0041 Neuronal circuits convergently disrupted in the genetic basis of sleep phenotypes and rare neurodevelopmental syndromes

Abstract

Abstract Introduction Sleep-related phenotypes have been frequently reported in early on-set epileptic encephalopathies (EE) and in developmental delay (DD) syndromes, in particular in syndromes related to autism spectrum disorder (ASD). Yet the convergent pathogenetic mechanisms between these comorbidities are largely unknown. Methods We first performed a gene enrichment study that identified shared risk genes among rare EE/neurodevelopmental disorders (NDD), rare DD genetic syndromes and sleep disturbances. We then determined cellular and molecular pathways enriched among genes shared between sleep phenotypes and those two early onset mental illnesses, aiming to identify genetic disparities and commonalities among these phenotypic groups. Results The sleep gene set was observed as significantly overlapped with the two gene lists associated to rare genetic syndromes (i.e. EE/NDD and DD gene sets), suggesting shared genetic contribution. Similarities across significantly enriched pathways between the two intersect lists comprehended mostly synapse-related pathways, such as retrograde endocannabinoid signaling, serotonergic and GABAergic synapse. Network analysis indicates EE/NDD vs sleep specific clusters and DD vs sleep specific clusters related to synaptic and transcriptional regulation, respectively. Longstanding functional patterns previously described in EE and NDD genetic architecture were recaptured after dissecting the overlap between the genes associated to those developmental phenotypes and sleep disturbances, suggesting that during neurodevelopment different molecular and functional mechanisms are related to alterations on circadian rhythm. Conclusion The overlapping gene set and biological pathways highlighted by this study may serve as a primer for new functional investigations of shared molecular mechanisms between sleep disturbances and rare developmental syndromes, with or without epilepsy. Support (if any) Our studies are supported by Associação Fundo de Incentivo à Pesquisa (AFIP). S.T. and M.L.A. received CNPq fellowships.