Abstract
KCNQ2-related disorders are, although rare, among the most frequent monogenic causes of epilepsy in newborns and represent key models for precision medicine in genetic epilepsies. They encompass a large phenotypic spectrum regarding seizure and neurodevelopmental outcomes. Although variant-specific genotype-phenotype correlations have transformed the field and targeted therapies are emerging, clinical outcomes remain strikingly heterogeneous. This unexplained variability is a critical barrier to accurate counselling and clinical trial readiness. We hypothesise that disease trajectory is determined by the interaction between early treatment exposure, network-level brain dysfunction, and the broader genetic background. To address this, we propose an integrated translational strategy. First, we will expand our large international KCNQ2 cohort to define natural history across the full phenotypic spectrum and identify environmental modifiers. Second, we will investigate advanced quantitative EEG features to identify biomarkers of brain network dysfunction. Third, we will use whole-genome sequencing to explore how genetic background, consisting of both common and rare variants, shapes the clinical picture. By integrating clinical, electrophysiological, and genomic data, we will develop first-in-kind multimodal prediction models enabling early individualised risk stratification, addressing a major unmet need in genetic epilepsies, ultimately accelerating precision trial design.
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