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Nixon, K.C.J., Rousseau, J., Stone, M.H., Sarikahya, M., Ehresmann, S., Mizuno, S., Matsumoto, N., Miyake, N., DDD Study, , Baralle, D., McKee, S., Izumi, K., Ritter, A.L., Heide, S., Héron, D., Depienne, C., Titheradge, H., Kramer, J.M., Campeau, P.M. (2019). A Syndromic Neurodevelopmental Disorder Caused by Mutations in SMARCD1, a Core SWI/SNF Subunit Needed for Context-Dependent Neuronal Gene Regulation in Flies.  Am. J. Hum. Genet. 104(4): 596--610.
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Research paper

Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on five individuals with mutations in SMARCD1; the individuals present with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. Trio exome sequencing proved the mutations to be de novo in four of the five individuals. Mutations in other SWI/SNF components cause Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs. Although the individuals presented here have dysmorphisms and some clinical overlap with these syndromes, they lack their 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 an NDD caused by SMARCD1 mutations and establish a role for the SMARCD1 ortholog Bap60 in the regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development when neuronal circuits that are required for learning and memory are formed.

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PMC6451697 (PMC) (EuropePMC)
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    Am. J. Hum. Genet.
    American Journal of Human Genetics
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    Alleles (5)
    Genes (17)
    Human Disease Models (1)
    Transgenic Constructs (5)