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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.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
Clinical exome sequencing: results from 2819 samples reflecting 1000 families.
Wiedemann-Steiner syndrome
DD, ID
Support
A novel deletion mutation in KMT2A identified in a child with ID/DD and blood eosinophilia.
DD, ID
Stereotypies
Support
De novo mutations in MLL cause Wiedemann-Steiner syndrome.
Wiedemann-Steiner syndrome
DD, ID, ASD
Support
High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.
Wiedemann-Steiner syndrome
ID
Support
Description of the molecular and phenotypic spectrum of Wiedemann-Steiner syndrome in Chinese patients.
Wiedemann-Steiner syndrome
Support
Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.
ID
Support
Molecular and cellular issues of KMT2A variants involved in Wiedemann-Steiner syndrome.
Wiedemann-Steiner syndrome
ID, hypotonia, stereotypies
Support
Congenital immunodeficiency in an individual with Wiedemann-Steiner syndrome due to a novel missense mutation in KMT2A.
Wiedemann-Steiner syndrome
Epilepsy/seizures, microcephaly, DD, ID
Support
Exome Pool-Seq in neurodevelopmental disorders.
ID
Support
Whole exome sequencing reveals a MLL de novo mutation associated with mild developmental delay and without 'hairy elbows': expanding the phenotype ...
Wiedemann-Steiner syndrome
DD
Support
Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.
Congenital heart disease (CHD)
Neurodevelopmental disorders (NDD)
Support
Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations.
Wiedemann-Steiner syndrome
DD, ID
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.
ASD
Support
Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.
Microcephaly
DD
Support
The contribution of de novo coding mutations to autism spectrum disorder.
ASD
Recent Recommendation
Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants.
Wiedemann-Steiner syndrome
ASD, ID, ADHD
Recent Recommendation
Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.
Wiedemann-Steiner syndrome
ASD
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission.
ASD
Recent Recommendation
Large-scale discovery of novel genetic causes of developmental disorders.
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN700R001 
 frameshift_variant 
 del(C) 
  
 De novo 
  
 Simplex 
 GEN700R002 
 missense_variant 
 c.2944T>A 
 p.Ser982Thr 
 De novo 
  
  
 GEN700R003 
 frameshift_variant 
 del(G) 
  
 De novo 
  
 Simplex 
 GEN700R004 
 stop_gained 
 c.6571C>T 
 p.Arg2191Ter 
 De novo 
  
 Simplex 
 GEN700R005 
 stop_gained 
 c.2758G>T 
 p.Glu920Ter 
 De novo 
  
 Simplex 
 GEN700R006 
 frameshift_variant 
 c.10234dupT 
 p.Tyr3412LeufsTer22 
 De novo 
  
 Simplex 
 GEN700R007 
 frameshift_variant 
 c.2124_2125delCT 
 p.Ser709Ter 
 De novo 
  
  
 GEN700R008 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN700R009 
 frameshift_variant 
 c.8806_8809delGTCT 
 p.Val2936Ter 
 De novo 
  
 Simplex 
 GEN700R010 
 frameshift_variant 
 c.8267delT 
 p.Leu2756Ter 
 De novo 
  
 Simplex 
 GEN700R011 
 frameshift_variant 
 c.6913delT 
 p.Ser2305LeufsTer2 
 De novo 
  
