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Relevance to Autism

A de novo LoF variant in the KMT2C gene was identified in an ASD proband from the Simon Simplex Collection (PMIDs 22495309), while a second de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified KMT2C as a gene meeting high statistical significance with a 0.01 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760). Additional de novo probably damaging missense variants in KMT2C were identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014; Krumm et al., 2015). A de novo LoF variant in KMT2C was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015). Koemans et al., 2017 identified four patients with intellectual disability, language delay, and motor delay that carried de novo LoF variants in the KMT2C gene; two of these patients presented with autism, one patient presented with PDD-NOS, and one presented with autistic traits. Three de novo variants (two protein-truncating variants, one missense variant) were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified KMT2C as a candidate gene with a false discovery rate (FDR) 0.01. Additional de novo loss-of-function variants and potentially damaging missense variants in the KMT2C gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified KMT2C as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

Histone methyltransferase that methylates 'Lys-4' of histone H3; H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. Central component of the MLL2/3 complex, a coactivator complex of nuclear receptors, involved in transcriptional coactivation. KMT2C/MLL3 may be a catalytic subunit of this complex.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
ASD
Support
Diagnostic findings and yield of investigations for children with developmental regression
Developmental regression
ASD, ID
Support
Trio-based exome sequencing reveals a high rate of the de novo variants in intellectual disability
ASD, ID
Support
De novo genic mutations among a Chinese autism spectrum disorder cohort.
ASD
Support
ASD, DD, ID
Support
Mutations in ASH1L confer susceptibility to Tourette syndrome.
TS
Support
Novel germline variants in KMT2C in Chinese patients with Kleefstra syndrome-2
Kleefstra syndrome 2, DD, ID
ASD, ADHD
Support
Analysis of recent shared ancestry in a familial cohort identifies coding and noncoding autism spectrum disorder variants
ASD
Support
The Contribution of Mosaic Variants to Autism Spectrum Disorder.
ASD
Support
Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
ASD
Support
Identification of two novel autism genes, TRPC4 and SCFD2, in Qatar simplex families through exome sequencing
ASD
DD, ID
Support
Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings
ASD
Support
Excess of rare, inherited truncating mutations in autism.
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Support
Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
DD
ASD, microcephaly
Support
ASD
DD, ID
Support
De novo variants in neurodevelopmental disorders-experiences from a tertiary care center
DD, ID
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort
DD
Autistic behavior
Support
Impaired Neurodevelopmental Genes in Slovenian Autistic Children Elucidate the Comorbidity of Autism With Other Developmental Disorders
ADHD, DD
Autistic behavior
Support
Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.
ASD
Support
Exploring the biological role of postzygotic and germinal de novo mutations in ASD
ASD
Support
Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability.
ID
Support
Whole genome sequencing analysis identifies sex differences of familial pattern contributing to phenotypic diversity in autism
ASD
Support
Genetic and Phenotype Analysis of a Chinese Cohort of Infants and Children With Epilepsy
Epilepsy/seizures
ID
Support
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD
Support
Utility of clinical exome sequencing in a complex Emirati pediatric cohort
DD
Support
Experience of the first adult-focussed undiagnosed disease program in Australia (AHA-UDP): solving rare and puzzling genetic disorders is ageless
ID
Support
De Novo Mutation in KMT2C Manifesting as Kleefstra Syndrome 2: Case Report and Literature Review
Kleefstra syndrome 2, ASD, DD, ID
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD
Support
ASD
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Recent Recommendation
De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.
Congenital heart disease (CHD)
ASD, DD
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission.
ASD
Recent Recommendation
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Recent recommendation
Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes
DD, cognitive impairment
ASD or autistic features, ADHD or features of ADHD
Recent Recommendation
Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor
ASD, Kleefstra syndrome 2
Recent recommendation
Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype.
Kleefstra syndrome
Recent Recommendation
Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder.
ID
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN659R001 
 stop_gained 
 c.14073C>A 
 p.Tyr4691Ter 
 De novo 
  
 Simplex 
 GEN659R002 
 frameshift_variant 
 c.2694del 
 p.Ala899GlnfsTer14 
 De novo 
  
