Human Gene Module / Chromosome 11 / KMT2A

KMT2ALysine (K)-specific methyltransferase 2A

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
5 / 16
Rare Variants / Common Variants
68 / 0
Aliases
KMT2A, hCG_1732268,  ALL-1,  CXXC7,  HRX,  HTRX1,  MLL,  MLL/GAS7,  MLL1,  MLL1A,  TET1-MLL,  TRX1,  WDSTS
Associated Syndromes
Wiedemann-Steiner syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
11q23.3
Associated Disorders
EP, ASD, EPS, DD/NDD, ID
Relevance to Autism

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in Jones et al., 2012 (PMID 22795537). Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in this gene have also been identified in additional individuals presenting with developmental delay/intellectual disability (PMIDs 25533962, 27479843, 27848944)

Molecular Function

This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis via its histone H3 lysine 4 (H3K4) methyltransferase activity, which mediates chromatin modifications associated with epigenetic transcriptional activation. Mutations in this gene are associated with Wiedemann-Steiner syndrome (OMIM:605130), a syndrome characterized by hairy elbows (hypertrichosis cubiti), intellectual disability, a distinctive facial appearance, and short stature.

Reports related to KMT2A (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo mutations in MLL cause Wiedemann-Steiner syndrome. Jones WD , et al. (2012) No DD, ID, ASD
2 Primary Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
4 Recent Recommendation Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) Yes -
5 Support Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations. Miyake N , et al. (2015) No DD, ID
6 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
7 Support Whole exome sequencing reveals a MLL de novo mutation associated with mild developmental delay and without 'hairy elbows': expanding the phenotype ... Steel D , et al. (2015) No DD
8 Support Congenital immunodeficiency in an individual with Wiedemann-Steiner syndrome due to a novel missense mutation in KMT2A. Stellacci E , et al. (2016) No Epilepsy/seizures, microcephaly, DD, ID
9 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
10 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. Martnez F , et al. (2016) No ID
11 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No DD, ID
12 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
13 Support Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Jin SC , et al. (2017) No Neurodevelopmental disorders (NDD)
14 Support Exome Pool-Seq in neurodevelopmental disorders. Popp B , et al. (2017) No -
15 Support Molecular and cellular issues of KMT2A variants involved in Wiedemann-Steiner syndrome. Lebrun N , et al. (2017) No ID, hypotonia, stereotypies
16 Recent Recommendation Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases. Baer S , et al. (2018) No ASD
Rare Variants   (68)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.8806_8809delGTCT p.Val2936Ter frameshift_variant De novo - Simplex 22795537 Jones WD , et al. (2012)
c.8267delT p.Leu2756Ter frameshift_variant De novo - Simplex 22795537 Jones WD , et al. (2012)
c.6913delT p.Ser2305LeufsTer2 frameshift_variant De novo - Simplex 22795537 Jones WD , et al. (2012)
c.7144C>T p.Arg2382Ter stop_gained De novo - Simplex 22795537 Jones WD , et al. (2012)
c.4599dup p.Lys1534Ter frameshift_variant De novo - Simplex 22795537 Jones WD , et al. (2012)
del(C) - frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2944T>A p.Ser982Thr missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
del(G) - frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.6571C>T p.Arg2191Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2758G>T p.Glu920Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.10234dupT p.Tyr3412LeufsTer22 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.2124_2127delCTCTinsCT p.Ser709Ter frameshift_variant De novo - - 25533962 Deciphering Developmental Disorders Study (2014)
- - copy_number_loss De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.7438C>T p.Arg2480Ter stop_gained De novo - - 25810209 Miyake N , et al. (2015)
c.6781C>T p.Gln2261Ter stop_gained De novo - - 25810209 Miyake N , et al. (2015)
c.3566G>A p.Cys1189Tyr missense_variant De novo - - 25810209 Miyake N , et al. (2015)
c.838C>A p.Pro280Thr missense_variant Unknown - - 25810209 Miyake N , et al. (2015)
c.1038delA p.Val347LeufsTer53 frameshift_variant De novo - - 25810209 Miyake N , et al. (2015)
c.2148delC p.Leu717CysfsTer39 frameshift_variant De novo - - 25810209 Miyake N , et al. (2015)
c.4897C>T p.Arg1633Ter stop_gained De novo - - 26690532 Steel D , et al. (2015)
c.3481T>G p.Cys1161Gly missense_variant De novo - - 27320412 Stellacci E , et al. (2016)
c.8531G>T p.Cys2844Phe missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.2461dup p.Ser821fs frameshift_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.6533_6534insA p.Val2179fs frameshift_variant De novo - - 27620904 Martnez F , et al. (2016)
c.9682_9682delC p.Arg3228fs frameshift_variant De novo - - 27620904 Martnez F , et al. (2016)
c.3473G>A p.Cys1158Thr missense_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.5251A>T p.Lys1751Ter stop_gained De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.10780C>T p.Gln3594Ter stop_gained De novo - - 27848944 Trujillano D , et al. (2016)
c.6158delG;c.6167delG p.Arg2053fs;p.Arg2056fs frameshift_variant De novo - - 28263302 C Yuen RK , et al. (2017)
c.7686_7687del;c.7695_7696del p.Ser2562fs;p.Ser2565fs frameshift_variant De novo - - 28263302 C Yuen RK , et al. (2017)
c.4205_4206insAGTGGACTTTAAGGTAAAGGTGTTCAGTGATCAT p.Arg1402fs frameshift_variant Unknown - - 28263302 C Yuen RK , et al. (2017)
delA p.Arg1927fs frameshift_variant De novo - - 28991257 Jin SC , et al. (2017)
c.3334+1G>A p.? splice_site_variant De novo - - 29158550 Popp B , et al. (2017)
c.3460C>T p.Arg1154Trp missense_variant De novo - - 29203834 Lebrun N , et al. (2017)
c.8558T>G p.Met2853Arg missense_variant De novo - - 29203834 Lebrun N , et al. (2017)
c.3581G>A p.Cys1194Tyr missense_variant De novo - - 29203834 Lebrun N , et al. (2017)
c.11322-1G>A p.Lys3775SerfsTer32 splice_site_variant De novo - - 29203834 Lebrun N , et al. (2017)
c.7975C>T p.Arg2659Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.3301C>T p.Arg1101Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.269C>A p.Ser90Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.4897C>T p.Arg1633Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.6487C>T p.Arg2163Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.7630G>T p.Glu2544Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.7438C>T p.Arg2480Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.478C>T p.Arg160Ter stop_gained De novo - - 29574747 Baer S , et al. (2018)
c.6002_6005del p.Phe2001TrpfsTer8 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.9714_9735del p.Pro3239LeufsTer10 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.1142dup p.Ala383GlyfsTer6 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.4012del p.Gly1338ValfsTer18 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.5603del p.Pro1868GlnfsTer3 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.654_679delinsT p.Glu219LeufsTer27 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.8174_8177del p.Glu2725ValfsTer22 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.4032delG p.Val1347TrpfsTer9 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.4667_4668del p.Cys1556SerfsTer2 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.2318dupC p.Ser774ValfsTer12 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.8270dup p.Ile2758AspfsTer2 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.3895_3896del p.Ser1299ProfsTer26 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
c.10850T>C p.Leu3617Pro missense_variant Familial Maternal Multi-generational 29574747 Baer S , et al. (2018)
c.9440C>T p.Ser3147Phe missense_variant Familial Maternal Multi-generational 29574747 Baer S , et al. (2018)
c.3460C>T p.Arg1154Trp missense_variant De novo - - 29574747 Baer S , et al. (2018)
c.3464G>A p.Cys1155Tyr missense_variant De novo - - 29574747 Baer S , et al. (2018)
c.3542G>A p.Gly1181Asp missense_variant De novo - - 29574747 Baer S , et al. (2018)
c.3460C>T p.Arg1154Trp missense_variant Familial Paternal Multiplex 29574747 Baer S , et al. (2018)
c.2618G>T p.Ser873Asn missense_variant De novo - - 29574747 Baer S , et al. (2018)
c.6080G>A p.Gly2027Glu missense_variant De novo - - 29574747 Baer S , et al. (2018)
c.5873A>G p.His1958Arg missense_variant De novo - - 29574747 Baer S , et al. (2018)
c.4696+1G>A p.? splice_site_variant De novo - - 29574747 Baer S , et al. (2018)
c.2318dup p.Ser774ValfsTer12 frameshift_variant De novo - - 29574747 Baer S , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

