Human Gene Module / Chromosome 7 / EN2

EN2engrailed homolog 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
13 / 27
Rare Variants / Common Variants
4 / 8
Aliases
EN2, AUTS1,  engrailed 2,  engrailed-2
Associated Syndromes
-
Chromosome Band
7q36.3
Associated Disorders
-
Relevance to Autism

Several studies have found genetic association between the EN2 gene and autism. In particular, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

Molecular Function

The encoded protein is a transcription factor.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to EN2 (27 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Negative Association No association between the EN2 gene and autistic disorder Zhong H , et al. (2003) Yes -
2 Primary Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder Gharani N , et al. (2004) Yes -
3 Positive Association Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus Benayed R , et al. (2005) Yes -
4 Recent Recommendation The transcription factor Engrailed-2 guides retinal axons Brunet I , et al. (2005) No -
5 Recent Recommendation En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder Cheh MA , et al. (2006) No -
6 Recent Recommendation Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a polycomb-like protein Lee MG , et al. (2007) No -
7 Positive Association Heterogeneous association between engrailed-2 and autism in the CPEA network Brune CW , et al. (2007) Yes -
8 Positive Association Association of the ENGRAILED 2 (EN2) gene with autism in Chinese Han population Wang L , et al. (2007) Yes -
9 Positive Association Association of the homeobox transcription factor gene ENGRAILED 2 with autistic disorder in Chinese children Yang P , et al. (2008) Yes -
10 Recent Recommendation Engrailed-2 regulates genes related to vesicle formation and transport in cerebellar Purkinje cells Holst MI , et al. (2008) No -
11 Negative Association Association study of the CNS patterning genes and autism in Han Chinese in Taiwan Chien YL , et al. (2011) Yes -
12 Support Cut-like homeobox 1 and nuclear factor I/B mediate ENGRAILED2 autism spectrum disorder-associated haplotype function Choi J , et al. (2011) No -
13 Negative Association The association of rs4307059 and rs35678 markers with autism spectrum disorders is replicated in Italian families Prandini P , et al. (2012) Yes -
14 Recent Recommendation Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development Rossman IT , et al. (2014) No -
15 Support Autism associated gene, engrailed2, and flanking gene levels are altered in post-mortem cerebellum Choi J , et al. (2014) No -
16 Recent Recommendation Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum James SJ , et al. (2014) No -
17 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
18 Support Serotonin abnormalities in Engrailed-2 knockout mice: New insight relevant for a model of Autism Spectrum Disorder Viaggi C , et al. (2015) No -
19 Support Whole-exome sequencing identifies a novel heterozygous missense variant of the EN2 gene in two unrelated patients with autism spectrum disorder Hnoonual A , et al. (2016) Yes -
20 Recent Recommendation Increased signaling by the autism-related Engrailed-2 protein enhances dendritic branching and spine density, alters synaptic structural matching, and exaggerates protein synthesis Soltani A , et al. (2017) No -
21 Highly Cited Expression patterns of the homeo box-containing genes En-1 and En-2 and the proto-oncogene int-1 diverge during mouse development Davis CA and Joyner AL (1988) No -
22 Recent Recommendation Impaired Neuronal Differentiation of Neural Stem Cells Lacking the Engrailed-2 Gene Boschian C , et al. (2018) No -
23 Support - Zhou J et al. (2019) Yes -
24 Recent Recommendation - Chen X et al. (2021) Yes -
25 Support - Giulia Lazzarini et al. (2024) Yes -
26 Support - Lorenzo Mattioni et al. (2024) Yes -
27 Highly Cited Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse Engrailed-2 mutants Millen KJ , et al. (1994) No -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
C>T - intergenic_variant De novo - Simplex 31133750 Zhou J et al. (2019)
c.425C>G p.Pro142Arg missense_variant Familial Paternal Simplex 27755371 Hnoonual A , et al. (2016)
c.425C>G p.Pro142Arg missense_variant Familial Maternal Multiplex 27755371 Hnoonual A , et al. (2016)
c.996C>T p.Ser332= synonymous_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.686-921T>C C/T intron_variant - - - 18424904 Yang P , et al. (2008)
c.686-1568C>T A/G intron_variant - - - 17948901 Wang L , et al. (2007)
c.686-1073G>A A/G intron_variant - - - 18424904 Yang P , et al. (2008)
c.686-1073G>A A/G intron_variant - - - 17948868 Brune CW , et al. (2007)
c.686-921T>C C/T intron_variant - - - 16252243 Benayed R , et al. (2005)
c.686-1073G>A A/G intron_variant - - - 16252243 Benayed R , et al. (2005)
c.686-921T>C C to T intron_variant - - - 15024396 Gharani N , et al. (2004)
c.686-1073G>A A to G intron_variant - - - 15024396 Gharani N , et al. (2004)
SFARI Gene score
2