 Simplex 
 GEN659R003 
 missense_variant 
 c.13761G>C 
 p.Trp4587Cys 
 De novo 
  
 Simplex 
 GEN659R004 
 missense_variant 
 c.3373C>T 
 p.Pro1125Ser 
 Familial 
 Maternal 
 Simplex 
 GEN659R006 
 missense_variant 
 c.6275A>T 
 p.Asp2092Val 
 Familial 
 Maternal 
 Simplex 
 GEN659R008 
 missense_variant 
 c.1252C>T 
 p.Leu418Phe 
 Familial 
 Maternal 
 Simplex 
 GEN659R009 
 missense_variant 
 c.11662T>G 
 p.Leu3888Val 
 Familial 
 Paternal 
 Simplex 
 GEN659R010 
 missense_variant 
 c.6136C>G 
 p.Pro2046Ala 
 Familial 
 Maternal 
 Simplex 
 GEN659R012 
 missense_variant 
 c.5006C>G 
 p.Pro1669Arg 
 Familial 
 Paternal 
 Simplex 
 GEN659R013 
 missense_variant 
 c.6720A>C 
 p.Arg2240Ser 
 Familial 
 Paternal 
 Simplex 
 GEN659R014 
 missense_variant 
 c.14621G>A 
 p.Arg4874Gln 
 Familial 
 Paternal 
 Simplex 
 GEN659R015 
 missense_variant 
 c.404G>A 
 p.Ser135Asn 
 Familial 
 Paternal 
 Simplex 
 GEN659R016 
 missense_variant 
 c.11486G>A 
 p.Gly3829Asp 
 Familial 
 Maternal 
 Simplex 
 GEN659R017 
 missense_variant 
 c.8342T>A 
 p.Ile2781Asn 
 Familial 
 Maternal 
 Simplex 
 GEN659R018 
 missense_variant 
 c.10102G>A 
 p.Gly3368Arg 
 Unknown 
  
 Unknown 
 GEN659R019 
 missense_variant 
 c.9530G>A 
 p.Arg3177His 
 Unknown 
  
 Unknown 
 GEN659R020 
 missense_variant 
 c.7787G>A 
 p.Arg2596Gln 
 Unknown 
  
 Unknown 
 GEN659R021 
 missense_variant 
 c.6985G>A 
 p.Gly2329Arg 
 Unknown 
  
 Unknown 
 GEN659R022 
 missense_variant 
 c.5006C>G 
 p.Pro1669Arg 
 Unknown 
  
 Unknown 
 GEN659R023 
 missense_variant 
 c.3782T>G 
 p.Val1261Gly 
 Unknown 
  
 Unknown 
 GEN659R024 
 missense_variant 
 c.9065C>T 
 p.Thr3022Ile 
 Unknown 
  
 Unknown 
 GEN659R025 
 missense_variant 
 c.8076T>A 
 p.Asp2692Glu 
 Unknown 
  
 Unknown 
 GEN659R026 
 missense_variant 
 c.6386A>G 
 p.Asp2129Gly 
 Unknown 
  
 Unknown 
 GEN659R027 
 missense_variant 
 c.6197G>A 
 p.Arg2066Gln 
 Unknown 
  
 Unknown 
 GEN659R028 
 missense_variant 
 c.6164A>T 
 p.Asp2055Val 
 Unknown 
  
 Unknown 
 GEN659R029 
 missense_variant 
 c.5180C>T 
 p.Pro1727Leu 
 Unknown 
  
 Unknown 
 GEN659R030 
 missense_variant 
 c.5171G>T 
 p.Ser1724Ile 
 Unknown 
  
 Unknown 
 GEN659R031 
 missense_variant 
 c.4775C>T 
 p.Ser1592Phe 
 Unknown 
  
 Unknown 
 GEN659R032 
 missense_variant 
 c.13298C>T 
 p.Ala4433Val 
 De novo 
  
 Simplex 
 GEN659R033 
 missense_variant 
 c.2861C>T 
 p.Thr954Ile 
 De novo 
  
 Simplex 
 GEN659R034 
 stop_gained 
 c.3358G>T 
 p.Glu1120Ter 
 De novo 
  
  
 GEN659R035 
 frameshift_variant 
 c.6592_6593del 
 p.Arg2198AlafsTer3 
 Unknown 
 Not maternal 
  
