Brain Somatic Variants in Pediatric Epilepsy Patients – a Single Center Experience
Abstract number :
2.32
Submission category :
9. Surgery / 9B. Pediatrics
Year :
2023
Submission ID :
517
Source :
www.aesnet.org
Presentation date :
12/3/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Ara Ko, MD – Severance Children's Hospital, Yonsei University College of Medicine
Won Seok Chang, MD – Neurosurgery – Severance Hospital, Yonsei University College of Medicine; Hoon-Chul Kang, MD, PhD – Pediatric Neurology – Severance Children's Hospital, Yonsei University College of Medicine; Heung Dong Kim, MD, PhD – Pediatric Neurology – Severance Children's Hospital, Yonsei University College of Medicine; Se Hee Kim, MD – Pediatric Neurology – Severance Children's Hospital, Yonsei University College of Medicine; Jeong Ho Lee, MD, PhD – GSMSE, KAIST; Joon Soo Lee, MD – Pediatric Neurology – Severance Children's Hospital, Yonsei University College of Medicine
Rationale:
While the majority of childhood epilepsies can be managed with treatment, around 15% of cases are resistant to drugs, with malformation of cortical development (MCD) being a leading cause. Focal cortical dysplasia (FCD) is a specific type of MCD that frequently necessitates epilepsy surgery in children. Although there is much more to explore, recent research has highlighted the significance of de novo somatic mutations leading to mosaic variants as a causative factor in a significant proportion of epilepsy patients with MCD. This study aims to provide an overview of the findings from gene panel analysis on brain somatic variants in pediatric epilepsy patients who underwent epilepsy surgery.
Methods:
Over a 10-year period, patients who underwent resective epilepsy surgery at Severance Children's Hospital were included in this study. Brain somatic MCD gene panel analysis was performed on the resected brain tissues. Patients with structural etiologies such as ischemia or hemorrhage, those with hippocampal sclerosis as the cause of epilepsy, and individuals who did not consent to participate were excluded from the genetic analysis. Patients with tuberous sclerosis or long-term epilepsy-associated tumors were included in the gene panel analysis but not considered in the current study. The targeted gene panel included 13 genes, and the analysis was performed with a read depth of over 1,000x. Somatic and germline variants were identified using Mutect2, Replow, and HaplotypeCaller. Candidate variants were subsequently validated through targeted amplicon sequencing.
Results:
A total of 253 patients were included in the study. Among them, 74 (29.2%) patients had identifiable causative variants linked to the underlying etiology of epilepsy. The most frequently detected variants were observed in the MTOR gene (33.8%), followed by SLC35A2 (32.4%), DEPDC5 (14.9%), TSC1 (8.1%), PIK3CA (5.4%), TSC2 (4.1%), and AKT3 (1.4%). Notably, all variants, except for DEPDC5, were somatic mutations. When considering pathologic subtypes, no variants were found in FCD type I, while mTOR pathway gene mutations were present in 38.9% of FCD type II patients. Additionally, 85% of patients with malformations of cortical development with hippocampal sclerosis (MOGHE) exhibited SLC35A2 variants. In FCD type II patients with identified genetic mutations, there was a correlation between the variant allele frequency and FCD type (IIa vs IIb). Hemimegalencephaly showed an association with gene variants in the mTOR pathway upstream.
Conclusions:
Somatic and germline variants were detected in approximately one-third of pediatric epilepsy patients undergoing resective epilepsy surgery for MCD, excluding tuberous sclerosis cases. FCD type II was associated with mutations in mTOR pathway genes, while MOGHE showed somatic SLC35A2 variants. Furthermore, a correlation was observed between FCD type and variant allele frequency in patients with somatic mTOR pathway gene mutations.
Funding: None
Surgery