Human Gene Module / Chromosome 11 / DEAF1

DEAF1DEAF1 transcription factor

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
19 / 32
Rare Variants / Common Variants
87 / 0
EAGLE Score
30.9
Strong Learn More
Aliases
DEAF1, SPN,  NUDR,  ZMYND5
Associated Syndromes
Vulto-van Silfout-de Vries syndrome, ASD, ADHD, DD
Chromosome Band
11p15.5
Associated Disorders
ADHD, ASD, EP, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic
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 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. Chen et al., 2017 identified potentially deleterious heterozygous DEAF1 variants in six novel individuals presenting with intellectual disability, motor delay, and autistic behavior. Rare de novo heterozygous missense variants that were predicted to be damaging have been observed in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014), as well as in ASD probands from the Autism Simplex Collection (TASC) and the Autism Clinical and Genetic Resources in China (ACGC) cohorts (Geisheker et al., 2017). Biallelic variants in the DEAF1 gene have also been observed in individuals presenting with an autosomal recessive neurodevelopmental disorder (dyskinesia, seizures, and intellectual developmental disorder; OMIM 617171); autistic features have been observed in a subset of these individuals (Rajab et al., 2015; Gund et al., 2016; Trujillano et al., 2017; Chen et al., 2017). Phentoypic characterization of a previously unreported cohort of 17 individuals with de novo DEAF1 variants and 5 individuals with biallelic DEAF1 variants in Nabais Sa et al., 2019 found that autism was present in 16 individuals with a de novo DEAF1 variant, as opposed to 1 individual with a biallelic DEAF1 variant. Furthermore, many of the de novo DEAF1 variants reported by Nabais Sa et al., 2019 were experimentally shown to impair transcriptional regulation of the DEAF1 promoter. Three additional de novo missense variants in the DEAF1 gene were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified DEAF1 as a candidate gene with a false discovery rate (FDR) 0.01. A de novo loss-of-function variant and three rare and potentially damaging missense variants in the DEAF1 gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified DEAF1 as a gene reaching exome-wide significance (P < 2.5E-06).

