SMARCE1 is part of the large ATP-dependent chromatin remodeling complex SWI/SNF, which is required for transcriptional activation of genes normally repressed by chromatin. SMARCE1 was first reported in relation to autosomal dominant Coffin-Siris syndrome in 2012 (Tsurusaki et al., PMID: 22426308). Coffin-Siris syndrome is a rare congenital disorder characterized by delayed psychomotor development, intellectual disability, coarse facial features, and hypoplasia of the distal phalanges, particularly the fifth digit. Other features may also be observed, including congenital heart defects, hypoplasia of the corpus callosum, and poor overall growth with short stature and microcephaly (PMID: 23906836). Of note, variants in SMARCE1 have also been reported in autosomal dominant familial meningioma; this gene disease-relationship has been curated separately.
Seven variants (6 missense and 1 splice variant leading to an in-frame deletion) reported in 13 probands in 11 publications (PMIDs: 22426308, 23906836, 23929686, 27264197, 30499906, 30548424, 31273213, 31530938, 31675646, 32732226, 37853563) 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. Several variants are recurrent (including p.Tyr73Ser, p.Tyr73Cys and p.Arg105Gln), and most cluster within the HMG domain of the SMARCE1 protein. The fact that all reported variants are either missense or in-frame deletions is consistent with a gain-of-function or dominant-negative effect, but no functional studies have been performed.
This gene-disease relationship is also supported by experimental evidence, including biochemical function and protein interactions. Several other members of the SWI/SNF complex have been involved in Coffin-Siris syndrome, including SMARCA4, SMARCB1, SMARCC2, SMARCD1, DPF2, ARID1A, ARID1B, ARID2 and BICRA. Variants in SMARCA2, another member of the SWI/SNF complex, cause a related disorder, Nicolaides-Baraitser syndrome.
In summary, there is definitive evidence supporting the relationship between SMARCE1 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 Panels on September 18, 2024 (SOP Version 11).
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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