Detection of brain somatic variation in epilepsy‐associated developmental lesions

• DOI: 10.1111/epi.17323
• Publication Date: 2022-06-10T15:27:33Z
• Authors: Tracy A. Bedrosian; Katherine E. Miller; Olivia E. Grischow; Kathleen M. Schie...; Stephanie LaHaye; Hyojung Yoon; Anthony R. Miller; Jason Navarro; Jesse Westfall; Kristen Leraas; Samantha Choi; Rachel Williamson; James Fitch; Benjamin J. Kelly; Peter White; Kristy Lee; Sean McGrath; Catherine E. Cott...; Vincent Magrini; Jeffrey Leonard; Jonathan Pindrik; Ammar Shaikhouni; Daniel R. Boué; Diana L. Thomas; Christopher R. Pi...; Richard K. Wilson; Adam P. Ostendorf; Elaine R. Mardis; Daniel C. Koboldt
• Keywords: GNAS complex locus; PDGFRA

Abstract Objective Epilepsy‐associated developmental lesions, including malformations of cortical development and low‐grade tumors, represent a major cause drug‐resistant seizures requiring surgical intervention in children. Brain‐restricted somatic mosaicism has been implicated the genetic etiology these lesions; however, many contributory genes remain unidentified. Methods We enrolled 50 children who were undergoing epilepsy surgery into translational research study. Resected tissue was divided for clinical neuropathologic evaluation genomic analysis. performed exome RNA sequencing to identify variation we confirmed our findings using high‐depth targeted DNA sequencing. Results uncovered candidate disease‐causing affecting 28 patients (56%), as well germline variants 4 (8%). In agreement with previous studies, identified solute carrier family 35 member A2 ( SLC35A2 ) mechanistic target rapamycin kinase MTOR pathway focal dysplasia. Somatic gains chromosome 1q detected 30% (3 10) Type I dysplasia (FCD)s. mitogen‐activated protein MAPK) (i.e., fibroblast growth factor receptor 1 [ FGFR1 ], FGFR2 , B‐raf proto‐oncogene, serine/threonine BRAF KRAS GTPase ]) associated epilepsy‐associated tumors. enabled detection structural that would have otherwise missed, which accounted more than one‐half tumor diagnoses. Sampling across multiple anatomic regions revealed variant allele fractions vary widely within epileptogenic tissue. Finally, putative not yet Significance These results further elucidate basis brain abnormalities leading point new disease genes.