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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DEAF1 (32 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 p.R226W DEAF1 mutation 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) phenotype 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 -
15 Support Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations Zhou WZ , et al. (2019) Yes -
16 Recent Recommendation De novo and biallelic DEAF1 variants cause a phenotypic spectrum Nabais S MJ , et al. (2019) No ASD
17 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing Aspromonte MC , et al. (2019) Yes -
18 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
19 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
20 Support - Taşkıran EZ et al. (2021) No ADHD, autistic features
21 Support - Chen S et al. (2021) Yes DD, ID, epilepsy/seizures
22 Support - Hu C et al. (2022) Yes -
23 Support - Chen Y et al. (2021) No -
24 Support - McGee SR et al. (2022) Yes Epilepsy/seizures
25 Support - Zhou X et al. (2022) Yes -
26 Support - Spataro N et al. (2023) No Autistic features
27 Support - Wang J et al. (2023) Yes -
28 Support - Cirnigliaro M et al. (2023) Yes -
29 Support - Sheth F et al. (2023) Yes DD, ID
30 Support - et al. () Yes -
31 Support - et al. () Yes -
32 Support - et al. () Yes ADHD, BPD, OCD, ID, learning disability
Rare Variants   (87)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.664+989C>T - missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.597C>G p.Tyr199Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.664+2T>G - splice_site_variant De novo - - 30763456 Zhou WZ , et al. (2019)
c.674G>T p.Gly225Val missense_variant De novo - Simplex 38025430 et al. ()
c.782G>C p.Arg261Pro missense_variant De novo - Simplex 38073621 et al. ()
c.608T>C p.Leu203Pro missense_variant De novo - - 34800434 Chen S et al. (2021)
c.670C>T p.Arg224Trp missense_variant De novo - - 34800434 Chen S et al. (2021)
c.825C>G p.His275Gln missense_variant De novo - - 34800434 Chen S et al. (2021)
c.634G>A p.Gly212Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.664+1G>T - splice_site_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.664+988G>A - missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.1540G>A p.Glu514Lys missense_variant Familial - Multiplex 38256266 et al. ()
c.1016G>A p.Gly339Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.664+2T>G - splice_site_variant De novo - Simplex 29366832 Li SJ , et al. (2018)
c.664+1013G>A - missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.664+1018C>G - missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.332A>C p.Asp111Ala missense_variant De novo - - 35981081 McGee SR et al. (2022)
c.662C>T p.Ser221Leu missense_variant De novo - - 35981081 McGee SR et al. (2022)
c.712A>C p.Thr238Pro missense_variant De novo - - 35981081 McGee SR et al. (2022)
c.748A>G p.Lys250Glu missense_variant De novo - - 35981081 McGee SR et al. (2022)
c.754T>C p.Trp252Arg missense_variant De novo - - 35981081 McGee SR et al. (2022)
c.767T>G p.Ile256Ser missense_variant De novo - - 35981081 McGee SR et al. (2022)
c.825C>G p.His275Gln missense_variant De novo - - 35981081 McGee SR et al. (2022)
c.836G>C p.Cys279Ser missense_variant De novo - - 35981081 McGee SR et al. (2022)
c.880G>A p.Val294Ile missense_variant De novo - - 35981081 McGee SR et al. (2022)
c.890T>C p.Phe297Ser missense_variant De novo - - 35981081 McGee SR et al. (2022)
c.730+1G>A - splice_site_variant Unknown - - 31209962 Aspromonte MC , et al. (2019)
c.664+1040A>C - missense_variant De novo - Simplex 23020937 Rauch A , et al. (2012)
c.634G>T p.Gly212Cys missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.634G>A p.Gly212Ser missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.637A>C p.Thr213Pro missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.640C>G p.Leu214Val missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.641T>C p.Leu214Pro missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.646A>G p.Lys216Glu missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.648G>T p.Lys216Asn missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.674G>A p.Gly225Glu missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.683T>C p.Ile228Thr missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.706A>G p.Ser236Gly missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.757A>G p.Thr253Ala missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.791A>C p.Gln264Pro missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.815T>C p.Ile272Thr missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.826G>C p.Ala276Pro missense_variant De novo - - 30923367 Nabais S MJ , et al. (2019)
c.634G>A p.Gly212Ser missense_variant Familial Maternal - 35741772 Hu C et al. (2022)
c.63_80del p.Val25_Ala30del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.646A>G p.Lys216Glu missense_variant De novo - Simplex 35873028 Chen Y et al. (2021)
c.758A>T p.Lys253Ile missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.596A>G p.Tyr199Cys missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.635G>A p.Gly212Asp missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.634G>A p.Gly212Ser missense_variant De novo - Simplex 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.664+1024G>A - missense_variant De novo - Simplex 28628100 Geisheker MR , et al. (2017)
c.664+961A>C - missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.664+916G>A - missense_variant Familial Maternal - 28628100 Geisheker MR , et al. (2017)
c.762_764del p.Ser255del inframe_deletion De novo - - 30923367 Nabais S MJ , et al. (2019)
c.619T>C p.Cys207Arg missense_variant De novo - - 33739554 Taşkıran EZ et al. (2021)
c.290-3C>G - splice_site_variant Familial Maternal Simplex 25167861 Redin C , et al. (2014)
c.683T>G p.Ile228Ser missense_variant De novo - Simplex 21076407 Vissers LE , et al. (2010)
c.656T>C p.Leu219Pro missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.658G>A p.Gly220Ser missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.716A>G p.Glu239Gly missense_variant Unknown - Simplex 30923367 Nabais S MJ , et al. (2019)
c.664+1003T>C - missense_variant Unknown Not maternal - 28628100 Geisheker MR , et al. (2017)
c.676C>T p.Arg226Trp missense_variant Familial Both parents - 28940898 Chen L , et al. (2017)
c.913_915del p.Tyr305del inframe_deletion De novo - Multiplex 28940898 Chen L , et al. (2017)
c.620G>A p.Cys207Tyr missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.648G>T p.Lys216Asn missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.471C>T p.Ile157= synonymous_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.828G>A p.Pro276= synonymous_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.336T>A p.Asn112Lys missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.701G>A p.Trp234Ter stop_gained Familial Maternal Simplex 30923367 Nabais S MJ , et al. (2019)
c.731-1143A>C - splice_site_variant Familial Both parents - 27848944 Trujillano D , et al. (2016)
c.664+1025C>T - missense_variant Familial Paternal Simplex 28628100 Geisheker MR , et al. (2017)
c.671G>A p.Arg224Gln missense_variant Familial Maternal Simplex 32094338 Husson T , et al. (2020)
c.563_1045del p.Gly188_Phe349delinsVal copy_number_loss De novo - - 35981081 McGee SR et al. (2022)
c.731-1143A>C - splice_site_variant Familial Both parents Multiplex 26048982 Rajab A , et al. (2015)
c.676C>T p.Arg226Trp missense_variant Familial Both parents Multiplex 26834045 Gund C , et al. (2016)
c.664+1030C>T - stop_gained Familial Paternal Extended multiplex 37506195 Cirnigliaro M et al. (2023)
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.664+925C>T - missense_variant Familial Both parents Extended multiplex 24668509 Faqeih EA , et al. (2014)
c.1355_1357del p.Phe452del inframe_deletion Familial Paternal Simplex 30923367 Nabais S MJ , et al. (2019)
c.671G>A p.Arg224Gln missense_variant Familial Both parents Multiplex 30923367 Nabais S MJ , et al. (2019)
c.130del p.Arg44GlyfsTer25 frameshift_variant Familial Maternal Simplex 30923367 Nabais S MJ , et al. (2019)
c.1617dup p.Cys540MetfsTer18 frameshift_variant Familial Maternal Simplex 30923367 Nabais S MJ , et al. (2019)
c.791A>C p.Gln264Pro missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.837_838insCG p.Asp280ArgfsTer51 frameshift_variant Familial Paternal Simplex 30923367 Nabais S MJ , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

