Intellectual disabilityGene: SMARCC2
Machol et al. (https://doi.org/10.1016/j.ajhg.2018.11.007) report on 15 unrelated individuals with heterozygous pathogenic SMARCC2 variants.
SMARCC2 (BAF170) is one of the subunits of the chromatin remodeling BAF complex and the phenotype of these subjects resembled the phenotype of other "BAFopathies", notably Coffin-Siris and Nicolaides-Baraitser syndrome. DD and/or ID were universal features (a few individuals were too young). Other common features included speech impairment, hypotonia, feeding problems, behavioral anomalies as well as some overlapping facial features (similar to other BAFopathies). Seizures were noted in 4/15 individuals.
8 missense variants, 1 in-frame deletion, 4 splice-site variants, 1 frameshift and 1 nonsense variant are reported. De novo occurrence was the case for 12 of these variants while for 2 individuals one/both parents were unavailable. One subject with mild DD had inherited a nonsense variant from his affected father (with borderline ID) in whom the mutation had occurred as a de novo event.
Several of the missense variants (but not all) clustered in the SANT domain, while individuals with the specific variants seemed to present with a more severe phenotype.
The de novo in-frame deletion, which was observed in one mildly affected individual, has been reported once in gnomAD.
Exon skipping was demonstrated for 1 splice-site variant while expression studies for another splice-site variant showed reduced mRNA expression. mRNA expression was normal for the in-frame deletion.
Similarly to what has been observed in other disorders of this group, some mutations are thought to act through a dominant-negative mechanism.
Transcriptome analysis in fibroblasts from affected individuals suggested the presence of a group of differentially expressed genes possibly involved in regulation of neuronal development/function.
As the authors note, studies in Smarcc2-deficient mice suggest a role in learning as well as behavioral adaptation (PMID: 27392482).
SMARCC2 is not associated with any phenotype in OMIM, nor in G2P.
The gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc - participating in this study).
As a result, this gene should be considered for upgrade to green.
Created: 20 Dec 2018, 11:46 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of head or neck
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: Updated rating from Red to Green following review from Konstantinos Varvagiannis and recent paper: PMID:30580808 (Machol et al., 2019) report on 15 unrelated individuals with varying degrees of neurodevelopmental delay in all 15 cases, harbouring one of 13 heterozygous pathogenic SMARCC2 variants. Therefore sufficient unrelated cases in this paper to support causation. Konstantinos Varvagiannis notes that SMARCC2 is not yet associated with a phenotype in OMIM or Gene2Phenotype, but this is most likely because the 2019 paper PMID:30580808 has not yet been curated in these databases.
Created: 25 Feb 2019, 4:13 p.m.
Comment on publications: PMID:27392482 (Tuoc et al., 2017, demonstrating a mouse model of learning and memory as included in the review by Konstantinos Varvagiannis) use BAF170 nomenclature; BAF170 is a synonym of SMARCC2.
Created: 25 Feb 2019, 4 p.m.
Comment on mode of inheritance: Monoallelic MOI supported by PMID:30580808.
Created: 25 Feb 2019, 3:59 p.m.
Candidate ID gene in PMID:26350204 but no strong evidence to support ID causation.
Created: 31 Oct 2017, 9:24 a.m.
Gene: smarcc2 has been classified as Green List (High Evidence).
Phenotypes for gene: SMARCC2 were changed from to Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features
Publications for gene: SMARCC2 were set to 26350204; 27392482
Publications for gene: SMARCC2 were set to 26350204
Mode of inheritance for gene: SMARCC2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Publications for gene SMARCC2 was set to ['26350204']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
SMARCC2 was added to Intellectual disabilitypanel. Sources: Expert Review Red
SMARCC2 was created by ellenmcdonagh