A de novo LoF variant in this gene was identified in an ASD proband from the Autism Sequencing Consortium (Neale et al., 2012). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A second de novo LoF variant in this gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in this gene in ASD probands, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), SMARCC2 was determined to be an ASD candidate gene in Yuen et al., 2017. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified SMARCC2 as an ASD risk gene with a false discovery rate (FDR) < 0.3; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant and a splicing SNV. Machol et al., 2018 reported 15 unrelated individuals with variants in the SMARCC2 gene that presented with a neurodevelopmental syndrome characterized by developmental delay/intellectual disability, speech delay, and hypotonia; behavioral abnormalities were also frequently observed in this cohort, with one individual presenting with ASD and three others presenting with difficulties with social interactions. A de novo protein-truncating variant in SMARCC2 was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified SMARCC2 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). Three additional de novo loss-of-function variants in the SMARCC2 gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified SMARCC2 as a gene reaching exome-wide significance (P < 2.5E-06).. The protein encoded by the SMARCC2 gene interacts with the protein encoded by the high-confidence ASD gene ADNP (Mandel and Gozes, 2007).
Molecular Function
The protein encoded by this gene is a member of the SWI/SNF family of proteins, whose members display helicase and ATPase activities and which are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI and contains a predicted leucine zipper motif typical of many transcription factors.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Patterns and rates of exonic de novo mutations in autism spectrum disorders.
