Human Gene Module / Chromosome 9 / EHMT1

EHMT1Euchromatic histone-lysine N-methyltransferase 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
13 / 32
Rare Variants / Common Variants
38 / 0
EAGLE Score
13.5
Strong Learn More
Aliases
EHMT1, RP11-188C12.1,  DKFZp667M072,  EUHMTASE1,  Eu-HMTase1,  FLJ12879,  FP13812,  GLP,  GLP1,  KIAA1876,  KMT1D,  bA188C12.1
Associated Syndromes
Kleefstra syndrome
Chromosome Band
9q34.3
Associated Disorders
DD/NDD, ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (Talkowski et al., 2012). This BCA-disrupted gene was also individually implicated by case-control CNV burden or by a minimum of 3 CNVs in neuodevelopmental disorder (NDD) cases with none in controls in a follow-up study in the same report.

Molecular Function

The protein encoded by this gene is a histone methyltransferase that is part of the E2F6 complex, which represses transcription. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition. Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome).

SFARI Genomic Platforms
Reports related to EHMT1 (32 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome Kleefstra T , et al. (2005) No -
2 Highly Cited Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome Kleefstra T , et al. (2006) No -
3 Support Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype Kleefstra T , et al. (2009) No -
4 Primary Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries Talkowski ME , et al. (2012) Yes -
5 Recent Recommendation EHMT1 protein binds to nuclear factor-?B p50 and represses gene expression Ea CK , et al. (2012) No -
6 Support Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing Jiang YH , et al. (2013) Yes -
7 Support Intragenic duplication of EHMT1 gene results in Kleefstra syndrome Schwaibold EM , et al. (2014) No DD
8 Support Exon resequencing of H3K9 methyltransferase complex genes, EHMT1, EHTM2 and WIZ, in Japanese autism subjects Balan S , et al. (2014) Yes -
9 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
10 Recent Recommendation A structured assessment of motor function and behavior in patients with Kleefstra syndrome Schmidt S , et al. (2016) No -
11 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder Alvarez-Mora MI , et al. (2016) Yes -
12 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
13 Support Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and normal intellectual performance Bock I , et al. (2016) No ASD
14 Support Establishment of EHMT1 mutant induced pluripotent stem cell (iPSC) line from a 11-year-old Kleefstra syndrome (KS) patient with autism and normal intellectual performance Varga E , et al. (2016) No ASD, DD
15 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No Autistic features, behavioral problems
16 Support A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPL X Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding Blackburn PR , et al. (2017) No ASD, ID
17 Support A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors Mitra AK , et al. (2017) No ASD, ID
18 Support A novel de novo frameshift deletion in EHMT1 in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation Blackburn PR , et al. (2017) No ASD, ID
19 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No -
20 Support Expanding the genetic heterogeneity of intellectual disability Anazi S , et al. (2017) Yes -
21 Support Hypogonadotropic Hypogonadism and Kleefstra Syndrome due to a Pathogenic Variant in the EHMT1 Gene: An Underrecognized Association Torga AP , et al. (2018) No -
22 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children Long S , et al. (2019) Yes -
23 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing Aspromonte MC , et al. (2019) Yes -
24 Recent recommendation Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype Frega M , et al. (2020) No -
25 Support Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability Chevarin M et al. (2020) No Marfanoid habitus
26 Support Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression Yin J et al. (2020) Yes Developmental regression, DD
27 Support EHMT1 regulates Parvalbumin-positive interneuron development and GABAergic input in sensory cortical areas Negwer M et al. (2020) No -
28 Support - Ohashi K et al. (2021) Yes -
29 Support - Balan S et al. (2021) Yes -
30 Support - Mahjani B et al. (2021) Yes -
31 Support - Chen S et al. (2021) Yes DD, ID
32 Support - Carvalho LML et al. (2022) Yes -
Rare Variants   (38)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo NA - 27841880 Redin C , et al. (2016)
- - copy_number_gain De novo NA Simplex 25349628 Schwaibold EM , et al. (2014)
c.3385C>T p.Gln1129Ter stop_gained De novo NA - 34800434 Chen S et al. (2021)
c.1468C>T p.Arg490Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.3413G>A p.Trp1138Ter stop_gained De novo NA - 27651234 Bock I , et al. (2016)
c.448C>A p.His150Asn missense_variant Unknown - - 34262135 Balan S et al. (2021)
c.499G>A p.Ala167Thr missense_variant Unknown - - 34262135 Balan S et al. (2021)
c.2644G>A p.Val882Met missense_variant Unknown - - 34262135 Balan S et al. (2021)
c.673C>T p.Arg225Ter stop_gained De novo NA - 28554332 Bowling KM , et al. (2017)
c.3259-2A>G - splice_site_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.989A>T p.Lys330Met missense_variant Unknown - Unknown 32722525 Yin J et al. (2020)
c.1513G>A p.Gly505Ser missense_variant Unknown - Unknown 32722525 Yin J et al. (2020)
c.1171-7T>C - splice_region_variant Familial Paternal - 31139143 Long S , et al. (2019)
c.2691+1G>A - splice_site_variant De novo NA Simplex 30370152 Torga AP , et al. (2018)
c.2608-1G>C - splice_site_variant De novo NA Simplex 32277047 Chevarin M et al. (2020)
c.2426C>T p.Pro809Leu missense_variant Unknown - - 28057753 Blackburn PR , et al. (2017)
c.1468C>T p.Arg490Ter stop_gained De novo NA Simplex 32277047 Chevarin M et al. (2020)
c.2426C>T p.Pro809Leu missense_variant De novo NA - 28057753 Blackburn PR , et al. (2017)
c.631G>A p.Val211Ile missense_variant Familial Paternal - 33590427 Ohashi K et al. (2021)
c.2704C>T p.Arg902Ter stop_gained De novo NA Simplex 35597848 Carvalho LML et al. (2022)
c.2062G>A p.Ala688Thr missense_variant Unknown - - 26845707 Alvarez-Mora MI , et al. (2016)
c.2186C>T p.Ser729Leu missense_variant Familial Maternal - 33590427 Ohashi K et al. (2021)
c.1145dup p.Met382IlefsTer5 frameshift_variant Unknown - - 34615535 Mahjani B et al. (2021)
- - copy_number_loss Familial Maternal Multi-generational 29416845 de Boer A , et al. (2018)
- - copy_number_loss Familial Paternal Multi-generational 29416845 de Boer A , et al. (2018)
c.3577G>C p.Gly1193Arg missense_variant De novo NA - 31209962 Aspromonte MC , et al. (2019)
c.2882A>G p.Lys961Arg missense_variant Unknown Not maternal - 34262135 Balan S et al. (2021)
c.2749G>T p.Gly917Cys splice_site_variant De novo NA Simplex 28361099 Mitra AK , et al. (2017)
- - translocation De novo NA Multiplex (monozygotic twins) 22521361 Talkowski ME , et al. (2012)
c.1043C>T p.Ser348Leu missense_variant Familial Paternal Simplex 25400900 Balan S , et al. (2014)
c.514C>T p.Pro172Ser missense_variant Familial Maternal Multiplex 25400900 Balan S , et al. (2014)
c.1585del p.Ser529ValfsTer34 frameshift_variant De novo NA - 31209962 Aspromonte MC , et al. (2019)
c.3295C>G p.Pro1099Ala missense_variant Familial Maternal Simplex 23849776 Jiang YH , et al. (2013)
c.928_929del p.Arg310AspfsTer4 frameshift_variant De novo NA - 28361100 Blackburn PR , et al. (2017)
c.2903A>G p.Lys968Arg missense_variant Unknown Not maternal Simplex 25400900 Balan S , et al. (2014)
c.2968C>T p.Gln990Ter stop_gained De novo NA Not simplex (positive family history) 28940097 Anazi S , et al. (2017)
c.3047G>A p.Arg1016Gln missense_variant Familial Maternal Multi-generational 26845707 Alvarez-Mora MI , et al. (2016)
c.1134del p.Lys379ArgfsTer38 frameshift_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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.