 Simplex 
 GEN700R012 
 stop_gained 
 c.7144C>T 
 p.Arg2382Ter 
 De novo 
  
 Simplex 
 GEN700R013 
 frameshift_variant 
 c.4599dup 
 p.Lys1534Ter 
 De novo 
  
 Simplex 
 GEN700R014 
 stop_gained 
 c.7438C>T 
 p.Arg2480Ter 
 De novo 
  
  
 GEN700R015 
 stop_gained 
 c.6781C>T 
 p.Gln2261Ter 
 De novo 
  
  
 GEN700R016 
 missense_variant 
 c.3566G>A 
 p.Cys1189Tyr 
 De novo 
  
  
 GEN700R017 
 missense_variant 
 c.838C>A 
 p.Pro280Thr 
 Unknown 
  
  
 GEN700R018 
 frameshift_variant 
 c.1038delA 
 p.Val347LeufsTer53 
 De novo 
  
  
 GEN700R019 
 frameshift_variant 
 c.2148delC 
 p.Leu717CysfsTer39 
 De novo 
  
  
 GEN700R020 
 stop_gained 
 c.4897C>T 
 p.Arg1633Ter 
 De novo 
  
  
 GEN700R021 
 missense_variant 
 c.8531G>T 
 p.Cys2844Phe 
 De novo 
  
  
 GEN700R022 
 frameshift_variant 
 c.2461dup 
 p.Ser821fs 
 De novo 
  
  
 GEN700R023 
 missense_variant 
 c.3481T>G 
 p.Cys1161Gly 
 De novo 
  
  
 GEN700R024 
 frameshift_variant 
 c.6533_6534insA 
 p.Val2179fs 
 De novo 
  
  
 GEN700R025 
 frameshift_variant 
 c.9682_9682delC 
 p.Arg3228fs 
 De novo 
  
  
 GEN700R026 
 missense_variant 
 c.3473G>A 
 p.Cys1158Thr 
 De novo 
  
 Simplex 
 GEN700R027 
 stop_gained 
 c.5251A>T 
 p.Lys1751Ter 
 De novo 
  
 Simplex 
 GEN700R028 
 stop_gained 
 c.10780C>T 
 p.Gln3594Ter 
 De novo 
  
  
 GEN700R029 
 frameshift_variant 
 c.6158delG;c.6167delG 
 p.Arg2053fs;p.Arg2056fs 
 De novo 
  
  
 GEN700R030 
 frameshift_variant 
 c.7686_7687del;c.7695_7696del 
 p.Ser2562fs;p.Ser2565fs 
 De novo 
  
  
 GEN700R031 
 frameshift_variant 
 c.4205_4206insAGTGGACTTTAAGGTAAAGGTGTTCAGTGATCAT 
 p.Arg1402fs 
 Unknown 
  
