Human Gene Module / Chromosome 11 / DEAF1

DEAF1DEAF1 transcription factor

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
3 / 11
Rare Variants / Common Variants
12 / 0
Aliases
DEAF1, SPN,  NUDR,  ZMYND5
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
11p15.5
Associated Disorders
ASD, EP, EPS
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 (11 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 (1 case)
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 Autism/autistic behavior (3 cases)
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 -
Rare Variants   (12)
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 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)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

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.

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."

04-01-2017
2S

Initial score established: 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.

CNVs associated with DEAF1(1 CNVs)
11p15.5 19 Deletion-Duplication 30  /  65
Animal Models associated with DEAF1(9 Models)
DEAF1_1_HM_KO Genetic
DEAF1_1_HT_KO Genetic
DEAF1_3_HM_KO Genetic
DEAF1_3_HT_KO Genetic
DEAF1_4_cKO_HM_Nes-Cre Genetic
DEAF1_4_cKO_HT_Nes-Cre Genetic
DEAF1_5_HM_KO Genetic
DEAF1_6_KO_HM Genetic
DEAF1_6_KO_HT Genetic
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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