Human Gene Module / Chromosome 12 / KMT2D

KMT2Dlysine methyltransferase 2D

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
13 / 13
Rare Variants / Common Variants
20 / 0
Aliases
-
Associated Syndromes
Kabuki syndrome 1, ASD, DD, ID, Kabuki syndrome 1, ASD, DD, ID, epilepsy/seizures
Chromosome Band
12q13.12
Associated Disorders
-
Relevance to Autism

Shangguan et al., 2025 assembled genotype and phenotype data for 9 affected individuals from 9 unrelated families with predicted deleterious KMT2D variants through literature (Parisi et al., 2015; Sertelik et al., 2016; Luo et al., 2021) and two web-based databases (ClinVar and DECIPHER); all 9 probands were diagnosed with autism and presented with intellectual disability and dysmorphic facial features. In the same report, the authors observed that selective knockdown of Kmt2d in the mouse hippocampus resulted in defects in social behaviors and increased repetitive behavior, as well as decreased excitatory and increased inhibitory synaptic transmission. De novo variants in the KMT2D gene, including a loss-of-function variant and several potentially deleterious missense variants, have also been identified in ASD probands from the Simons Simplex Collection, the SPARK cohort, the Autism Sequencing Consortium, the MSSNG cohort, and a Korean ASD cohort (Iossifov et al., 2014; Yuen et al., 2017; Krupp et al., 2017; Satterstrom et al., 2020; Zhou et al., 2022; Kim et al., 2024; Tan et al., 2024).

Molecular Function

The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome.

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Reports related to KMT2D (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support - L Parisi et al. (2015) Yes -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support - Mehmet Sertçelik et al. (2016) Yes -
5 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
6 Support Family-based exome sequencing and case-control analysis implicate CEP41 as an ASD gene Patowary A , et al. (2019) Yes -
7 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
8 Support - Jianhua Luo et al. (2021) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Ana Karen Sandoval-Talamantes et al. (2023) Yes -
11 Support - Soo-Whee Kim et al. (2024) Yes -
12 Support - Senwei Tan et al. () Yes -
13 Primary - Huakun Shangguan et al. (2025) Yes -
Rare Variants   (20)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
C>T p.? splice_site_variant De novo - Simplex 39472663 Senwei Tan et al. ()
c.9397C>T p.Gln3133Ter stop_gained De novo - - 40883562 Huakun Shangguan et al. (2025)
c.181G>A p.Gly61Ser missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.1712G>A p.Arg571His missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.5356C>T p.Arg1786Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.14653G>T p.Ala4885Ser missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.12066G>T p.Thr4022= synonymous_variant De novo - Unknown 35982159 Zhou X et al. (2022)
c.15928G>A p.Gly5310Arg missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.13398A>G p.Leu4466= synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.7753G>C p.Gly2585Arg missense_variant De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.3103C>A p.Gln1035Lys missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.4389C>T p.Thr1463= synonymous_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.16529A>G p.Tyr5510Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.13058delG p.Pro4353ArgfsTer31 frameshift_variant De novo - - 34487531 Jianhua Luo et al. (2021)
c.1530del p.Pro511LeufsTer419 frameshift_variant De novo - - 40883562 Huakun Shangguan et al. (2025)
c.6597del p.Pro2200LeufsTer64 frameshift_variant De novo - - 40883562 Huakun Shangguan et al. (2025)
c.1769dupT p.Met590fs frameshift_variant Familial Maternal - 40883562 Huakun Shangguan et al. (2025)
c.15634G>C p.Ala5212Pro missense_variant De novo - Simplex 28373809 Mehmet Sertçelik et al. (2016)
c.8156G>C p.Ser2719Thr missense_variant Familial - Extended multiplex 30664616 Patowary A , et al. (2019)
c.13885A>C p.Thr4629Pro missense_variant Unknown - - 38003033 Ana Karen Sandoval-Talamantes et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2025
3

Initial score established: 3

Krishnan Probability Score

Score 0.45246199193884

Ranking 10486/25841 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.
Original Source
ExAC Score

Score 1

Ranking 18/18225 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
Original Source
Iossifov Probability Score

Score 0.981

Ranking 44/239 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
Original Source
Sanders TADA Score

Score 0.9491044728737

Ranking 17955/18665 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).
Original Source
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