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Relevance to Autism

Two de novo missense variants in the SMARCA4 gene were identified in ASD probands from the Autism Sequencing Consortium in De Rubeis et al., 2014; both of these variants were later determined to be postzygotic mosaic mutations (PZMs) in Lim et al., 2017. A third non-synonymous PZM in SMARCA4 was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (3/571 observed vs. 11/84,448 expected; hypergeometric P-value of 4.9E-05). Furthermore, Lim et al., 2017 demonstrated that overexpression of SMARCA4 mutants in mouse neuroblastoma (N2A) cells resulted in significantly lower expression of GRIN2B compared to wild-type SMARCA4.

Molecular Function

The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and 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, which is required for transcriptional activation of genes normally repressed by chromatin. Mutations in this gene are associated with Coffin-Siris syndrome 4 (CSS4; OMIM 614609).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
The variability of SMARCA4-related Coffin-Siris syndrome: Do nonsense candidate variants add to milder phenotypes?
Coffin-Siris syndrome-4
ADHD, ASD
Support
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
ASD
Support
Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability.
ID
Hypotonia, dysmorphic features
Support
Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A.
Coffin-Siris syndrome-4 (CSS4)
Support
Clinical correlations of mutations affecting six components of the SWI/SNF complex: detailed description of 21 patients and a review of the literat...
Coffin-Siris syndrome-4 (CSS4)
Support
Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing
ASD, DD
Support
De novo variants in neurodevelopmental disorders-experiences from a tertiary care center
DD
Highly Cited
Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome.
Coffin-Siris syndrome-4 (CSS4)
Recent Recommendation
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN923R001 
 missense_variant 
 c.326C>T 
 p.Pro109Leu 
 De novo 
 NA 
  
 GEN923R002 
 missense_variant 
 c.551T>C 
 p.Ile184Thr 
 De novo 
 NA 
  
 GEN923R003 
 missense_variant 
 c.427C>G 
 p.Pro143Ala 
 De novo 
 NA 
 Simplex 
 GEN923R004 
 inframe_deletion 
 c.1636_1638del 
 p.Lys546del 
 De novo 
 NA 
  
 GEN923R005 
 missense_variant 
 c.2576C>T 
 p.Thr859Met 
 De novo 
 NA 
  
 GEN923R006 
 missense_variant 
 c.2653C>T 
 p.Arg885Cys 
 De novo 
 NA 
  
 GEN923R007 
 missense_variant 
 c.2761C>T 
 p.Leu921Phe 
 De novo 
 NA 
  
 GEN923R008 
 missense_variant 
 c.3032T>C 
 p.Met1011Thr 
 Unknown 
  
  
 GEN923R009 
 missense_variant 
 c.3469C>G 
 p.Arg1157Gly 
 De novo 
 NA 
  
 GEN923R010 
 missense_variant 
 c.4543G>A 
 p.Glu1515Lys 
 De novo 
 NA 
 Simplex 
 GEN923R011 
 splice_site_variant 
 c.4171-1754_4171-1753del 
  
 Familial 
 Paternal 
  
 GEN923R012 
 missense_variant 
 c.3728G>A 
 p.Arg1243Gln 
 De novo 
 NA 
  
 GEN923R013 
 missense_variant 
 c.3512T>G 
 p.Val1171Gly 
 De novo 
 NA 
  
 GEN923R014 
 stop_gained 
 c.3310C>T 
 p.Gln1104Ter 
 De novo 
 NA 
  
 GEN923R015 
 missense_variant 
 c.2477C>T 
 p.Ala826Val 
 De novo 
 NA 
  
 GEN923R016 
 missense_variant 
 c.3641T>C 
 p.Ile1214Thr 
 De novo 
 NA 
  
 GEN923R017 
 missense_variant 
 c.2282G>A 
 p.Gly761Asp 
 Unknown 
 Not maternal 
  
 GEN923R018 
 missense_variant 
 c.2654G>A 
 p.Arg885His 
 De novo 
 NA 
  
 GEN923R019 
 missense_variant 
 c.2681C>T 
 p.Thr894Met 
 De novo 
 NA 
  
 GEN923R020 
 stop_gained 
 c.4200C>G 
 p.Ile1400Met 
 Unknown 
  
  
 GEN923R021 
 missense_variant 
 c.1351C>T 
 p.Arg451Cys 
 De novo 
 NA 
  
 GEN923R022 
 missense_variant 
 c.2936G>A 
 p.Arg979Gln 
 De novo 
 NA 
  
 GEN923R023 
 missense_variant 
 c.2681C>T 
 p.Thr894Met 
 De novo 
 NA 
  
 GEN923R024 
 missense_variant 
 c.2851G>A 
 p.Gly951Arg 
 De novo 
 NA 
  
 GEN923R025 
 missense_variant 
 c.2900G>C 
 p.Arg967Pro 
 Unknown 
  
  
 GEN923R026 
 missense_variant 
 c.3508A>G 
 p.Thr1170Ala 
 De novo 
 NA 
  
 GEN923R027 
 missense_variant 
 c.1675G>A 
 p.Glu559Lys 
 De novo 
 NA 
 Unknown 
 GEN923R028 
 missense_variant 
 c.1537C>T 
 p.Arg513Trp 
 De novo 
 NA 
 Simplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
19
Deletion-Duplication
 28
 
19
Deletion-Duplication
 5
 
19
Deletion-Duplication
 3
 
19
Duplication
 1
 
19
Duplication
 1
 

No Animal Model Data Available

 

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