mTOR Pathway Somatic Pathogenic Variants in Focal Malformations of Cortical Development
Eric Krochmalnek, Andrea Accogli, Judith St‐Onge, Nassima Addour-Boudrahem, Gyan Prakash, Sung‐Hoon Kim, Tristan Brunette‐Clément, Ghadd Alhajaj, Lina Mougharbel, Elena Bruneau, Kenneth A. Myers, François Dubeau, Jason Karamchandani, Jean‐Pierre Farmer, Jeffrey Atkinson, Jeffrey W. Hall, Chantal Poulin, Bernard Rosenblatt, Joël Lafond‐Lapalme, Alexander G. Weil, Catherine Fallet‐Bianco, Steffen Albrecht, Nahum Sonenberg, Jean‐Baptiste Rivière, Roy Dudley, Myriam Srour
Abstract
Background and Objectives: Somatic and germline pathogenic variants in genes of the mammalian target of rapamycin (mTOR) signaling pathway are a common mechanism underlying a subset of focal malformations of cortical development (FMCDs) referred to as mTORopathies, which include focal cortical dysplasia (FCD) type II, subtypes of polymicrogyria, and hemimegalencephaly. Our objective is to screen resected FMCD specimens with mTORopathy features on histology for causal somatic variants in mTOR pathway genes, describe novel pathogenic variants, and examine the variant distribution in relation to neuroimaging, histopathologic classification, and clinical outcomes. Methods: variant. Results: (c.2802-1G>C). Discussion: The AAF of somatic pathogenic variants correlated with the topographic distribution, histopathology, and postsurgical outcomes. Moreover, cortical regions with absent histologic FCD features had negligible or undetectable pathogenic variant loads. By contrast, specimens with frank histologic abnormalities had detectable pathogenic variant loads, which raises important questions as to whether there is a tolerable variant threshold and whether surgical margins should be clean, as performed in tumor resections. In addition, we describe 2 novel pathogenic variants, expanding the mTORopathy genetic spectrum. Although most pathogenic somatic variants are located at mutation hotspots, screening the full-coding gene sequence remains necessary in a subset of patients.