Human Gene Module / Chromosome 11 / DEAF1

DEAF1DEAF1 transcription factor

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
5 / 14
Rare Variants / Common Variants
28 / 0
Aliases
DEAF1, SPN,  NUDR,  ZMYND5
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
11p15.5
Associated Disorders
EP, EPS, ASD
Relevance to Autism

De novo missense variants in the DEAF1 gene that resulted in impaired transcriptional regulation of the DEAF1 promoter were identified in four individuals with intellectual disability, mild motor delay, and severely affected speech development; three of these individuals also displayed severe behavioral problems consisting of autistic, hyperactive, compulsive, and aggressive behavior with striking mood swings and poor eye contact (Vulto-van Silfhout et al., 2014; Rauch et al., 2012; Vissers et al., 2010).

Molecular Function

Transcription factor that binds to sequence with multiple copies of 5'-TTC[CG]G-3' present in its own promoter and that of the HNRPA2B1 gene and down-regulates transcription of these genes. Binds to the retinoic acid response element (RARE) 5'-AGGGTTCACCGAAAGTTCA-3'. Activates the proenkephalin gene independently of promoter binding, probably through protein-protein interaction. When secreted, behaves as an inhibitor of cell proliferation, by arresting cells in the G0 or G1 phase. Required for neural tube closure and skeletal patterning.

Reports related to DEAF1 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A de novo paradigm for mental retardation. Vissers LE , et al. (2010) No -
2 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Rauch A , et al. (2012) No -
3 Support Novel homozygous DEAF1 variant suspected in causing white matter disease, intellectual disability, and microcephaly. Faqeih EA , et al. (2014) No Epilepsy/seizures
4 Primary Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems. Vulto-van Silfhout AT , et al. (2014) No ASD or autistic behavior
5 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. Redin C , et al. (2014) No -
6 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
7 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
8 Support Recessive DEAF1 mutation associates with autism, intellectual disability, basal ganglia dysfunction and epilepsy. Rajab A , et al. (2015) No Dyskinesia, absent speech
9 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
10 Support Identification of a syndrome comprising microcephaly and intellectual disability but not white matter disease associated with a homozygous c.676C>T... Gund C , et al. (2016) No Microcephaly
11 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) Yes -
12 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Geisheker MR , et al. (2017) Yes -
13 Support Functional analysis of novel DEAF1 variants identified through clinical exome sequencing expands DEAF1-associated neurodevelopmental disorder (DAND... Chen L , et al. (2017) No Epilepsy/seizures, ASD
14 Support Two de novo variations identified by massively parallel sequencing in 13 Chinese families with children diagnosed with autism spectrum disorder. Li SJ , et al. (2018) Yes -
Rare Variants   (28)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.683T>G p.Ile228Ser missense_variant De novo - Simplex 21076407 Vissers LE , et al. (2010)
c.791A>C p.Gln264Pro missense_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.[676C>T];[676C>T] p.[Arg226Trp];[Arg226Trp] missense_variant Familial Both parents Multiplex 24668509 Faqeih EA , et al. (2014)
c.670C>T p.Arg224Trp missense_variant De novo - Simplex 24726472 Vulto-van Silfhout AT , et al. (2014)
c.762A>C p.Arg254Ser missense_variant De novo - Simplex 24726472 Vulto-van Silfhout AT , et al. (2014)
c.290-3C>G p.Glu97ValfsTer3 splice_site_variant Familial Maternal Simplex 25167861 Redin C , et al. (2014)
c.658G>A p.Gly220Ser missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.656T>C p.Leu219Pro missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.791A>C;c.153A>C p.Gln264Pro;p.Gln52Pro missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.[997+4A>C];[997+4A>C] p.[Gly292ProfsTer];[Gly292ProfsTer] splice_site_variant;splice_site_variant Familial Both parents Multiplex 26048982 Rajab A , et al. (2015)
c.[676C>T];[676C>T] p.[Arg226Trp];[Arg226Trp] missense_variant Familial Both parents Multiplex 26834045 Gund C , et al. (2016)
c.[997+4A>C];[997+4A>C] p.? splice_site_variant;splice_site_variant Familial Both parents - 27848944 Trujillano D , et al. (2016)
c.775C>T p.Ala259Thr missense_variant De novo - Simplex 28628100 Geisheker MR , et al. (2017)
c.764C>T p.Ser255Asn missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.739C>T p.Ala247Thr missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.635C>T p.Gly212Asp missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.667C>T p.Gly223Ser missense_variant Familial Maternal - 28628100 Geisheker MR , et al. (2017)
c.776G>A p.Ala259Val missense_variant Familial Paternal Simplex 28628100 Geisheker MR , et al. (2017)
c.754A>G p.Trp252Arg missense_variant Unknown Not maternal - 28628100 Geisheker MR , et al. (2017)
c.769G>C p.Arg257Gly missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.596T>C p.Tyr199Cys missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.634G>A p.Gly212Ser missense_variant De novo - Simplex 28940898 Chen L , et al. (2017)
c.[676C>T];[676C>T] p.[Arg226Trp];[Arg226Trp] missense_variant Familial Both parents - 28940898 Chen L , et al. (2017)
c.700T>A p.Trp234Arg missense_variant De novo - Simplex 28940898 Chen L , et al. (2017)
c.737G>C p.Arg246Thr missense_variant De novo - Simplex 28940898 Chen L , et al. (2017)
c.791A>C p.Gln264Pro missense_variant De novo - Simplex 28940898 Chen L , et al. (2017)
c.913_915del p.Lys305del inframe_deletion De novo - Mulitplex 28940898 Chen L , et al. (2017)
c.664+2T>G p.? splice_site_variant De novo - Simplex 29366832 Li SJ , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

