An integrated genetic analysis of epileptogenic brain malformed lesions

Abstract

Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.

Epilepsy in Legius syndrome: Coincidence or causation?

“…Recently published data have reported somatic pathogenic variants in Ras/MAPK pathway genes in patients with low-grade epilepsy-associated tumors and focal cortical dysplasias, raising the possibility that development of subtle focal brain malformations, possibly related to overactivity of the mammalian target of rapamycin (mTOR) pathway, could be an epileptogenic mechanism (Bedrosian et al, 2022;Fujita et al, 2023;L opez-Rivera et al, 2023;Zhao et al, 2019). However, enrichment of somatic genetic variants predicted to activate the Ras/MAPK pathway was also recently reported in the hippocampi of patients with drug-resistant mesial temporal lobe epilepsy, a form of focal epilepsy in which the pathology of resected specimens is quite different from that of focal cortical dysplasia and low-grade epilepsy-associated tumors (Khoshkhoo et al, 2023).…”