The SMARCA1 gene encodes a member of the SWI/SNF family of proteins. Also known as SNF2L, the encoded protein is an ATPase which is expressed in diverse tissues and forms chromatin remodeling complexes with different partners to regulate transcription. In 2015, Karaca et al. reported a nonsense SMARCA1 variant of unknown inheritance in a male with intellectual disability, microcephaly, spasticity, cortical atrophy, and Coffin-Siris-like dysmorphic features (PMID: 26539891). In 2016, a large exome study reported a de novo frameshift variant in a male patient with intellectual disability (PMID: 27479843). In addition, at least four missense variants have been reported in individuals with intellectual disability: a de novo variant in a female with a Rett syndrome–like phenotype (PMID: 26740508), two de novo variants in individuals with developmental delay/intellectual disability (PMID: 33057194), and a maternally-inherited missense variant in two affected brothers (PMID: 27457812). While SMARCA1 is highly intolerant to truncating variants (pLI 1, gnomAD v2.1.1), it is not significantly constrained for missense variants (Z = 2.44). Thus, in the absence of functional evidence of pathogenicity, none of the missense variants were scored.
This gene-disease relationship is supported by experimental evidence. SMARCA1 and BPTF are part of the human NURF complex, an ISWI-containing ATP-dependent chromatin-remodeling complex (PMID: 14609955); variants in BPTF are implicated in autosomal dominant syndromic intellectual disability. In addition, transfection of mouse neuroblastoma cells by wild type but not mutant SMARCA1 protein has been shown to promote neurite outgrowth (PMID: 14609955).
In summary, there is limited evidence at this time to support the relationship between SMARCA1 and X-linked intellectual disability. Additional studies are required to verify this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 3, 2022 (SOP Version 9). Please note: this gene was originally curated for Coffin-Siris syndrome by the General Gene Curation Expert Panel in 2016 and classified as Moderate. The current classification of Limited reflects updated scoring practices in SOP version 9 and the consensus of the ID/Autism Gene Curation Expert panel.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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