 GEN659R036 
 frameshift_variant 
 c.1378del 
 p.Tyr460ThrfsTer35 
 De novo 
  
 Multiplex 
 GEN659R037 
 splice_site_variant 
 c.7443dup 
 p.Phe2482IlefsTer7 
 Familial 
  
 Simplex 
 GEN659R038 
 stop_gained 
 c.3168G>A 
 p.Trp1056Ter 
 De novo 
  
 Simplex 
 GEN659R039 
 missense_variant 
 c.14416C>G 
 p.Arg4806Gly 
 De novo 
  
 Simplex 
 GEN659R040 
 frameshift_variant 
 c.5216del 
 p.Pro1739LeufsTer2 
 De novo 
  
  
 GEN659R041 
 stop_gained 
 c.7550C>G 
 p.Ser2517Ter 
 De novo 
  
  
 GEN659R042 
 stop_gained 
 c.1690A>T 
 p.Lys564Ter 
 De novo 
  
  
 GEN659R043 
 frameshift_variant 
 c.10812_10815del 
 p.Lys3605GlufsTer24 
 De novo 
  
  
 GEN659R044 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN659R045 
 stop_gained 
 c.4441C>T 
 p.Arg1481Ter 
 Unknown 
  
 Simplex 
 GEN659R046 
 stop_gained 
 c.4744G>T 
 p.Gly1582Ter 
 De novo 
  
  
 GEN659R047 
 frameshift_variant 
 c.8849_8850del 
 p.His2950ArgfsTer17 
 De novo 
  
  
 GEN659R048 
 frameshift_variant 
 c.14526dup 
 p.Pro4843AlafsTer12 
 De novo 
  
  
 GEN659R049 
 frameshift_variant 
 c.6910dup 
 p.Met2304AsnfsTer8 
 Familial 
 Maternal 
 Simplex 
 GEN659R050 
 missense_variant 
 c.1474G>T 
 p.Val492Phe 
 De novo 
  
 Simplex 
 GEN659R051 
 stop_gained 
 c.5716C>T 
 p.Arg1906Ter 
 De novo 
  
 Simplex 
 GEN659R052 
 frameshift_variant 
 c.6617del 
 p.Pro2206LeufsTer33 
 De novo 
  
 Simplex 
 GEN659R053 
 frameshift_variant 
 c.1378del 
 p.Tyr460ThrfsTer35 
 De novo 
  
 Multiplex 
 GEN659R054 
 missense_variant 
 c.13289T>G 
 p.Leu4430Trp 
 De novo 
  
 Simplex 
 GEN659R055 
 intron_variant 
 c.9375-38C>T 
  
 De novo 
  
 Simplex 
 GEN659R056 
 stop_gained 
 c.9391C>T 
 p.Gln3131Ter 
 Unknown 
  
 Simplex 
 GEN659R057 
 missense_variant 
 c.11851T>C 
 p.Phe3951Leu 
 De novo 
  
 Simplex 
 GEN659R058 
 missense_variant 
 c.991A>G 
 p.Ile331Val 
 De novo 
  
 Simplex 
 GEN659R059 
 missense_variant 
 c.2375C>T 
 p.Pro792Leu 
 De novo 
  
 Simplex 
 GEN659R060 
 stop_gained 
 c.2689C>T 
 p.Arg897Ter 
 De novo 
  
 Simplex 
 GEN659R061 
 frameshift_variant 
 c.1951_1952del 
 p.Glu651LysfsTer3 
 De novo 
  
 Unknown 
 GEN659R062 
 missense_variant 
 c.12898T>C 
 p.Ser4300Pro 
 Familial 
 Paternal 
 Multiplex 
 GEN659R063a 
 missense_variant 
 c.4817C>T 
 p.Pro1606Leu 
 Familial 
 Paternal 
 Simplex 
 GEN659R063b 
 missense_variant 
 c.4154A>G 
 p.Asn1385Ser 
 Familial 
 Maternal 
 Simplex 
 GEN659R064 
 frameshift_variant 
 c.5667dup 
 p.Arg1890ThrfsTer24 
 De novo 
  