  
 GEN700R032 
 frameshift_variant 
 delA 
 p.Arg1927fs 
 De novo 
  
  
 GEN700R033 
 splice_site_variant 
 c.3334+1G>A 
 p.? 
 De novo 
  
  
 GEN700R034 
 missense_variant 
 c.3460C>T 
 p.Arg1154Trp 
 De novo 
  
  
 GEN700R035 
 missense_variant 
 c.8558T>G 
 p.Met2853Arg 
 De novo 
  
  
 GEN700R036 
 missense_variant 
 c.3581G>A 
 p.Cys1194Tyr 
 De novo 
  
  
 GEN700R037 
 splice_site_variant 
 c.11322-1G>A 
 p.Lys3775SerfsTer32 
 De novo 
  
  
 GEN700R038 
 stop_gained 
 c.7975C>T 
 p.Arg2659Ter 
 De novo 
  
  
 GEN700R039 
 stop_gained 
 c.3301C>T 
 p.Arg1101Ter 
 De novo 
  
  
 GEN700R040 
 stop_gained 
 c.269C>A 
 p.Ser90Ter 
 De novo 
  
  
 GEN700R041 
 stop_gained 
 c.4897C>T 
 p.Arg1633Ter 
 De novo 
  
  
 GEN700R042 
 stop_gained 
 c.6487C>T 
 p.Arg2163Ter 
 De novo 
  
  
 GEN700R043 
 stop_gained 
 c.7630G>T 
 p.Glu2544Ter 
 De novo 
  
  
 GEN700R044 
 stop_gained 
 c.7438C>T 
 p.Arg2480Ter 
 De novo 
  
  
 GEN700R045 
 stop_gained 
 c.478C>T 
 p.Arg160Ter 
 De novo 
  
  
 GEN700R046 
 frameshift_variant 
 c.6002_6005del 
 p.Phe2001TrpfsTer8 
 De novo 
  
  
 GEN700R047 
 frameshift_variant 
 c.9714_9735del 
 p.Pro3239LeufsTer10 
 De novo 
  
  
 GEN700R048 
 frameshift_variant 
 c.1142dup 
 p.Ala383GlyfsTer6 
 De novo 
  
  
 GEN700R049 
 frameshift_variant 
 c.4012del 
 p.Gly1338ValfsTer18 
 De novo 
  
  
 GEN700R050 
 frameshift_variant 
 c.5603del 
 p.Pro1868GlnfsTer3 
 De novo 
  
  
 GEN700R051 
 frameshift_variant 
 c.654_679delinsT 
 p.Glu219LeufsTer27 
 De novo 
  
  
 GEN700R052 
 frameshift_variant 
 c.8174_8177del 
 p.Glu2725ValfsTer22 
 De novo 
  
  
 GEN700R053 
 frameshift_variant 
 c.4032delG 
 p.Val1347TrpfsTer9 
 De novo 
  
  
 GEN700R054 
 frameshift_variant 
 c.4667_4668del 
 p.Cys1556SerfsTer2 
 De novo 
  
  
 GEN700R055 
 frameshift_variant 
 c.2318dupC 
 p.Ser774ValfsTer12 
 De novo 
  
  
 GEN700R056 
 frameshift_variant 
 c.8270dup 
 p.Ile2758AspfsTer2 
 De novo 
  
  
 GEN700R057 
 frameshift_variant 
 c.3895_3896del 
 p.Ser1299ProfsTer26 
 De novo 
  
  
 GEN700R058 
 missense_variant 
 c.10850T>C 
 p.Leu3617Pro 
 Familial 
 Maternal 
 Multi-generational 
 GEN700R059 
 missense_variant 
 c.9440C>T 
 p.Ser3147Phe 
 Familial 
 Maternal 
 Multi-generational 
 GEN700R060 
 missense_variant 
 c.3460C>T 
 p.Arg1154Trp 
 De novo 
  
  
 GEN700R061 
 missense_variant 
 c.3464G>A 
 p.Cys1155Tyr 
 De novo 
  
  
 GEN700R062 
 missense_variant 
 c.3542G>A 
 p.Gly1181Asp 
 De novo 
  
  
 GEN700R063 
 missense_variant 
 c.3460C>T 
 p.Arg1154Trp 
 Familial 
 Paternal 
 Multiplex 
 GEN700R064 
 missense_variant 
 c.2618G>T 
 p.Ser873Asn 
 De novo 
  