1S

Score Delta: Score remained at 1.1 + S

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.

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."

10/1/2017
1S
icon
1S

Score remained at 1S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in Jones et al., 2012 (PMID 22795537). Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017 (PMID 28263302). Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in this gene have also been identified in additional individuals presenting with developmental delay/intellectual disability (PMIDs 25533962, 27479843, 27848944)

4/1/2017
2S
icon
1S

Decreased from 2S to 1S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in PMID 22795537. Two additional de novo LoF variants in KMT2A were identified in ASD probands from the ASD: Genomes to Outcome Study cohort in Yuen et al., 2017. Based on multiple de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), KMT2A was determined to be an ASD candidate gene in Yuen et al., 2017.

10/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in PMID 22795537.

7/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in PMID 22795537.

1/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in PMID 22795537.

4/1/2015
2S
icon
2S

Decreased from 2S to 2S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in PMID 22795537.

1/1/2015
icon
2S

Increased from to 2S

Description

De novo loss-of-function variants in the KMT2A gene have been identified in ASD probands from three independent case cohorts: one from the Autism Sequencing Consortium (PMID 25363760), the second from the Simons Simplex Collection (PMID 25363768), and the third from the Deciphering Developmental Disorders Study (PMID 25533962). De novo mutations in this gene are also responsible for Wiedemann-Steiner syndrome (OMIM 605130), a disorder characterized by intellectual disability, excessive growth of terminal hair around the elbows (hypertrichosis cubiti), short stature, and a distinct facial appearance; autism was noted in 2/6 individuals with this syndrome in PMID 22795537.

Krishnan Probability Score

Score 0.61112172006711

Ranking 205/25841 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 1

Ranking 9/18225 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
Iossifov Probability Score

Score 0.999

Ranking 4/239 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
Sanders TADA Score

Score 0.18886989801149

Ranking 105/18665 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).
CNVs associated with KMT2A(1 CNVs)
11q23.3 14 Deletion-Duplication 26  /  40
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