Distinct pathogenic genes causing intellectual disability and autism exhibit a common neuronal network hyperactivity phenotype

Pathogenic mutations in either one of the epigenetic modifiers EHMT1, MBD5, MLL3 or SMARCB1 have been identified to be causative for Kleefstra syndrome spectrum (KSS), a neurodevelopmental disorder with clinical features of both intellectual disability (ID) and autism spectrum disorder (ASD). To understand how these variants lead to the phenotypic convergence in KSS we employed a loss of function approach to assess neuronal network development at the molecular, single cell and network activity level. KSS-gene deficient neuronal networks all developed into hyperactive networks with altered network organization and excitatory-inhibitory balance. Interestingly, even though transcriptional data revealed distinct regulatory mechanisms, KSS-target genes share similar functions in regulating neuronal excitability and synaptic function, several of which are associated with ID and ASD. Our results show that KSS-genes mainly converge at the level of neuronal network communication, providing new insights into the pathophysiology of KSS and phenotypically congruent disorders.