  
 GEN700R065 
 missense_variant 
 c.6080G>A 
 p.Gly2027Glu 
 De novo 
  
  
 GEN700R066 
 missense_variant 
 c.5873A>G 
 p.His1958Arg 
 De novo 
  
  
 GEN700R067 
 splice_site_variant 
 c.4696+1G>A 
 p.? 
 De novo 
  
  
 GEN700R068 
 frameshift_variant 
 c.2318dup 
 p.Ser774ValfsTer12 
 De novo 
  
  
 GEN700R069 
 frameshift_variant 
 c.3837delT 
 p.Pro1281LeufsTer75 
 De novo 
  
  
 GEN700R070 
 frameshift_variant 
 c.10752dupA 
 p.Gly3585ArgfsTer8 
 De novo 
  
  
 GEN700R071 
 frameshift_variant 
 c.2318dupC 
 p.Ser774ValfsTer12 
 De novo 
  
  
 GEN700R072 
 missense_variant 
 c.11716C>T 
 p.Arg3906Cys 
 De novo 
  
  
 GEN700R073 
 missense_variant 
 c.3503G>A 
 p.Gly1168Asp 
 De novo 
  
  
 GEN700R074 
 stop_gained 
 c.3241C>T 
 p.Arg1081Ter 
 De novo 
  
  
 GEN700R075 
 frameshift_variant 
 c.2318dupC 
 p.Ser774ValfsTer12 
 De novo 
  
  
 GEN700R076 
 splice_site_variant 
 c.10900+2T>C 
 p.? 
 De novo 
  
  
 GEN700R077 
 stop_gained 
 c.10837C>T 
 p.Gln3613Ter 
 Unknown 
  
  
 GEN700R078 
 stop_gained 
 c.5871T>A 
 p.Tyr1957Ter 
 De novo 
  
  
 GEN700R079 
 frameshift_variant 
 c.4059delC 
 p.Pro1354LeufsTer2 
 De novo 
  
  
 GEN700R080 
 frameshift_variant 
 c.6052delG 
 p.Glu2018fsTer7 
 De novo 
  
  
 GEN700R081 
 stop_gained 
 c.901C>T 
 p.Arg301Ter 
 De novo 
  
  
 GEN700R082 
 frameshift_variant 
 c.2510dupC 
 p.Trp838llefsTer9 
 De novo 
  
  
 GEN700R083 
 frameshift_variant 
 c.74delG 
 p.Gly26AlafsTer2 
 De novo 
  
 Simplex 
 GEN700R084 
 frameshift_variant 
 c.8724del 
 p.Glu2908AspfsTer21 
 De novo 
  
 Simplex 
 GEN700R085 
 frameshift_variant 
 c.10324delG 
 p.Ala3442ProfsTer17 
 De novo 
  
  
 GEN700R086 
 frameshift_variant 
 c.7087_7090del 
 p.Ser2363LeufsTer12 
 De novo 
  
  
 GEN700R087 
 frameshift_variant 
 c.6169del 
 p.Val2057TyrfsTer18 
 De novo 
  
  
 GEN700R088 
 frameshift_variant 
 c.7695_7696del 
 p.Glu2566LysfsTer14 
 De novo 
  
  
 GEN700R089 
 missense_variant 
 c.8543T>C 
 p.Leu2848Pro 
 De novo 
  
  
 GEN700R090 
 stop_gained 
 c.8095C>T 
 p.Arg2699Ter 
 De novo 
  
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Duplication
 1
 
11
Duplication
 1
 
11
Duplication
 1
 
11
Deletion-Duplication
 15
 
11
Deletion
 5
 

Model Summary

Kmt2a null mutation is embryonic lethal, heterozygous mice have impaired growth and skeletal development. Kmt2a conditional knockout in forebrain neurons causes mutant mice have increased locomotor activity in the dark and changes in synaptic plasticity in the nucleus accumbens.

References

Type
Title
Author, Year
Additional
Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal.
Primary
Neuronal Deletion of Kmt2a/Mll1 Histone Methyltransferase in Ventral Striatum is Associated with Defective Spike-Timing-Dependent Striatal Synaptic...

M_KMT2A_3_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Mutant mice were generated in which truncation of exon 1-5 of Kmt2a (Mll) was achieved by integrating stop codons in exon 5 followed by an IRES-lacZ reporter with stop codons in all three reading frames in the targeting vector, followed by homologous recombination in ES cells. Authors note that the truncated protein might retain some function as the three truncated isoforms were present in tissues (one of them containing the AT Hook and the DMT domains). Following generation of chimaeras and germline transmission, heterozygous mice were mated to homozygosity.
Allele Type: Targeted (knockout)
Strain of Origin:
Genetic Background: C57Bl/6
ES Cell Line: RI and GK129
Mutant ES Cell Line:
Model Source: PMID: 11536426

M_KMT2A_1_CKO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of exon 3 of the Kmt2a gene (alias Mll1) using CamkII-cre, in excitatory neurons of the forebrain
Allele Type: Conditional loss-of-function
Strain of Origin: 129S2/SvPas
Genetic Background: 129S2/SvPas*C57BL/6*SJL
ES Cell Line:
Mutant ES Cell Line:
Model Source: PMID: 27485686

M_KMT2A_2_CKO_HM_VStr

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of exon 3 of the Kmt2a gene using AAV-cre under synapsin I promoter, stereotactically injected into the ventral striatum in adults (>10 weeks) leading to loss from ventral striatal neurons. Experiments were performed at least 2 weeks after surgery.
Allele Type: Conditional loss-of-function
Strain of Origin: 129S2/SvPas
Genetic Background: 129S2/SvPas*C57BL/6*SJL
ES Cell Line:
Mutant ES Cell Line:
Model Source: PMID: 27485686