S

Syndromic

See all Category S Genes

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."

4/1/2021
1
icon
1

Score remained at 1

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. Chen et al., 2017 identified potentially deleterious heterozygous DEAF1 variants in six novel individuals presenting with intellectual disability, motor delay, and autistic behavior. Rare de novo heterozygous missense variants that were predicted to be damaging have been observed in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014), as well as in ASD probands from the Autism Simplex Collection (TASC) and the Autism Clinical and Genetic Resources in China (ACGC) cohorts (Geisheker et al., 2017). Biallelic variants in the DEAF1 gene have also been observed in individuals presenting with an autosomal recessive neurodevelopmental disorder (dyskinesia, seizures, and intellectual developmental disorder; OMIM 617171); autistic features have been observed in a subset of these individuals (Rajab et al., 2015; Gund et al., 2016; Trujillano et al., 2017; Chen et al., 2017). Phentoypic characterization of a previously unreported cohort of 17 individuals with de novo DEAF1 variants and 5 individuals with biallelic DEAF1 variants in Nabais Sa et al., 2019 found that autism was present in 16 individuals with a de novo DEAF1 variant, as opposed to 1 individual with a biallelic DEAF1 variant. Furthermore, many of the de novo DEAF1 variants reported by Nabais Sa et al., 2019 were experimentally shown to impair transcriptional regulation of the DEAF1 promoter.

Reports Added
[Diagnostic yield of whole-exome sequencing in non-syndromic intellectual disability2021]
1/1/2020
1
icon
1

Score remained at 1

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. Chen et al., 2017 identified potentially deleterious heterozygous DEAF1 variants in six novel individuals presenting with intellectual disability, motor delay, and autistic behavior. Rare de novo heterozygous missense variants that were predicted to be damaging have been observed in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014), as well as in ASD probands from the Autism Simplex Collection (TASC) and the Autism Clinical and Genetic Resources in China (ACGC) cohorts (Geisheker et al., 2017). Biallelic variants in the DEAF1 gene have also been observed in individuals presenting with an autosomal recessive neurodevelopmental disorder (dyskinesia, seizures, and intellectual developmental disorder; OMIM 617171); autistic features have been observed in a subset of these individuals (Rajab et al., 2015; Gund et al., 2016; Trujillano et al., 2017; Chen et al., 2017). Phentoypic characterization of a previously unreported cohort of 17 individuals with de novo DEAF1 variants and 5 individuals with biallelic DEAF1 variants in Nabais Sa et al., 2019 found that autism was present in 16 individuals with a de novo DEAF1 variant, as opposed to 1 individual with a biallelic DEAF1 variant. Furthermore, many of the de novo DEAF1 variants reported by Nabais Sa et al., 2019 were experimentally shown to impair transcriptional regulation of the DEAF1 promoter.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]
10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
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. Chen et al., 2017 identified potentially deleterious heterozygous DEAF1 variants in six novel individuals presenting with intellectual disability, motor delay, and autistic behavior. Rare de novo heterozygous missense variants that were predicted to be damaging have been observed in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014), as well as in ASD probands from the Autism Simplex Collection (TASC) and the Autism Clinical and Genetic Resources in China (ACGC) cohorts (Geisheker et al., 2017). Biallelic variants in the DEAF1 gene have also been observed in individuals presenting with an autosomal recessive neurodevelopmental disorder (dyskinesia, seizures, and intellectual developmental disorder; OMIM 617171); autistic features have been observed in a subset of these individuals (Rajab et al., 2015; Gund et al., 2016; Trujillano et al., 2017; Chen et al., 2017). Phentoypic characterization of a previously unreported cohort of 17 individuals with de novo DEAF1 variants and 5 individuals with biallelic DEAF1 variants in Nabais Sa et al., 2019 found that autism was present in 16 individuals with a de novo DEAF1 variant, as opposed to 1 individual with a biallelic DEAF1 variant. Furthermore, many of the de novo DEAF1 variants reported by Nabais Sa et al., 2019 were experimentally shown to impair transcriptional regulation of the DEAF1 promoter.

