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Intellectual disability syndromic and non-syndromic

Gene: SMARCA2

Green List (high evidence)

SMARCA2 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2)
EnsemblGeneIds (GRCh38): ENSG00000080503
EnsemblGeneIds (GRCh37): ENSG00000080503
OMIM: 600014, Gene2Phenotype
SMARCA2 is in 8 panels

1 review

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Heterozygous pathogenic SMARCA2 variants cause Nicolaides-Baraitser syndrome (MIM #601358). DD/ID are universal features. A dominant-negative or gain-of-function effect appear to be the most likely mechanism (Abdul-Rahman O. - PMID: 26468571).

Please also note that Cappuccio et al (2020 - PMID: 32694869) report on individuals with de novo SMARCA2 variants with features of a novel, blepharophimosis-intellectual disability syndrome (BIS) but whose clinical presentation did not fit a diagnosis of Nicolaides-Baraitser (NB) syndrome.

Clinical details on 14 subjects with BIS were provided, DD/ID being a universal feature (14/14 - moderate to severe ID). Compared to other syndromes with blepharophimosis, lack of ptosis (observed in only 14% in this cohort), epicanthus inversus and limb abnormalities were proposed to distinguish BIS from other recognizable syndromes with blepharophimosis.

All individuals with BIS were found to harbor de novo missense variants. These clustered outside the helicase domain and localized within exons 8,9 and 19.

Few (6) additional individuals with de novo missense variants (in ex. 8, 14, 19) did not fit either diagnosis (NB or BIS) with the SNVs classified as VUS.

According to Cappuccio et al, most individuals with diagnosis of NB syndrome harbor variants spanning exons 15 to 25 [corresponding to the ATPase domain, which in turn is split in a Helicase ATP-Binding domain (720-912) and a helicase C-terminal domain (1080-1164)]. Most NB-associated variants are missense and rarely in-frame exon deletions.

As also commented on, CNVs (deletions or duplications) encompassing SMARCA2 have been reported in individuals with DD/ID although these did not fit a diagnosis of NB syndrome (and CNVs were rather not intragenic/limited to SMARCA2) [cited PMIDs: 31530938, 28846756].

Transcriptomic and methylation signatures confirmed molecular stratification of affected individuals with SMARCA2-related disorders (and controls).
Created: 26 Jul 2020, 11:12 a.m. | Last Modified: 26 Jul 2020, 11:12 a.m.
Panel Version: 0.2783

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome

Publications

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Genetic Health Queensland
Phenotypes
  • Nicolaides-Baraitser syndrome, MIM #601358
  • Blepharophimosis-intellectual disability syndrome, MIM#619293
OMIM
600014
Clinvar variants
Variants in SMARCA2
Penetrance
None
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

2 May 2021, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: SMARCA2 were changed from Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome to Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome, MIM#619293

26 Jul 2020, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: smarca2 has been classified as Green List (High Evidence).

26 Jul 2020, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: SMARCA2 were changed from to Nicolaides-Baraitser syndrome, MIM #601358; Blepharophimosis-intellectual disability syndrome

26 Jul 2020, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: SMARCA2 were set to

26 Jul 2020, Gel status: 3

Set mode of pathogenicity

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of pathogenicity for gene: SMARCA2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

26 Jul 2020, Gel status: 3

Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Mode of inheritance for gene: SMARCA2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

22 Nov 2019, Gel status: 3

Created, Added New Source, Set mode of inheritance

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

gene: SMARCA2 was added gene: SMARCA2 was added to Intellectual disability, syndromic and non-syndromic_GHQ. Sources: Expert Review Green,Genetic Health Queensland Mode of inheritance for gene: SMARCA2 was set to Unknown