4/1/2022
1

Initial score established: 1

10/1/2021
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

7/1/2021
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

4/1/2021
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

1/1/2021
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

10/1/2020
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

7/1/2020
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

4/1/2020
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

1/1/2020
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

10/1/2019
1

Initial score established: 1

New Scoring Scheme
Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

Reports Added
[New Scoring Scheme]
7/1/2019
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

4/1/2019
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

1/1/2019
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

10/1/2018
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

7/1/2018
3S

Initial score established: 3S

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

4/1/2018
4.4 + acc2 + S

Initial score established: 4.4 + acc2 + S

Description

3S

1/1/2018
3S

Initial score established: 3S

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

10/1/2017
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

7/1/2017
3S

Initial score established: 3S

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

4/1/2017
3S

Initial score established: 3S

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

Reports Added
[Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.2012] [Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.2013] [Exon resequencing of H3K9 methyltransferase complex genes, EHMT1, EHTM2 and WIZ, in Japanese autism subjects.2014] [Intragenic duplication of EHMT1 gene results in Kleefstra syndrome.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [EHMT1 protein binds to nuclear factor-B p50 and represses gene expression.2012] [A structured assessment of motor function and behavior in patients with Kleefstra syndrome.2016] [Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome.2005] [Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome.2006] [Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to th...2009] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Establishment of EHMT1 mutant induced pluripotent stem cell (iPSC) line from a 11-year-old Kleefstra syndrome (KS) patient with autism and normal i...2016] [Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and...2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Fo...2017] [A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors.2017] [A novel de novo frameshift deletion in EHMT1 in a patient with Kleefstra Syndrome results in decreased H3K9 dimethylation.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
1/1/2017
3S

Initial score established: 3S

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

10/1/2016
1

Initial score established: 1

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

7/1/2016
3S

Initial score established: 3S

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

4/1/2016
3S

Initial score established: 3S

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

1/1/2016
3S

Initial score established: 3S

Description

Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD.

10/1/2015
1

Initial score established: 1

Description

EHTM1is the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability. This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD).

7/1/2015
3S

Initial score established: 3S

Description

EHTM1is the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability. This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD).

4/1/2015
3S

Initial score established: 3S

Description

EHTM1is the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability. This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD).

1/1/2015
3S

Initial score established: 3S

Description

EHTM1is the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability. This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD).

10/1/2014
1

Initial score established: 1

Description

EHTM1is the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability. This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD).

7/1/2014
3S

Initial score established: 3S

Description

EHTM1is the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability. This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD).

4/1/2014
3S

Initial score established: 3S

Description

EHTM1is the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability. This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD).

Krishnan Probability Score

Score 0.41197405286074

Ranking 22250/25841 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 0.99999990401202

Ranking 197/18225 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
Sanders TADA Score

Score 0.59142817574477

Ranking 681/18665 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 12

Ranking 157/461 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 0.43802429013816

Ranking 1053/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
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