Fetal anomalies
Gene: SMARCA2

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

Created: 26 Jul 2020, 11:12 a.m.
Last Modified: 26 Jul 2020, 11:12 a.m.
Panel version: Imported from Intellectual disability syndromic and non-syndromic panel version 0.2783

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Green
Genomics England PanelApp

Phenotypes

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

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