Characterizing the Clinical and Genetic Landscape of KCNT1-Related Disorders

KCNT1-related disorders represent clinically heterogeneous severe epilepsies associated with profound neurodevelopmental impairment. The full phenotypic spectrum and longitudinal disease trajectory remain incompletely characterized, which is a critical gap limiting the establishment of quantifiable endpoints necessary for future clinical trials. Compounding this challenge, identical pathogenic variants result in phenotypically distinct syndromes, including early infantile developmental and epileptic encephalopathy (EIDEE) and autosomal dominant sleep-related hypermotor epilepsy (ADSHE), underscoring unresolved genotype-phenotype relationships. To address these gaps, we performed a comprehensive analysis of 159 individuals with KCNT1-related disorders, including a longitudinally characterized subgroup of 62 individuals across 390 patient years, systematically defining disease progression, seizure trajectories, developmental outcomes, and treatment response across the full spectrum of the disorder. Seizures were nearly universal, affecting 157 of 159 individuals, with 81% (n=126/156) having seizure onset within the first year of life. Stratification by clinical subgroup revealed divergent seizure onset patterns. Recurrent variants did not significantly differ in age of seizure onset yet exhibited variant-specific clinical fingerprints, such as the preponderance of focal clonic seizures (OR=5.03, 95% CI 1.60-15.7, f=0.47) in those with the p.Gly288Ser variant. Comparison with a broader cohort of 14,893 individuals with neurodevelopmental disorders revealed phenotypic features such as migrating focal seizures (OR=21716, 95% CI 2409-Inf, f=0.42) and hypertonia (OR=26.5, 95% CI 18.2-38.3, f=0.45) to be more common in EIDEE, and nocturnal seizures (OR=29787, 95% CI 3062-Inf, f=0.5) and hyperactivity (OR=13.7, 95% CI 4.70-35.9, f=0.32) to be more common in ADSHE. These findings corroborate and extend those reported in the existing literature. Developmental milestones revealed marked delays across all domains. Analysis of longitudinal medication prescription patterns exposed striking therapeutic variability, reflecting the absence of a consistent treatment framework. Several anti-seizure medications frequently cited as beneficial, quinidine and cannabidiol, were not associated with seizure improvement or sustained seizure freedom in our cohort. In contrast, clobazam (OR=1.39, 95% CI 1.12-1.72, f=0.85), ketogenic diet (OR=1.30, 95% CI 1.07-1.57, f=0.75), and lacosamide (OR=2.03, 95% CI 1.54-2.66, f=0.59) demonstrated positive comparative effectiveness. Quantitative EEG analysis distinguished individuals with KCNT1-related disorders from age-matched controls with high accuracy (AUC=0.906), with key discriminating spectral features, including alpha power in the central and parietal regions, demonstrating significant reduction across childhood and adolescence. Collectively, these findings expand the phenotypic and genotypic landscape of KCNT1-related disorders through large-scale real-world clinical data, establish quantifiable longitudinal clinical endpoints, and provide actionable insights into genotype-phenotype relationships and differential treatment response. Together, these findings will help identify outcome measures and biomarkers to inform future clinical trial design.