PT - JOURNAL ARTICLE AU - Nixon, Kevin C.J. AU - Rousseau, Justine AU - Stone, Max H. AU - Sarikahya, Mohammed AU - Ehresmann, Sophie AU - Mizuno, Seiji AU - Matsumoto, Naomichi AU - Miyake, Noriko AU - , TI - Identification of <em>SMARCD1</em> as a syndromic intellectual disability gene that is required for memory and context-dependent regulation of neuronal genes in <em>Drosophila</em> AID - 10.1101/422188 DP - 2018 Jan 01 TA - bioRxiv PG - 422188 4099 - http://biorxiv.org/content/early/2018/09/25/422188.short 4100 - http://biorxiv.org/content/early/2018/09/25/422188.full AB - Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause syndromic intellectual disability (ID). Here, we report on 5 individuals with mutations in the SMARCD1 gene, presenting with ID, developmental delay, hypotonia, feeding difficulties, and small extremities. The mutations were proven to be de novo in 4 of the 5 individuals. Mutations in other SWI/SNF components cause Coffin-Siris, Nicolaides-Baraitser, or other syndromic ID disorders. Although the individuals presented here have some clinical overlap with these disorders, they lack the typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog, Bap60, in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom body specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify SMARCD1 mutations as a novel cause of ID, and establish a role for the SMARCD1 ortholog Bap60 in regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development that is essential in establishing neuronal circuits that are required for learning and memory.