Strong Candidate

EN2 is located in a linkage region with variable evidence for association with autism. For example, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

EN2 is located in a linkage region with variable evidence for association with autism. For example, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

EN2 is located in a linkage region with variable evidence for association with autism. For example, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

Reports Added
[New Scoring Scheme]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

EN2 is located in a linkage region with variable evidence for association with autism. For example, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

Reports Added
[Cut-like homeobox 1 and nuclear factor I/B mediate ENGRAILED2 autism spectrum disorder-associated haplotype function.2011] [Serotonin abnormalities in Engrailed-2 knockout mice: New insight relevant for a model of Autism Spectrum Disorder.2015]
7/1/2018
4
icon
4

Decreased from 4 to 4

Description

EN2 is located in a linkage region with variable evidence for association with autism. For example, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

Reports Added
[Impaired Neuronal Differentiation of Neural Stem Cells Lacking the Engrailed-2 Gene.2018]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

EN2 is located in a linkage region with variable evidence for association with autism. For example, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

Reports Added
[Increased signaling by the autism-related Engrailed-2 protein enhances dendritic branching and spine density, alters synaptic structural matching, ...2017]
10/1/2016
4
icon
4

Decreased from 4 to 4

Description

EN2 is located in a linkage region with variable evidence for association with autism. For example, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

Reports Added
[Whole-exome sequencing identifies a novel heterozygous missense variant of the EN2 gene in two unrelated patients with autism spectrum disorder.2016]
1/1/2015
4
icon
4

Decreased from 4 to 4

Description

EN2 is located in a linkage region with variable evidence for association with autism. For example, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
10/1/2014
4
icon
4

Decreased from 4 to 4

Description

EN2 is located in a linkage region with variable evidence for association with autism. For example, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

Reports Added
[Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in aut...2014]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

EN2 is located in a linkage region with variable evidence for association with autism. For example, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

EN2 is located in a linkage region with variable evidence for association with autism. For example, studies have found associations in the Chinese Han population as well as AGRE, NIMH and CPEA cohorts. However, another study found no genetic association between EN2 and autism in an AGRE cohort (Zhong et al., 2003).

Krishnan Probability Score

Score 0.56677281727376

Ranking 1204/25841 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 0.43310737895365

Ranking 5802/18225 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
Sanders TADA Score

Score 0.90504414661926

Ranking 6917/18665 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 47.5

Ranking 34/461 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 -0.25487339216838

Ranking 16456/20870 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
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Foxa2 forkhead box A2 Rat Protein Binding 25099 P32182
MIR181A1 microRNA 181a-1 Human RNA Binding 406995 N/A
PAX2 paired box 2 Human DNA Binding 5076 Q02962
PAX3 paired box 3 Human Protein Binding 5077 P23760
PAX5 paired box 5 Human DNA Binding 5079 Q02548
PAX8 paired box 8 Human DNA Binding 7849 Q06710
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