摘要Mediator Complex Subunit 16(MED16,MIM:604062)is a member of the Mediator complex,which controls many aspects of transcriptional activity in all eukaryotes.Here,we report two individuals from a non-consanguineous family with biallelic variants in MED16 identified by exome sequencing.The affected in-dividuals present with global developmental delay,intellectual disability,and dysmorphisms.To assess the pathogenicity of the variants,functional studies are performed in Drosophila and patient-derived cells.The fly ortholog med16 is expressed in neurons and some glia of the developing central nervous system(CNS).Loss of med16 leads to a reduction in eclosion and lifespan,as well as impaired synaptic transmission.In neurons differentiated from the patient-derived induced pluripotent stem cells(iPSCs),the neurite outgrowth is impaired and rescued by expression of exogenous MED16.The patient-associated variants behave as loss-of-function(LoF)alleles in flies and iPSCs.Additionally,the transcription of genes related to neuronal maturation and function is preferentially altered in patient cells relative to differentiated H9 con-trols.In summary,our findings support that MED16 is important for appropriate development and function,and that biallelic MED16 variants cause a neurodevelopmental disease.