Human Gene Module / Chromosome 7 / KMT2E

KMT2ELysine (K)-specific methyltransferase 2E

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
7 / 9
Rare Variants / Common Variants
37 / 1
Aliases
KMT2E, HDCMC04P,  MLL5,  NKp44L
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
7q22.3
Associated Disorders
-
Relevance to Autism

De novo frameshift variants in this gene have been identified in unrelated ASD cases from the Simons Simplex Collection (Iossifov et al., 2012; Dong et al., 2014).

Molecular Function

Histone methyltransferase that specifically mono- and dimethylates 'Lys-4' of histone H3 (H3K4me1 and H3K4me2). H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation.

Reports related to KMT2E (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
2 Primary De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. Dong S , et al. (2014) Yes -
3 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
4 Support De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis. Wang S , et al. (2018) No -
5 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
6 Recent Recommendation Identification of common genetic risk variants for autism spectrum disorder. Grove J , et al. (2019) Yes -
7 Recent Recommendation Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy. O'Donnell-Luria AH , et al. (2019) No -
8 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
9 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
Rare Variants   (37)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.2414A>G p.Lys805Arg missense_variant De novo NA - 31452935 Feliciano P et al. (2019)
c.2416G>A p.Glu806Lys missense_variant De novo NA - 31452935 Feliciano P et al. (2019)
c.556+1G>A - splice_site_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.1130+2T>C - splice_site_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.2452C>T p.Arg818Ter stop_gained De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.2620C>T p.Arg874Ter stop_gained De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.3430G>A p.Gly1144Arg missense_variant De novo NA Unknown 30257206 Wang S , et al. (2018)
c.3070C>T p.Gln1024Ter stop_gained De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.3554C>G p.Ser1185Ter stop_gained De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.418G>A p.Val140Ile missense_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.850T>C p.Tyr284His missense_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.2720A>T p.Asp907Val missense_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.4126C>T p.Pro1376Ser missense_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.3269C>T p.Ser1090Leu missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.167del p.Tyr56SerfsTer34 frameshift_variant De novo NA Simplex 25284784 Dong S , et al. (2014)
c.2261del p.Ser754Ter frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.280del p.Thr94LeufsTer25 frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.1603del p.Leu535TyrfsTer15 frameshift_variant Unknown - - 31079897 O'Donnell-Luria AH , et al. (2019)
c.3198del p.Trp1067GlyfsTer2 frameshift_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.997del p.Glu333ArgfsTer32 frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.2936del p.Leu979TrpfsTer9 frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.3672_3673del p.Tyr1224Ter frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.1812del p.Ile605SerfsTer41 frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.3527_3530del p.Thr1176ArgfsTer16 frameshift_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.4829dup p.Leu1610PhefsTer259 frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.4872dup p.Val1625ArgfsTer244 frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.2602_2605del p.Thr868HisfsTer3 frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.1773_1777del p.Lys593ArgfsTer17 frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.1776_1780del p.Lys593ArgfsTer17 frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.3494_3495del p.Arg1165ThrfsTer3 frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.4485_4486del p.Gln1496LysfsTer39 frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
c.1239del p.Asn414MetfsTer4 frameshift_variant Unknown Not maternal - 31079897 O'Donnell-Luria AH , et al. (2019)
c.3198_3234del p.Trp1067GlnfsTer2 frameshift_variant Unknown Not maternal - 31079897 O'Donnell-Luria AH , et al. (2019)
c.5453_5460del p.Val1818AlafsTer48 frameshift_variant Unknown Not maternal - 31079897 O'Donnell-Luria AH , et al. (2019)
c.450dup p.Arg151Ter frameshift_variant Unknown Not maternal Multi-generational 31079897 O'Donnell-Luria AH , et al. (2019)
c.4397_4398insCACAGCATGGTTATCTTTC p.Pro1467ThrfsTer75 frameshift_variant De novo NA - 31079897 O'Donnell-Luria AH , et al. (2019)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.2196+1578A>G - intron_variant - - - 30804558 Grove J , et al. (2019)
SFARI Gene score
1

High Confidence

De novo loss-of-function frameshift variants in the KMT2E gene have been identified in two unrelated ASD cases from the Simons Simplex Collection (PMIDs 22542183, 25284784); no similar indels were observed in controls. A maternally-inherited frameshift variant in this gene was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. An intronic polymorphism in the KMT2E gene (rs111931861) that was determined by Hi-C analysis to be a loss-of-function variant was found to be the index variant for a genome-wide significant locus (P = 3.53E-08) identified in a combined analysis of 18,381 ASD cases and 27,969 controls from iPSYCH and the Psychiatric Genomic Consortium (PGC) and five cohorts of European ancestry including a total of 2,119 additional ASD cases and 142,379 controls (Grove et al., 2019). A study including 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and three previously reported in ASD probands from the Simons Simplex Collection and the Autism Clinical and Genetic Resources in China cohort) and four individuals with microdeletions encompassing KMT2E identified a neurodevelopmental disorder characterized by developmental delay, intellectual disability, epilepsy, hypotonia, and either microcephaly or macrocephaly; a quarter of the 38 individuals in this cohort met criteria for autism spectrum disorder (ODonnell-Luria et al., 2019).

