分析 1386 例致痫性脑病变，提示与 DYRK1A 和 EGFR 相关。

Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR.

机构信息

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

出版信息

Nat Commun. 2024 Nov 30;15(1):10429. doi: 10.1038/s41467-024-54911-w.

DOI:10.1038/s41467-024-54911-w

PMID:39616148

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11608322/

Abstract

Lesional focal epilepsy (LFE) is a common and severe seizure disorder caused by epileptogenic lesions, including malformations of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT). Understanding the genetic etiology of these lesions can inform medical and surgical treatment. We conducted a somatic variant enrichment mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( > 1600x) targeted panel sequencing. Here we confirm four known associations (BRAF, SLC35A2, MTOR, PTPN11), support eight associations without prior statistical support (FGFR1, PIK3CA, AKT3, NF1, PTEN, RHEB, KRAS, NRAS), and identify novel associations for two genes, DYRK1A and EGFR. Both novel genes show specific histopathological phenotypes, interact with LFE genes and pathways, and may represent promising candidates as biomarkers and potentially druggable targets.

摘要

病灶性局灶性癫痫（LFE）是一种由致痫性病变引起的常见且严重的癫痫发作疾病，包括皮质发育畸形（MCD）和低级别癫痫相关肿瘤（LEAT）。了解这些病变的遗传病因可以为医疗和手术治疗提供信息。我们对 1386 名接受癫痫手术的个体的脑组织进行了体细胞变异富集 mega 分析，其中包括 599 名以前未发表的具有超高深度（> 1600x）靶向面板测序的个体。在这里，我们证实了四个已知的关联（BRAF、SLC35A2、MTOR、PTPN11），支持了八个以前没有统计学支持的关联（FGFR1、PIK3CA、AKT3、NF1、PTEN、RHEB、KRAS、NRAS），并确定了两个基因 DYRK1A 和 EGFR 的新关联。这两个新基因都表现出特定的组织病理学表型，与 LFE 基因和途径相互作用，可能是有前途的生物标志物和潜在的可药物治疗靶点。