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Early onset or syndromic epilepsy v1.331 SMARCC2 Rebecca Foulger Source Wessex and West Midlands GLH was added to SMARCC2.
Early onset or syndromic epilepsy v1.330 SMARCC2 Rebecca Foulger Source NHS GMS was added to SMARCC2.
Early onset or syndromic epilepsy v1.321 SMARCC2 Rebecca Foulger commented on gene: SMARCC2: Kept rating as Green based on Green post-Webex review from Helen Lord.
Early onset or syndromic epilepsy v1.321 SMARCC2 Rebecca Foulger Phenotypes for gene: SMARCC2 were changed from Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features to Coffin-Siris syndrome 8, 618362; Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features
Early onset or syndromic epilepsy v1.262 SMARCC2 Rebecca Foulger edited their review of gene: SMARCC2: Added comment: Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.; Changed rating: AMBER
Early onset or syndromic epilepsy v1.261 SMARCC2 Helen Lord reviewed gene: SMARCC2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.25 SMARCC2 Rebecca Foulger Classified gene: SMARCC2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.25 SMARCC2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Green following review from Konstantinos Varvagiannis highlighting recent paper: PMID:30580808 (Machol et al., 2019) report on 15 unrelated individuals with harbouring one of 13 heterozygous pathogenic SMARCC2 variants, with seizures reported in 4 of the individuals. Therefore sufficient unrelated cases of seizures in this paper for diagnostic-rating. 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.
Early onset or syndromic epilepsy v1.25 SMARCC2 Rebecca Foulger Gene: smarcc2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.24 SMARCC2 Rebecca Foulger Phenotypes for gene: SMARCC2 were changed from Hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of head or neck; Seizures to Global developmental delay; Intellectual disability; neurodevelopmental delay and growth retardation; prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features
Early onset or syndromic epilepsy v1.23 SMARCC2 Rebecca Foulger Added comment: Comment on mode of inheritance: Monoallelic MOI supported by PMID:30580808.
Early onset or syndromic epilepsy v1.23 SMARCC2 Rebecca Foulger Mode of inheritance for gene: SMARCC2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.22 SMARCC2 Rebecca Foulger Added comment: 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.
Early onset or syndromic epilepsy v1.22 SMARCC2 Rebecca Foulger Publications for gene: SMARCC2 were set to 27392482
Early onset or syndromic epilepsy v1.6 SMARCC2 Konstantinos Varvagiannis gene: SMARCC2 was added
gene: SMARCC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SMARCC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SMARCC2 were set to 27392482
Phenotypes for gene: SMARCC2 were set to Hypotonia; Feeding difficulties; Global developmental delay; Intellectual disability; Behavioral abnormality; Abnormality of head or neck; Seizures
Penetrance for gene: SMARCC2 were set to unknown
Review for gene: SMARCC2 was set to AMBER
Added comment: Gene present in the ID panel :

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.

As a result, this gene should be considered for inclusion in this panel as amber (or green).
Sources: Literature