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 / 12
Rare Variants / Common Variants
31 / 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 identifed in three ASD probands from independent case cohorts: one from the Simons Simplex Collection (Iossifov et al., 2014), the second from the Autism Sequencing Consortium (De Rubeis et al., 2014), and the third from the Deciphering Developmental Disorders Study (Fitzgerald et al., 2014).

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; autism was noted in 2 out of 6 individuals with this syndrome in Jones et al., 2012.

Reports related to KMT2A (12 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 cases)
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 -
Rare Variants   (31)
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_2127​delCTCT​insCT 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)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

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.

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."

04-01-2017
1S

Initial score established: 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.

CNVs associated with KMT2A(1 CNVs)
11q23.3 13 Deletion-Duplication 24  /  36
Animal Models associated with KMT2A(3 Models)
KMT2A_1_CKO_HM Genetic
KMT2A_2_CKO_HM Genetic
KMT2A_3_KO_HM Genetic
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