Human Gene Module / Chromosome 19 / KMT2B

KMT2Blysine methyltransferase 2B

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
8 / 10
Rare Variants / Common Variants
69 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
19q13.12
Associated Disorders
-
Relevance to Autism

De novo frameshift variants in the KMT2B were recently reported in two unrelated individuals diagnosed with autism spectrum disorder: the first was from the Children's Neurodevelopmental Center, Hasbro Children's Hospital and also presented with dysmorphic features, developmental delay/intellectual disability, and additional behavioral comorbidities, while the second was from a cohort of 112 Chinese ASD patients and their non-ASD parents from Peking University Sixth Hospital (Chang et al., 2024; Lob et al., 2024). Additional de novo variants in the KMT2B gene, incluiding a de novo nonsense variant, a de novo splice-donor variant, and five de novo missense variants, have been observed in ASD probands from the Autism Sequencing Consortium, the Simons Simplex Collection, the SPARK cohort, and the MSSNG cohort (Iossifov et al., 2014; Yuen et al., 2017; Feliciano et al., 2019; Satterstrom et al., 2020; Zhou et al., 2022; Fu et al., 2022). Heterozygous mutations in the KMT2B gene are also responsible for autosomal dominant intellectual developmental disorder 68 (MRD68; OMIM 619934) and childhood-onset dystonia 28 (DYT28; OMIM 617284). Cif et al., 2020 described a cohort of 53 patients with KMT2B mutations presenting with either dystonia (n=44) or a non-dystonic neurodevelopmental phenotype (n=9); autism spectrum disorder was reported in individuals from both subsets of KMT2B-associated disease.