  
 GEN659R065 
 missense_variant 
 c.9244C>T 
 p.Pro3082Ser 
 De novo 
  
 Simplex 
 GEN659R066 
 frameshift_variant 
 c.11586_11587del 
 p.Pro3863SerfsTer18 
 Unknown 
  
  
 GEN659R067 
 stop_gained 
 c.2961C>G 
 p.Tyr987Ter 
 Unknown 
  
  
 GEN659R068 
 missense_variant 
 c.1017G>C 
 p.Lys339Asn 
 De novo 
  
 Simplex 
 GEN659R069 
 stop_gained 
 c.2710C>T 
 p.Arg904Ter 
 De novo 
  
  
 GEN659R070 
 missense_variant 
 c.14330G>A 
 p.Arg4777Gln 
 De novo 
  
  
 GEN659R071 
 frameshift_variant 
 c.11760_11762delinsGG 
 p.Phe3920LeufsTer14 
 De novo 
  
  
 GEN659R072 
 splice_site_variant 
 c.9375-1G>A 
  
 De novo 
  
  
 GEN659R073 
 missense_variant 
 c.3805G>A 
 p.Gly1269Ser 
 De novo 
  
  
 GEN659R074 
 synonymous_variant 
 c.3315A>G 
 p.Gln1105%3D 
 De novo 
  
  
 GEN659R075 
 splice_site_variant 
 c.1736-2A>G 
  
 De novo 
  
  
 GEN659R076 
 missense_variant 
 c.584A>G 
 p.Gln195Arg 
 De novo 
  
  
 GEN659R077 
 missense_variant 
 c.14596C>T 
 p.His4866Tyr 
 De novo 
  
  
 GEN659R078 
 missense_variant 
 c.13199G>A 
 p.Arg4400Gln 
 De novo 
  
  
 GEN659R079 
 stop_gained 
 c.5344C>T 
 p.Gln1782Ter 
 De novo 
  
  
 GEN659R080 
 missense_variant 
 c.4168G>A 
 p.Gly1390Arg 
 De novo 
  
  
 GEN659R081 
 missense_variant 
 c.2675G>A 
 p.Gly892Glu 
 Familial 
  
 Multiplex 
 GEN659R082 
 translocation 
  
  
 De novo 
  
 Simplex 
 GEN659R083 
 splice_region_variant 
 c.2770-4dup 
  
 De novo 
  
  
 GEN659R084 
 missense_variant 
 c.12092C>G 
 p.Pro4031Arg 
 Familial 
 Maternal 
  
 GEN659R085 
 stop_gained 
 c.9451C>T 
 p.Gln3151Ter 
 De novo 
  
 Multiplex 
 GEN659R086 
 missense_variant 
 c.9291G>A 
 p.Met3097Ile 
 Familial 
 Maternal 
 Simplex 
 GEN659R087 
 missense_variant 
 c.13273G>A 
 p.Asp4425Asn 
 Familial 
 Paternal 
 Simplex 
 GEN659R088 
 splice_site_variant 
 c.1814-2A>C 
  
 Unknown 
  
 Simplex 
 GEN659R089 
 missense_variant 
 c.8009C>T 
 p.Thr2670Ile 
 Unknown 
  
 Simplex 
 GEN659R090 
 missense_variant 
 c.3902C>T 
 p.Ser1301Phe 
 Familial 
 Paternal 
 Simplex 
 GEN659R091 
 missense_variant 
 c.2573G>T 
 p.Trp858Leu 
 De novo 
  
 Simplex 
 GEN659R092 
 frameshift_variant 
 c.1759_1769del 
 p.Gln587SerfsTer7 
 De novo 
  
 Multiplex 
 GEN659R093 
 stop_gained 
 c.9166C>T 
 p.Gln3056Ter 
 De novo 
  
 Simplex 
 GEN659R094 
 frameshift_variant 
 c.9232_9247del 
 p.Gln3078SerfsTer14 
 De novo 
  
 Simplex 
 GEN659R095 
 frameshift_variant 
 c.5068dup 
 p.Arg1690LysfsTer11 
 De novo 
  
