The clinico‐pathological characterisation of focal cortical dysplasia type IIb genetically defined by MTOR mosaicism

Abstract Aims 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 20 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 2000×. The detected variants were validated by digital droplet PCR. Results Pathogenic MTOR variants were identified in 10 patients (50%). Further comparison with MTOR ‐wildtype FCDIIb suggested a profound genotype–phenotype association characterised by (1) a non‐temporal lobe lesion on MRI, (2) a larger lesion volume occupying grey and white matter (3.032 ± 1.859 cm 3 vs 1.110 ± 0.856 cm 3 , p = 0.014), (3) more balloon cells (50.20 ± 14.40 BC/mm 2 vs 31.64 ± 30.56 BC/mm 2 , p = 0.099) and dysmorphic neurons (48.72 ± 19.47DN/mm 2 vs 15.28 ± 13.95DN/mm 2 , p = 0.000) and (4) a positive correlation between VAF and the lesion volume ( r = 0.802, p = 0.017). Conclusions Our study identified frequent MTOR mutations in the cell‐rich FCDIIb phenotype, clinically characterised 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.