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

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 2000x. 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 cm³ vs 1.110 ± 0.856 cm³, p = 0.014), (3) more balloon cells (50.20 ± 14.40 BC/mm² vs 31.64 ± 30.56 BC/mm², p = 0.099) and dysmorphic neurons (48.72 ± 19.47 DN/mm² vs 15.28 ± 13.95 DN/mm², 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. [ABSTRACT FROM AUTHOR]