Genetic variants in chromatin remodeling complexes are one of the most frequently attributed genetic causes of autism spectrum disorder (ASD) and intellectual disability (ID). However, very little is known about how these complexes regulate gene expression required for brain development or how genetic variants in genes encoding chromatin remodelers lead to the development of ASD. Numerous genetic variants in subunits of the Brg1/Brm-associated factor (BAF) chromatin remodeling complex have recently been identified as associated with ASD, including 188 missense and 256 protein truncating variants in the SFARI gene database. Overall, the BAF complex is the most commonly mutated protein complex in ASD genetics.

The neuronal version of the BAF complex (nBAF) is critical for brain development and ASD-relevant behaviors. However, how the majority of ASD-associated variants impact BAF function in neural development is unknown. Annie Ciernia and Jamie Kramer hypothesize that ASD-associated variants impair nBAF complex regulation of neuronal chromatin and gene expression during development, resulting in impaired synapse formation and stunted neuronal connections.

Since many ASD variants have not been experimentally validated as pathogenic alleles, Kramer’s lab plans to develop a novel, high-throughput variant screening approach in Drosophila to screen ASD-associated missense variants in BAF subunits. Preliminary work has shown that Drosophila humanized rescue and/or gain-of-function (GoF) assays will be feasible for testing clinically identified variants for damaging effects on ASD-associated BAF complex subunits. Confirmed pathogenic variants will be further characterized in Ciernia’s lab for impacts on neuronal development using a mouse primary neuron culture system combined with genetic approaches to replace the endogenous mouse BAF gene with the human wildtype or ASD-associated variant.

Ciernia’s preliminary work has focused on BAF53B, a neuron-specific subunit of nBAF that has been implicated in controlling neuronal development, gene regulation and ASD relevant behaviors¹. As proof-of-concept, she and her team have identified several ASD-associated variants in BAF53B that impair neuronal dendritic branch formation during development. Together, findings from this project will confirm the pathogenicity of ASD-associated BAF variants and provide critical insights into how variation in BAF subunits causes abnormal neuronal development in ASD. The results will help improve the clinical interpretation of ASD-associated variants and lay the groundwork for future personalized medicine approaches for genetic forms of ASD.

1. Rowland M.E. et al. Front. Mol. Neurosci. 15, 805158 (2024) PubMed