 Simplex 
 GEN659R096 
 frameshift_variant 
 c.10815_10819del 
 p.Lys3605AsnfsTer8 
 De novo 
  
 Simplex 
 GEN659R097 
 frameshift_variant 
 c.6911_6912insA 
 p.Met2304IlefsTer8 
 Familial 
 Maternal 
 Simplex 
 GEN659R098 
 stop_gained 
 c.5419C>T 
 p.Gln1807Ter 
 Unknown 
  
  
 GEN659R099 
 stop_gained 
 c.6415C>T 
 p.Arg2139Ter 
 Familial 
 Paternal 
  
 GEN659R100 
 frameshift_variant 
 c.9915del 
 p.Met3306TrpfsTer55 
 De novo 
  
 Simplex 
 GEN659R101 
 stop_gained 
 c.11983C>T 
 p.Arg3995Ter 
 De novo 
  
 Simplex 
 GEN659R102 
 frameshift_variant 
 c.5481_5485del 
 p.Lys1827AsnfsTer17 
 De novo 
  
 Simplex 
 GEN659R103 
 stop_gained 
 c.3393dup 
 p.Asp1132Ter 
 De novo 
  
 Simplex 
 GEN659R104 
 frameshift_variant 
 c.9621dup 
 p.Ser3208IlefsTer2 
 De novo 
  
 Simplex 
 GEN659R105 
 stop_gained 
 c.9472C>T 
 p.Gln3158Ter 
 De novo 
  
 Simplex 
 GEN659R106 
 frameshift_variant 
 c.8390dup 
 p.Glu2798GlyfsTer11 
 De novo 
  
  
 GEN659R107 
 copy_number_loss 
  
  
 Familial 
 Paternal 
  
 GEN659R108 
 frameshift_variant 
 c.8390dup 
 p.Glu2798GlyfsTer11 
 De novo 
  
 Simplex 
 GEN659R109 
 frameshift_variant 
 c.10588del 
 p.Ser3530LeufsTer3 
 De novo 
  
 Simplex 
 GEN659R110 
 frameshift_variant 
 c.11566_11567del 
 p.Arg3856AspfsTer3 
 Familial 
 Maternal 
  
 GEN659R111 
 frameshift_variant 
 c.8849_8850del 
 p.His2950ArgfsTer17 
 Familial 
 Paternal 
  
 GEN659R112 
 splice_region_variant 
 c.1185-20_1185-7del 
  
 De novo 
  
 Simplex 
 GEN659R113 
 frameshift_variant 
 c.6939dup 
 p.Gly2314TrpfsTer8 
 De novo 
  
 Simplex 
 GEN659R114 
 frameshift_variant 
 c.466_478del 
 p.Thr156SerfsTer46 
 De novo 
  
 Simplex 
 GEN659R115 
 frameshift_variant 
 c.8224_8225dup 
 p.Asp2742GlufsTer9 
 De novo 
  
 Simplex 
 GEN659R116 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN659R117 
 stop_gained 
 c.3462del 
 p.Val1156Ter 
 De novo 
  
 Simplex 
 GEN659R118 
 frameshift_variant 
 c.8543del 
 p.Asn2848MetfsTer15 
 De novo 
  
 Simplex 
 GEN659R119 
 stop_gained 
 c.1864G>T 
 p.Glu622Ter 
 De novo 
  
 Simplex 
 GEN659R120 
 frameshift_variant 
 c.12584del 
 p.Pro4195HisfsTer23 
 De novo 
  
 Simplex 
 GEN659R121 
 frameshift_variant 
 c.2816_2817del 
 p.Ser939TyrfsTer10 
 De novo 
  
 Simplex 
 GEN659R122 
 splice_site_variant 
 c.14344-1G>A 
  
 De novo 
  
 Simplex 
 GEN659R123 
 stop_gained 
 c.6196C>T 
 p.Arg2066Ter 
 De novo 
  
  
 GEN659R124 
 splice_site_variant 
 c.3499+1G>T 
  
 De novo 
  
 Simplex 
 GEN659R125 
 stop_gained 
 c.4441C>T 
 p.Arg1481Ter 
 De novo 
  
 Simplex 
 GEN659R126 
 stop_gained 
 c.8395C>T 
 p.Gln2799Ter 
 Familial 
 Maternal 
  
