Relevance to Autism

Trio-exome sequencing of 745 participants with NDD and/or epilepsy from the Center for Medical Genetics of the University Hospital Antwerp in Smal et al., 2024 identified a de novo mosaic nonsense variant in the ARID1A gene (NM_139135.4:c.1687C>T;p.Gln563Ter) in a patient presenting with autism spectrum disorder, severe intellectual disability, and epilepsy. Two additional de novo nonsense variants and four de novo missense variants in the ARID1A gene have been identified in ASD probands from the SPARK cohort (Zhou et al., 2022; Fu et al., 2022). Heterozygous variants in ARID1A was also responsible for Coffin-Siris syndrome 2 (OMIM 614607); autism spectrum disorder was reported in 2/15 (13%) individuals with ARID1A-associated Coffin-Siris syndrome from the CSS/BAF complex registry in Vasko et al., 2021. Knockout of ARID1A in human embryonic stem cells (hESCs) in Liu et al., 2020 was found to result in spontaneous differentiation of neural cells together with globally enhanced expression of neurogenic genes in undifferentiated hESC; furthermore, when compared with wild-type hESCs, cardiac differentiation from ARID1A -/- hESCs was prominently suppressed, whereas neural differentiation was significantly promoted. Arid1a conditional knockout mice were found to exhibit reduced cortical thickness in the developing cortex, inhibition in the proliferation of radial glial cells, increased cell death during late cortical development, and dysregulated expression of genes associated with proliferation and differentiation (Liu et al., 2021).

Molecular Function

Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Binds DNA non-specifically. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, a

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References