Reports Added
[New Scoring Scheme]
7/1/2019
2S
icon
2S

Decreased from 2S 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. Chen et al., 2017 identified potentially deleterious heterozygous DEAF1 variants in six novel individuals presenting with intellectual disability, motor delay, and autistic behavior. Rare de novo heterozygous missense variants that were predicted to be damaging have been observed in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014), as well as in ASD probands from the Autism Simplex Collection (TASC) and the Autism Clinical and Genetic Resources in China (ACGC) cohorts (Geisheker et al., 2017). Biallelic variants in the DEAF1 gene have also been observed in individuals presenting with an autosomal recessive neurodevelopmental disorder (dyskinesia, seizures, and intellectual developmental disorder; OMIM 617171); autistic features have been observed in a subset of these individuals (Rajab et al., 2015; Gund et al., 2016; Trujillano et al., 2017; Chen et al., 2017). Phentoypic characterization of a previously unreported cohort of 17 individuals with de novo DEAF1 variants and 5 individuals with biallelic DEAF1 variants in Nabais Sa et al., 2019 found that autism was present in 16 individuals with a de novo DEAF1 variant, as opposed to 1 individual with a biallelic DEAF1 variant. Furthermore, many of the de novo DEAF1 variants reported by Nabais Sa et al., 2019 were experimentally shown to impair transcriptional regulation of the DEAF1 promoter.

Reports Added
[Characterization of intellectual disability and autism comorbidity through gene panel sequencing.2019]
4/1/2019
2S
icon
2S

Decreased from 2S 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.

Reports Added
[De novo and biallelic DEAF1 variants cause a phenotypic spectrum.2019]
1/1/2019
2S
icon
2S

Decreased from 2S 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.

Reports Added
[Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...2019]
10/1/2017
2S
icon
2S

Decreased from 2S 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.

Reports Added
[Functional analysis of novel DEAF1 variants identified through clinical exome sequencing expands DEAF1-associated neurodevelopmental disorder (DAND...2017]
7/1/2017
2S
icon
2S

Decreased from 2S 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.

Reports Added
[Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.2017]
10/1/2016
2S
icon
2S

Decreased from 2S 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.

Reports Added
[Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
1/1/2016
2S
icon
2S

Decreased from 2S 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.

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [A de novo paradigm for mental retardation.2010] [Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.2012] [Novel homozygous DEAF1 variant suspected in causing white matter disease, intellectual disability, and microcephaly.2014] [Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems.2014] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Recessive DEAF1 mutation associates with autism, intellectual disability, basal ganglia dysfunction and epilepsy.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Identification of a syndrome comprising microcephaly and intellectual disability but not white matter disease associated with a homozygous c.676C>T...2016]
4/1/2015
2S
icon
2S

Decreased from 2S 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.

Reports Added
[Recessive DEAF1 mutation associates with autism, intellectual disability, basal ganglia dysfunction and epilepsy.2015]
1/1/2015
2S
icon
2S

Decreased from 2S 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.

Reports Added
[Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014]
10/1/2014
2S
icon
2S

Decreased from 2S 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.

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
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.
Original Source
ExAC Score

Score 0.0001931573793153

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
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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.
Original Source
Interactome
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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