BICRA, encoding a SWI/SNF chromatin remodeling complex subunit, was first reported in relation to autosomal dominant Coffin-Siris syndrome in 2020 (Barish et al., PMID: 33232675). Affected individuals exhibit neurodevelopmental phenotypes that include developmental delay, mild to moderate intellectual disability, autism spectrum disorder, and other behavioral abnormalities. While most affected individuals have variable dysmorphic facial features, the coarse facial features and fifth digit/nail hypoplasia frequently seen in other forms of Coffin-Siris syndrome are often absent.
Eleven truncating variants (frameshift, nonsense) that have been reported in 11 probands in five publications (PMIDs: 33232675, 36437209, 37485815, 38117302, 38867597) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Most reported variants occur de novo. The mechanism of pathogenicity is loss of function. Two individuals with de novo missense variants have also been reported (PMID: 33232675) but were not scored in this curation due to lack of functional data; without this information, it is uncertain whether these variants are acting via a similar or different mechanism as the other scored variants.
This gene-disease relationship is also supported by experimental evidence, including biochemical function and protein interactions. Several other members of the SWI/SNF family of chromatin remodeling complexes have been involved in Coffin-Siris syndrome, including SMARCA4, SMARCB1, SMARCC2, SMARCD1, SMARCE1, DPF2, ARID1A, ARID1B, and ARID2. Variants in SMARCA2, another member of the SWI/SNF complex, cause a related disorder, Nicolaides-Baraitser syndrome. BICRA (BRD4 interacting chromatin remodeling complex associated protein) interacts with BRD4, a protein implicated in intellectual disability, and bridges it to the SWI/SNF complex.
In summary, there is definitive evidence supporting the relationship between BICRA and autosomal dominant Coffin-Siris syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 20, 2024 (SOP Version 11).
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