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). Chan et al., 2019 described six previously unreported individuals with de novo KMT2A variants; all six patients met clinical criteria for Wiedemann-Steiner syndrome, with five of these individuals also receiving a diagnosis of autism spectrum disorder following evaluation with ADOS-2, ADI-R, the Social Communication Questionnaire (SCQ), and the Social Responsive Scale, Second Edition (SRS-2). A retrospective, multicenter, observational study of 104 individuals with Wiedemann-Steiner syndrome from five continents in Sheppard et al., 2021 found that 21.3% of individuals in this cohort presented with autism spectrum disorder. Additional de novo loss-of-function variants in the KMT2A gene were reported in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and 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 KMT2A as a gene reaching study-wide significance based on 5,754 constraint genes (P < 8.69E-06).
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.
Neurocognitive and neurobehavioral characterization of two frequent forms of neurodevelopmental disorders: the DYRK1A and the Wiedemann-Steiner syndromes
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.
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
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
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
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Kmt2a knockout allele was generated through Cre-mediated deletion of exons 8 and 9 in a conditional-ready construct (MGI:3849323).
Allele Type: Knockout
Strain of Origin: 129S4/SvJae-Tg(Prm-cre)70Og
Genetic Background: 129S1/SvImJ
ES Cell Line: PC3
Mutant ES Cell Line: Model Source: Hugh Brady lab
Description: No homozygotes survive till birth and no homozygous embryos are detected even at e3.5 or e1.5 indicating early preimplantation embryonic lethality
Exp Paradigm: NA
Description: Mutants have two fold reduction in fetal liver cellularity and a four fold reduction in long-term hematopoietic stem cells (progenitor pool)
Exp Paradigm: NA
Description: Kmt2a cko mice have increased locomotor activity during the dark (active) cycle indicative of altered dopaminergic signaling
Exp Paradigm: NA
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
Exp Paradigm: NA
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
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
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
