Identification of genetic characteristics in pediatric epilepsy with focal cortical dysplasia type 2 using deep whole‐exome sequencing

• Published in: Molecular genetics & genomic medicine Vol. 10; no. 12; pp. e2086 - n/a
• Main Authors: Xu, Yan, Zhao, Rui, Wang, Min, Wang, Xin‐hua, Wang, Yi, Li, Hao, Ma, Yang‐yang, Wu, Bing‐bing, Zhou, Yuan‐feng
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.12.2022; John Wiley and Sons Inc; Wiley
• Subjects: Age; Brain; Child; Children & youth; Convulsions & seizures; deep whole‐exome sequencing; Deoxyribonucleic acid; DNA; Dysplasia; Epilepsies, Partial; Epilepsy; Epilepsy - genetics; Exome Sequencing; Females; Focal Cortical Dysplasia; focal cortical dysplasia type 2; Genes; Genomics; Histopathology; Humans; Magnetic resonance imaging; MED12; mTOR‐GATOR pathway; Mutation; Original; Pathogenesis; Pathology; Patients; Pediatrics; Peripheral blood; Rapamycin; Signal transduction; Signaling; somatic and germline variant; Surgery; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; MED12; mTOR-GATOR pathway; deep whole-exome sequencing; somatic and germline variant; focal cortical dysplasia type 2
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.2086

Background Focal cortical dysplasia type 2 (FCD2) is a malformation of cortical development that constitutes a common cause of pediatric focal epilepsy. Germline or somatic variants in the mammalian target of rapamycin (mTOR) signaling pathway genes are the pathogenesis of FCD2. Objective In this study, whole‐exome deep sequencing was performed on dysplastic cortex from focal epilepsy in children to explore genetic characteristics in FCD2. Methods Resected core lesions of FCD2 were confirmed by pathology, and peripheral blood was collected from 11 patients. Deep whole‐exome sequencing (>500X) was performed on derived genomic DNA, germline, or somatic variants in brain‐specific genes were analyzed and identified. Results In 11 patients, a heterozygous likely pathogenic germline variant of DEPDC5 was identified in one case, while somatic variants were found in four brain samples. The frequencies of the somatic variant allele were 2.52%–5.12%. Somatic variants in AKT3, TSC2, and MTOR (mTOR signaling pathway genes) were found in three samples. Besides, one somatic variant was detected in MED12 which has not been reported to associate with FCD2. Conclusion Our study expanded the variant spectrum in the mTOR‐GATOR pathway, and also detected a somatic variant in MED12 which was potentially associated with FCD 2. Whole‐exome deep sequencing was performed on dysplastic cortex from focal epilepsy in children to explore genetic characteristics in FCD2. Germline variant of DEPDC5 and somatic variants in AKT3, TSC2, and MTOR were found in this study. One somatic variant was detected in MED12 which has not been reported to associate with FCD2.