M_KMT2A_3_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Mortality/lethality: embryonic1
Increased
Description: No homozygotes survive till birth and no homozygous embryos are detected even at E3.5 or E1.5 indicating early preimplantation embryonic lethality
 Survival analysis
 E1.5, E3.5, P21
Cell differentiation: hematopoiesis1
Decreased
Description: Mutants have two fold reduction in fetal liver cellularity and a four fold reduction in long-term hematopoietic stem cells (progenitor pool)
 Flow cytometric analysis
 E14.5
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Homeostasis, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Repetitive behavior, Seizure, Sensory, Social behavior

M_KMT2A_1_CKO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Locomotor activity in diurnal cycle: dark phase1
Increased
Description: Kmt2a CKO mice have increased locomotor activity during the dark (active) cycle indicative of altered dopaminergic signaling
 Home cage behavior
 P80-100
Synaptic plasticity: striatal LTP1
Decreased
Description: Conditional knockout of Kmt2a from forebrain neurons specifically decreased action potential (spike) timing dependent long-term potentiation in the ventral striatum- nucleus accumbens (only 1 out of 12 neurons recorded showed LTP) compared to 50% of neurons recorded from controls
 Spike-timing-dependent stimulation
 P80-100
Targeted expression1
Decreased
Description: Kmt2a protein expression is immunoreactivity and Kmt2a RNA expression reduced in the telencephalon
 Immunohistochemistry
 P18
Brain morphology1
 No Change
 Histology: Histology
 P80-100
Synaptic plasticity: striatal LTD1
 No Change
 Whole-cell patch clamp
 P80-100
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Homeostasis, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Repetitive behavior, Seizure, Sensory, Social behavior

M_KMT2A_2_CKO_HM_VStr

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Anxiety1
Increased
Description: Deletion of Kmt2a selectively from ventral striatal neurons leads in adult mice leads to increased anxiety in all measures from tests conducted on these mice including time in the dark compartment in the light-dark exploration test, reduced time spent in the center of the open field test, reduced time in open arms of the elevated plus maze, compared to control or Mll2 conditional knockout mice (used as an additional control)
Exp Paradigm:  Elevated plus maze test
 Elevated plus maze test
 12-13 weeks
Anxiety1
Increased
Description: Deletion of Kmt2a selectively from ventral striatal neurons leads in adult mice leads to increased anxiety in all measures from tests conducted on these mice including time in the dark compartment in the light-dark exploration test, reduced time spent in the center of the open field test, reduced time in open arms of the elevated plus maze, compared to control or Mll2 conditional knockout mice (used as an additional control)
Exp Paradigm: Light-dark exploration test
 Light-dark exploration test: Light-dark exploration test
 12-13 weeks
Anxiety1
Increased
Description: Deletion of Kmt2a selectively from ventral striatal neurons leads in adult mice leads to increased anxiety in all measures from tests conducted on these mice including time in the dark compartment in the light-dark exploration test, reduced time spent in the center of the open field test, reduced time in open arms of the elevated plus maze, compared to control or Mll2 conditional knockout mice (used as an additional control)
Exp Paradigm:  Open field test
 Open field test
 12-13 weeks
Depression1
 No Change
 Forced swim test
 12-13 weeks
Depression1
 No Change
 Tail suspension test
 12-13 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Homeostasis, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Repetitive behavior, Seizure, Sensory, Social behavior


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
ASH2L ash2 (absent, small, or homeotic)-like (Drosophila) 9070 Q9UBL3 Co-crystal structure; in vitro binding assay; Fluorescence Polarization (FP)
Li Y , et al. 2016
RBBP5 retinoblastoma binding protein 5 5929 Q15291 Co-crystal structure; in vitro binding assay; Fluorescence Polarization (FP)
Li Y , et al. 2016
TOP3B topoisomerase (DNA) III beta 8940 O95985 HITS-CLIP
Xu D , et al. 2013

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