Score Delta: Score remained at 3S

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.

1/1/2020
3S
icon
3S

Score remained at 3S

Description

De novo loss-of-function frameshift variants in the KMT2E gene have been identified in two unrelated ASD cases from the Simons Simplex Collection (PMIDs 22542183, 25284784); no similar indels were observed in controls. A maternally-inherited frameshift variant in this gene was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. An intronic polymorphism in the KMT2E gene (rs111931861) that was determined by Hi-C analysis to be a loss-of-function variant was found to be the index variant for a genome-wide significant locus (P = 3.53E-08) identified in a combined analysis of 18,381 ASD cases and 27,969 controls from iPSYCH and the Psychiatric Genomic Consortium (PGC) and five cohorts of European ancestry including a total of 2,119 additional ASD cases and 142,379 controls (Grove et al., 2019). A study including 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and three previously reported in ASD probands from the Simons Simplex Collection and the Autism Clinical and Genetic Resources in China cohort) and four individuals with microdeletions encompassing KMT2E identified a neurodevelopmental disorder characterized by developmental delay, intellectual disability, epilepsy, hypotonia, and either microcephaly or macrocephaly; a quarter of the 38 individuals in this cohort met criteria for autism spectrum disorder (ODonnell-Luria et al., 2019).

10/1/2019
3S
icon
2S

Decreased from 3S to 2S

New Scoring Scheme
Description

De novo loss-of-function frameshift variants in the KMT2E gene have been identified in two unrelated ASD cases from the Simons Simplex Collection (PMIDs 22542183, 25284784); no similar indels were observed in controls. A maternally-inherited frameshift variant in this gene was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. An intronic polymorphism in the KMT2E gene (rs111931861) that was determined by Hi-C analysis to be a loss-of-function variant was found to be the index variant for a genome-wide significant locus (P = 3.53E-08) identified in a combined analysis of 18,381 ASD cases and 27,969 controls from iPSYCH and the Psychiatric Genomic Consortium (PGC) and five cohorts of European ancestry including a total of 2,119 additional ASD cases and 142,379 controls (Grove et al., 2019). A study including 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and three previously reported in ASD probands from the Simons Simplex Collection and the Autism Clinical and Genetic Resources in China cohort) and four individuals with microdeletions encompassing KMT2E identified a neurodevelopmental disorder characterized by developmental delay, intellectual disability, epilepsy, hypotonia, and either microcephaly or macrocephaly; a quarter of the 38 individuals in this cohort met criteria for autism spectrum disorder (ODonnell-Luria et al., 2019).

4/1/2019
3
icon
3

Decreased from 3 to 3

Description

De novo loss-of-function frameshift variants in the KMT2E gene have been identified in two unrelated ASD cases from the Simons Simplex Collection (PMIDs 22542183, 25284784); no similar indels were observed in controls. An intronic polymorphism in the KMT2E gene (rs111931861) that was determined by Hi-C analysis to be a loss-of-function variant was found to be the index variant for a genome-wide significant locus (P = 3.53E-08) identified in a combined analysis of 18,381 ASD cases and 27,969 controls from iPSYCH and the Psychiatric Genomic Consortium (PGC) and five cohorts of European ancestry including a total of 2,119 additional ASD cases and 142,379 controls (Grove et al., 2019).

1/1/2019
3
icon
3

Decreased from 3 to 3

Description

De novo loss-of-function frameshift variants in the KMT2E gene have been identified in two unrelated ASD cases from the Simons Simplex Collection (PMIDs 22542183, 25284784); no similar indels were observed in controls. An intronic polymorphism in the KMT2E gene (rs111931861) that was determined by Hi-C analysis to be a loss-of-function variant was found to be the index variant for a genome-wide significant locus (P = 3.53E-08) identified in a combined analysis of 18,381 ASD cases and 27,969 controls from iPSYCH and the Psychiatric Genomic Consortium (PGC) and five cohorts of European ancestry including a total of 2,119 additional ASD cases and 142,379 controls (Grove et al., 2019).

10/1/2018
3
icon
3

Decreased from 3 to 3

Description

De novo loss-of-function frameshift variants in the KMT2E gene have been identified in two unrelated ASD cases from the Simons Simplex Collection (PMIDs 22542183, 25284784); no similar indels were observed in controls.

10/1/2016
3
icon
3

Decreased from 3 to 3

Description

De novo loss-of-function frameshift variants in the KMT2E gene have been identified in two unrelated ASD cases from the Simons Simplex Collection (PMIDs 22542183, 25284784); no similar indels were observed in controls.

10/1/2014
icon
3

Increased from to 3

Description

De novo loss-of-function frameshift variants in the KMT2E gene have been identified in two unrelated ASD cases from the Simons Simplex Collection (PMIDs 22542183, 25284784); no similar indels were observed in controls.

Krishnan Probability Score

Score 0.49276089427939

Ranking 4417/25841 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 0.99999999470269

Ranking 125/18225 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 0.055167939906483

Ranking 48/18665 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 22

Ranking 92/461 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CDK11B cyclin-dependent kinase 11B Human Protein Binding 984 P21127
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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