 GEN659R127 
 frameshift_variant 
 c.5403_5404del 
 p.Pro1802LysfsTer2 
 De novo 
  
 Simplex 
 GEN659R128 
 stop_gained 
 c.307C>T 
 p.Gln103Ter 
 De novo 
  
 Simplex 
 GEN659R129 
 stop_gained 
 c.13621C>T 
 p.Arg4541Ter 
 De novo 
  
 Simplex 
 GEN659R130 
 stop_gained 
 c.11983C>T 
 p.Arg3995Ter 
 De novo 
  
 Simplex 
 GEN659R131 
 frameshift_variant 
 c.454del 
 p.Gln152AsnfsTer4 
 De novo 
  
 Simplex 
 GEN659R132 
 frameshift_variant 
 c.5743dup 
 p.Ser1915PhefsTer20 
 Familial 
 Maternal 
  
 GEN659R133 
 frameshift_variant 
 c.13107_13108dup 
 p.Thr4370ArgfsTer11 
 De novo 
  
 Simplex 
 GEN659R134 
 stop_gained 
 c.13618C>T 
 p.Gln4540Ter 
 De novo 
  
 Simplex 
 GEN659R135 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN659R136 
 stop_gained 
 c.14077C>T 
 p.Arg4693Ter 
 Unknown 
  
 Multiplex 
 GEN659R137 
 frameshift_variant 
 c.8470dup 
 p.Thr2824AsnfsTer9 
 De novo 
  
 Simplex 
 GEN659R138 
 frameshift_variant 
 c.8470dup 
 p.Thr2824AsnfsTer9 
 De novo 
  
 Simplex 
 GEN659R139 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN659R140 
 stop_gained 
 c.11506C>T 
 p.Gln3836Ter 
 De novo 
  
 Simplex 
 GEN659R141 
 splice_site_variant 
 c.1012+1G>C 
  
 Unknown 
  
  
 GEN659R142 
 splice_site_variant 
 c.1013-1G>A 
  
 De novo 
  
 Simplex 
 GEN659R143 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN659R144 
 frameshift_variant 
 c.10724_10725dup 
 p.Ile3576LeufsTer2 
 De novo 
  
 Simplex 
 GEN659R145 
 stop_gained 
 c.14458C>T 
 p.Gln4820Ter 
 Familial 
 Maternal 
  
 GEN659R146 
 missense_variant 
 c.14335C>G 
 p.Arg4779Gly 
 Unknown 
  
  
 GEN659R147 
 stop_gained 
 c.7042C>T 
 p.Gln2348Ter 
 Familial 
 Paternal 
  
 GEN659R148 
 copy_number_gain 
  
  
 De novo 
  
 Simplex 
 GEN659R149 
 frameshift_variant 
 c.8390dup 
 p.Glu2798GlyfsTer11 
 Familial 
 Paternal 
  
 GEN659R150 
 splice_site_variant 
 c.14031+5G>A 
  
 De novo 
  
 Simplex 
 GEN659R151 
 stop_gained 
 c.7828C>T 
 p.Arg2610Ter 
 Unknown 
  
  
 GEN659R152 
 copy_number_loss 
  
  
 Unknown 
 Not maternal 
  
 GEN659R153 
 frameshift_variant 
 c.1332del 
 p.Ser445LeufsTer10 
 De novo 
  
 Simplex 
 GEN659R154 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN659R155 
 frameshift_variant 
 c.9891del 
 p.Thr3298ProfsTer2 
 De novo 
  
  
 GEN659R156 
 frameshift_variant 
 c.3574del 
 p.Val1192LeufsTer13 
 De novo 
  
 Simplex 
 GEN659R157 
 missense_variant 
 c.3233G>A 
 p.Cys1078Tyr 
 De novo 
  
 Simplex 
 GEN659R158 
 missense_variant 
 c.13229A>G 
 p.Asp4410Gly 
 Unknown 
  
  
 GEN659R159 
 frameshift_variant 
 c.10374dup 
 p.Pro3459ThrfsTer3 
 De novo 
  
 Simplex 
 GEN659R160 
 stop_gained 
 c.14073C>A 
 p.Tyr4691Ter 
 De novo 
  
 Simplex 
 GEN659R161 
 frameshift_variant 
 c.1238_1254del 
 p.Tyr413SerfsTer28 
 Unknown 
  