2S

Score Delta: Score remained at 2.1 + S

2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2017
2S
icon
2S

Score remained at 2S

Description

De novo missense variants in the DEAF1 gene that resulted in impaired transcriptional regulation of the DEAF1 promoter were identified in four individuals from three reports (PMIDs 21076407, 23020937, 24726472). All four individuals presented with intellectual disability, mild motor delay, and severely affected speech development; three of these individuals also displayed severe behavioral problems consisting of autism/autistic behavior, hyperactive behavior, compulsive behavior, and aggressive behavior with striking mood swings and poor eye contact.

7/1/2017
2S
icon
2S

Score remained at 2S

Description

De novo missense variants in the DEAF1 gene that resulted in impaired transcriptional regulation of the DEAF1 promoter were identified in four individuals from three reports (PMIDs 21076407, 23020937, 24726472). All four individuals presented with intellectual disability, mild motor delay, and severely affected speech development; three of these individuals also displayed severe behavioral problems consisting of autism/autistic behavior, hyperactive behavior, compulsive behavior, and aggressive behavior with striking mood swings and poor eye contact.

10/1/2016
2S
icon
2S

Score remained at 2S

Description

De novo missense variants in the DEAF1 gene that resulted in impaired transcriptional regulation of the DEAF1 promoter were identified in four individuals from three reports (PMIDs 21076407, 23020937, 24726472). All four individuals presented with intellectual disability, mild motor delay, and severely affected speech development; three of these individuals also displayed severe behavioral problems consisting of autism/autistic behavior, hyperactive behavior, compulsive behavior, and aggressive behavior with striking mood swings and poor eye contact.

1/1/2016
2S
icon
2S

Score remained at 2S

Description

De novo missense variants in the DEAF1 gene that resulted in impaired transcriptional regulation of the DEAF1 promoter were identified in four individuals from three reports (PMIDs 21076407, 23020937, 24726472). All four individuals presented with intellectual disability, mild motor delay, and severely affected speech development; three of these individuals also displayed severe behavioral problems consisting of autism/autistic behavior, hyperactive behavior, compulsive behavior, and aggressive behavior with striking mood swings and poor eye contact.

