Monogenic epilepsies exhibit distinct sleep endophenotypes

Monogenic epilepsies are 1.6 times more likely to be treatment-resistant compared to other epilepsies, emphasizing the need for additional therapeutic strategies. Sleep dysfunction beyond sleep-related breathing disorders is common yet insufficiently characterized and treated in monogenic epilepsies. We therefore sought to study sleep phenotypes across these epilepsies, examine associations with seizure severity, and assess the diagnostic rate of sleep disorders. From 2,519 individuals enrolled in the Epilepsy Genetics Research Project at Children's Hospital of Philadelphia, we identified the monogenic epilepsies most frequently associated with sleep-related diagnoses, yielding 252 individuals across nine genetic diagnoses (STXBP1, n = 79; SCN1A, n = 57; SCN2A, n = 34; KCNQ2, n = 21; SLC6A1, n = 14; SYNGAP1, n = 13; WDR45, n = 13; KCNT1, n = 11; PCDH19, n = 10). Monogenic epilepsies exhibited distinct sleep endophenotypes, including insomnia, parasomnia, and sleep-related movement disorders in SCN1A-related disorders; frequent epileptiform discharges in sleep with insomnia symptoms in SCN2A-related disorders; sleep dysfunction restricted to the developmental and epileptic encephalopathy subtype in KCNQ2-related disorders; and insomnia without nocturnal seizure involvement in SYNGAP1-related disorders. Formal sleep diagnoses were present in only 25% of individuals (63/252), yet 58% (145/252) reported sleep difficulties, suggesting substantial underdiagnosis. Persistent seizures were associated with higher odds of sleep disorder diagnoses (OR 2.87, 95% CrI 1.57-5.36), disrupted sleep architecture (OR 2.06, 95% CrI 1.08-4.16), nocturnal seizures (OR 4.47, 95% CrI 2.50-8.28), hypersomnolence (OR 2.38, 95% CrI 1.27-4.58) and insomnia (OR 1.80, 95% CrI 1.06-3.05). Neuropsychiatric comorbidities were independently associated with sleep burden after adjustment for seizure severity (OR 2.49, 95% CrI 1.40-4.49). We find that monogenic epilepsies exhibit distinct, gene-specific sleep endophenotypes that are underdiagnosed. Treating sleep difficulties beyond obstructive sleep apnoea may improve seizure control and developmental outcomes, highlighting the need for timely diagnosis of co-occurring sleep disorders.