The clinico-pathological characterization of Focal Cortical Dysplasia type IIb genetically defined by MTOR mosaicism.

Abstract

Focal Cortical Dysplasia (FCD) is a major cause of drug-resistant paediatric epilepsy and is amenable to successful neurosurgical resection. FCD ILAE Type IIb is the most common FCD subtype, and brain somatic mutations affecting the mTOR pathway play a major pathogenic role. The aim of this study was to comprehensively describe the genotype-phenotype association of twenty patients with histopathologically confirmed FCDIIb using Next Generation Sequencing (NGS) of paired blood-brain samples METHODS: Clinical and neuropathological data were retrospectively reviewed from the hospital archive. The NGS panel included 11 mTOR-pathway-related genes with maximum coverage of 2000x. The detected variants were validated by digital droplet PCR. Pathogenic MTOR variants were identified in 10 patients (50%). Further comparison with MTOR-wildtype FCDIIb suggested a profound genotype-phenotype association characterized by (1) a non-temporal lobe lesion on MRI, (2) a larger lesion volume occupying grey and white matter (3.032±1.859cm3 vs. 1.110±0.856cm3 , p=0.014), (3) more balloon cells (50.20±14.40BC/mm2 vs. 31.64±30.56BC/mm2 , p=0.099) and dysmorphic neurons (48.72±19.47DN/mm2 vs. 15.28±13.95DN/mm2 , p=0.000), as well as (4) a positive correlation between VAF and the lesion volume (r=0.802, p=0.017). Our study identified frequent MTOR mutations in the cell-rich FCDIIb phenotype, clinically characterized by a non-temporal location and large lesion volume. Comprehensive genotype-phenotype associations will help us further explore and define the broad spectrum of FCD lesions to make more targeted therapies available in the realm of epileptology.