4/1/2015
2S
icon
2S

Score remained at 2S

Description

De novo missense variants in the DEAF1 gene that resulted in impaired transcriptional regulation of the DEAF1 promoter were identified in four individuals from three reports (PMIDs 21076407, 23020937, 24726472). All four individuals presented with intellectual disability, mild motor delay, and severely affected speech development; three of these individuals also displayed severe behavioral problems consisting of autism/autistic behavior, hyperactive behavior, compulsive behavior, and aggressive behavior with striking mood swings and poor eye contact.

1/1/2015
2S
icon
2S

Score remained at 2S

Description

De novo missense variants in the DEAF1 gene that resulted in impaired transcriptional regulation of the DEAF1 promoter were identified in four individuals from three reports (PMIDs 21076407, 23020937, 24726472). All four individuals presented with intellectual disability, mild motor delay, and severely affected speech development; three of these individuals also displayed severe behavioral problems consisting of autism/autistic behavior, hyperactive behavior, compulsive behavior, and aggressive behavior with striking mood swings and poor eye contact.

10/1/2014
2S
icon
2S

Score remained at 2S

Description

De novo missense variants in the DEAF1 gene that resulted in impaired transcriptional regulation of the DEAF1 promoter were identified in four individuals from three reports (PMIDs 21076407, 23020937, 24726472). All four individuals presented with intellectual disability, mild motor delay, and severely affected speech development; three of these individuals also displayed severe behavioral problems consisting of autism/autistic behavior, hyperactive behavior, compulsive behavior, and aggressive behavior with striking mood swings and poor eye contact.

7/1/2014
No data
icon
2S

Increased from No data to 2S

Description

De novo missense variants in the DEAF1 gene that resulted in impaired transcriptional regulation of the DEAF1 promoter were identified in four individuals from three reports (PMIDs 21076407, 23020937, 24726472). All four individuals presented with intellectual disability, mild motor delay, and severely affected speech development; three of these individuals also displayed severe behavioral problems consisting of autism/autistic behavior, hyperactive behavior, compulsive behavior, and aggressive behavior with striking mood swings and poor eye contact.

4/1/2014
No data
icon
2S

Increased from No data to 2S

Description

De novo missense variants in the DEAF1 gene that resulted in impaired transcriptional regulation of the DEAF1 promoter were identified in four individuals from three reports (PMIDs 21076407, 23020937, 24726472). All four individuals presented with intellectual disability, mild motor delay, and severely affected speech development; three of these individuals also displayed severe behavioral problems consisting of autism/autistic behavior, hyperactive behavior, compulsive behavior, and aggressive behavior with striking mood swings and poor eye contact.

Krishnan Probability Score

Score 0.49553468236266

Ranking 2911/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.00019315737931531

Ranking 12731/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score

Score 0.899

Ranking 141/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.58054022805151

Ranking 648/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 58

Ranking 28/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.077382648464168

Ranking 6605/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with DEAF1(1 CNVs)
11p15.5 20 Deletion-Duplication 32  /  68
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
AIMP2 aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 Human Protein Binding 7965 Q13155
ASCC2 activating signal cointegrator 1 complex subunit 2 Human Protein Binding 84164 Q9H1I8
BSPRY B box and SPRY domain-containing protein Human Protein Binding 54836 Q5W0U4
DEAF1 deformed epidermal autoregulatory factor 1 (Drosophila) Mouse Protein Binding 54006 Q9Z1T5
FHL1 four and a half LIM domains 1 Human Protein Binding 2273 Q13642
GDF5 growth differentiation factor 5 Human DNA Binding 8200 P43026
HRSP12 heat-responsive protein 12 Human Protein Binding 10247 P52758
IRF3 interferon regulatory factor 3 Human Protein Binding 3661 Q14653
IRF7 interferon regulatory factor 7 Human Protein Binding 3665 Q92985
PELI1 pellino E3 ubiquitin protein ligase 1 Human Protein Binding 57162 Q53T26
TK1 thymidine kinase 1, soluble Human Protein Binding 7083 P04183
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