  
 GEN659R162 
 missense_variant 
 c.13783C>T 
 p.Arg4595Cys 
 De novo 
  
 Simplex 
 GEN659R163 
 copy_number_loss 
  
  
 Familial 
 Paternal 
  
 GEN659R164 
 missense_variant 
 c.13394G>A 
 p.Cys4465Tyr 
 De novo 
  
  
 GEN659R165 
 stop_gained 
 c.11983C>T 
 p.Arg3995Ter 
 De novo 
  
  
 GEN659R166 
 missense_variant 
 c.10777T>C 
 p.Tyr3593His 
 Unknown 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
7
Deletion
 2
 
7
Duplication
 1
 
7
Duplication
 1
 
7
Duplication
 2
 
7
Deletion
 6
 
7
Deletion-Duplication
 5
 
7
Deletion
 2
 
7
Deletion-Duplication
 34
 
7
Duplication
 10
 
7
Deletion
 8
 

Model Summary

Mutations in KMT2C have recently been associated with autism spectrum disorder (ASD) in humans. In the conditional knockout model, there is a 50% reduction in the expression levels of KMT2C in both cortical and hippocampal tissue. Though model mice show no change in growth and general locomotor activity, as measured by the accelerating rotarod test and the open field test, they show increases in anxiety, as measured by a decrease in total distance traveled in the center of the open field. Additionally, the model shows changes in social behavior, with increased time spent engaging with a novel mouse in the three-chamber social approach test and increased social dominance in the tube test of social dominance. Model mice also show alterations in spatial learning and memory in the Barnes maze test, with increased latency to find the escape hole and less time spent in the escape hole target region.

References

Type
Title
Author, Year
Additional
Transcriptomic dysregulation and autistic-like behaviors in Kmt2c haploinsufficient mice rescued by an LSD1 inhibitor
Model Type: Genetic
Model Genotype: Transgene
Mutation: Kmt2c knockout mouse models were generated utilizing transgenic mice carrying the CRISPR/Cas9 system (MGI:5583838) to investigate the phenotypic consequences of KMT2C loss of function. Using adeno-associated viruses (AAV) as delivery vectors, exon 3 of KMT2C was targeted with sgRNA in newborn mice to produce the knockout of the gene.
Allele Type: Conditional knockout
Strain of Origin: (129X1/SvJ x 129S1/Sv)F1-Kitl+
Genetic Background: C57BL/6J
ES Cell Line: R1
Mutant ES Cell Line:
Model Source:
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Self grooming1
Increased
 Reciprocal social interaction test
 8 weeks
Repetitive digging1
Increased
 Marble-burying test
 8 weeks
Social interaction1
Decreased
 Reciprocal social interaction test
 8 weeks
Social dominance1
Increased
 Tube test of social dominance
 8 weeks
Exploratory activity1
Increased
 Three-chamber social approach test
 8 weeks
Anxiety1
Increased
 Open field test
 8 weeks
Spatial learning1
Decreased
 Barnes maze test
 8 weeks
Cued or contextual fear conditioning: memory of context: long term recall1
Decreased
 Fear conditioning test
 8 weeks
Spatial reference memory1
Decreased
 Barnes maze test
 8 weeks
Targeted expression1
Decreased
 Quantitative PCR (qRT-PCR)
 8 weeks
Targeted expression1
Decreased
 T7 endonuclease assay
 8 weeks
Size/growth1
 No change
 General observations
 8 weeks
Exploratory activity1
 No change
 Elevated zero maze test
 8 weeks
Exploratory activity1
 No change
 Light-dark exploration test
 8 weeks
General locomotor activity1
 No change
 Accelerating rotarod test
 8 weeks
General locomotor activity: ambulatory activity1
 No change
 Open field test
 8 weeks
Social approach1
 No change
 Three-chamber social approach test
 8 weeks
 Not Reported:


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

RBBP5
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