in CCDC22 were reported to be associated with intellectual disability. This study aimed to explore the association between CCDC22 and epilepsy. Trios-based whole-exome sequencing (WES) was performed in a cohort of patients with epilepsy of unknown cause recruited from the China Epilepsy Gene 1.0 Project. Damaging effects of variants were analysed using protein modelling. Hemizygous missense CCDC22 variants were identified in three unrelated cases. These variants had no hemizygous frequencies in controls. All missense variants identified in this study were predicted to be "damaging" by multiple in silico tools and to alter the hydrogen bonds with surrounding residues and/or protein stability. The three patients presented with focal epilepsy of varying severity, including one with refractory seizures and focal cortical dysplasia (FCD) and two with seizures responding to antiseizure medicine. Notably, the variant associated with the severe phenotype was located in the coiled-coil domain and predicted to alter hydrogen bonding and protein stability, whereas the two variants associated with mild epilepsy were located outside functional domains and had moderate molecular alterations. Analysis of spatiotemporal expression indicated that CCDC22 was expressed in brain subregions with three peaks in the fetal stage, infancy, and early adulthood, especially in the fetal stage, explaining the occurrence of developmental abnormities. CCDC22 variants are potentially associated with X-linked focal epilepsy and FCD. The molecular subregional effects supported the occurrence of FCD.

Sections du résumé

BACKGROUND BACKGROUND
The CCDC22 gene plays vital roles in regulating the NF-κB pathway, an essential pathway for neuroinflammation, neurodevelopment, and epileptogenesis. Previously, variants in CCDC22 were reported to be associated with intellectual disability. This study aimed to explore the association between CCDC22 and epilepsy.
METHODS METHODS
Trios-based whole-exome sequencing (WES) was performed in a cohort of patients with epilepsy of unknown cause recruited from the China Epilepsy Gene 1.0 Project. Damaging effects of variants were analysed using protein modelling.
RESULTS RESULTS
Hemizygous missense CCDC22 variants were identified in three unrelated cases. These variants had no hemizygous frequencies in controls. All missense variants identified in this study were predicted to be "damaging" by multiple in silico tools and to alter the hydrogen bonds with surrounding residues and/or protein stability. The three patients presented with focal epilepsy of varying severity, including one with refractory seizures and focal cortical dysplasia (FCD) and two with seizures responding to antiseizure medicine. Notably, the variant associated with the severe phenotype was located in the coiled-coil domain and predicted to alter hydrogen bonding and protein stability, whereas the two variants associated with mild epilepsy were located outside functional domains and had moderate molecular alterations. Analysis of spatiotemporal expression indicated that CCDC22 was expressed in brain subregions with three peaks in the fetal stage, infancy, and early adulthood, especially in the fetal stage, explaining the occurrence of developmental abnormities.
SIGNIFICANCE CONCLUSIONS
CCDC22 variants are potentially associated with X-linked focal epilepsy and FCD. The molecular subregional effects supported the occurrence of FCD.

Identifiants

DOI: 10.1016/j.seizure.2024.10.007 PMID: 39426154
pubmed: 39426154
pii: S1059-1311(24)00290-5
doi: 10.1016/j.seizure.2024.10.007
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1-8

Informations de copyright

Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest All the authors declare that there are no conflicts of interest.

Auteurs

Yu-Lei He (YL)

Department of Neurology, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University, Guangzhou, PR China; Department of Neurology, The First People's Hospital of Chenzhou affiliated to the University of South China, The First Affiliated Hospital of Xiangnan University, Chenzhou, PR China; Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, PR China.

Yi-Chen Ye (YC)

Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, PR China.

Peng-Yu Wang (PY)

Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, PR China.

Xiao-Yu Liang (XY)

Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, PR China.

Yu-Jie Gu (YJ)

Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, PR China.

Si-Qi Zhang (SQ)

Department of Neurology, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University, Guangzhou, PR China.

Dong-Qian Han (DQ)

Department of Neurology, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University, Guangzhou, PR China.

Qi Chi (Q)

Department of Neurology, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University, Guangzhou, PR China.

Wen-Hui Liu (WH)

Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, PR China.

Peng Zhou (P)

Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, PR China.

Qiong-Xiang Zhai (QX)

Department of Pediatrics, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, PR China.

Bing-Mei Li (BM)

Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, PR China.

Yong-Hong Yi (YH)

Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, PR China.

Sheng Luo (S)

Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, PR China. Electronic address: shengluo@189.cn.

Heng Meng (H)

Department of Neurology, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University, Guangzhou, PR China. Electronic address: memphisheng@163.com.

Classifications MeSH