Molecular Function

This gene encodes a protein which contains multiple domains including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains, and a SET (suppressor of variegation, enhancer of zeste, and trithorax) domain. The SET domain is a conserved C-terminal domain that characterizes proteins of the MLL (mixed-lineage leukemia) family. This gene is ubiquitously expressed in adult tissues.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KMT2B (10 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 Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
3 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
4 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
5 Support - Laura Cif et al. (2020) No ASD, ADHD
6 Support - Zhou X et al. (2022) Yes -
7 Support - Fu JM et al. (2022) Yes -
8 Recent recommendation - Suhua Chang et al. () Yes -
9 Primary - Karen Lob et al. () Yes DD, ID
10 Support - Hosneara Akter et al. () No ASD or autistic behavior, epilepsy/seizures
Rare Variants   (69)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 33150406 Laura Cif et al. (2020)
- - copy_number_loss Unknown - - 33150406 Laura Cif et al. (2020)
c.850C>T p.Gln284Ter stop_gained De novo - - 33150406 Laura Cif et al. (2020)
c.3058+1G>A - splice_site_variant De novo - - 33150406 Laura Cif et al. (2020)
c.3642+5G>A - splice_site_variant De novo - - 33150406 Laura Cif et al. (2020)
c.7297+1G>A - splice_site_variant De novo - - 33150406 Laura Cif et al. (2020)
c.7298-1G>A - splice_site_variant De novo - - 33150406 Laura Cif et al. (2020)
c.2425C>T p.Gln809Ter stop_gained De novo - - 33150406 Laura Cif et al. (2020)
c.2428C>T p.Gln810Ter stop_gained De novo - - 33150406 Laura Cif et al. (2020)
c.2434C>T p.Gln812Ter stop_gained Unknown - - 33150406 Laura Cif et al. (2020)
c.2999_3002+6del - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.3885G>A p.Trp1295Ter stop_gained De novo - - 33150406 Laura Cif et al. (2020)
c.4760dup p.Tyr1587Ter stop_gained De novo - - 33150406 Laura Cif et al. (2020)
c.4760dup p.Tyr1587Ter stop_gained Unknown - - 33150406 Laura Cif et al. (2020)
c.6439C>T p.Gln2147Ter stop_gained De novo - - 33150406 Laura Cif et al. (2020)
c.7759C>T p.Arg2587Ter stop_gained De novo - - 33150406 Laura Cif et al. (2020)
c.5381A>C p.His1794Pro missense_variant De novo - - 35982160 Fu JM et al. (2022)
c.6027C>T p.Ala2009= synonymous_variant De novo - - 35982160 Fu JM et al. (2022)
c.7506G>A p.Pro2502= synonymous_variant De novo - - 35982160 Fu JM et al. (2022)
c.2736G>A p.Ala912= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.6869C>T p.Pro2290Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.479C>T p.Pro160Leu missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.573G>T p.Gln191His missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.3014G>A p.Cys1005Tyr missense_variant De novo - - 33150406 Laura Cif et al. (2020)
c.3665G>A p.Cys1222Tyr missense_variant De novo - - 33150406 Laura Cif et al. (2020)
c.4789C>T p.Arg1597Trp missense_variant De novo - - 33150406 Laura Cif et al. (2020)
c.4847C>T p.Ala1616Val missense_variant De novo - - 33150406 Laura Cif et al. (2020)
c.4931G>T p.Cys1644Phe missense_variant De novo - - 33150406 Laura Cif et al. (2020)
c.5046C>G p.Cys1682Trp missense_variant De novo - - 33150406 Laura Cif et al. (2020)
c.7945C>T p.Arg2649Cys missense_variant Unknown - - 33150406 Laura Cif et al. (2020)
c.5335C>T p.Arg1779Ter stop_gained De novo - - 31981491 Satterstrom FK et al. (2020)
c.4198C>T p.Arg1400Cys missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.6683C>A p.Ala2228Asp missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.894T>G p.Gly298= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3050C>T p.Ala1017Val missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.6895dup p.Arg2299ProfsTer4 frameshift_variant De novo - - 39136901 Karen Lob et al. ()
c.2227_2228delinsTAG p.Ala743Ter stop_gained Unknown - - 33150406 Laura Cif et al. (2020)
c.4825_4827del p.Val1609del inframe_deletion De novo - - 33150406 Laura Cif et al. (2020)
c.2871C>T p.His957= synonymous_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.7348C>T p.Arg2450Ter stop_gained Unknown Not maternal - 33150406 Laura Cif et al. (2020)
c.3592_3626del p.Gly1198GlnfsTer14 stop_gained De novo - - 33150406 Laura Cif et al. (2020)
c.816dup p.Gly273ArgfsTer61 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.11_16dup p.Ala4_Ala5dup inframe_insertion De novo - Simplex 35982159 Zhou X et al. (2022)
c.1107dup p.Glu370ArgfsTer19 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.1656dup p.Lys553GlnfsTer46 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.5658del p.Ser1887ProfsTer8 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.6895dup p.Arg2299ProfsTer4 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.7271dup p.Ser2425GlnfsTer3 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.12_24dup p.Ser9GlyfsTer111 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.4368C>T p.Phe1456= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4960T>C p.Cys1654Arg missense_variant Familial Maternal - 33150406 Laura Cif et al. (2020)
c.5682del p.Thr1895ProfsTer39 frameshift_variant Unknown - - 33150406 Laura Cif et al. (2020)
c.6090dup p.Thr2031HisfsTer29 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.7614del p.Thr2539ProfsTer75 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.7715C>T p.Thr2572Met missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.4056C>T p.Ser1352= synonymous_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.3602del p.Pro1201ArgfsTer154 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.7943C>T p.Ala2648Val missense_variant Unknown Not maternal - 33150406 Laura Cif et al. (2020)
c.5475T>G p.Asp1825Glu missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1127_1130del p.Lys376ArgfsTer10 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.5724_5751del p.Pro1909LeufsTer16 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.6245_6266dup p.Val2090HisfsTer25 frameshift_variant De novo - - 33150406 Laura Cif et al. (2020)
c.3325del p.Arg1109GlufsTer73 frameshift_variant Unknown - Multiplex 33150406 Laura Cif et al. (2020)
c.2137dup p.Thr713AsnfsTer4 frameshift_variant Unknown Not maternal - 33150406 Laura Cif et al. (2020)
c.6754_6755insGC p.Ala2252GlyfsTer10 frameshift_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.3997del p.Glu1333ArgfsTer22 frameshift_variant Unknown Not maternal - 33150406 Laura Cif et al. (2020)
c.3147_3160del p.Gly1050ProfsTer33 frameshift_variant Familial Maternal - 33150406 Laura Cif et al. (2020)
c.5230_5233del p.Ser1744IlefsTer150 frameshift_variant Unknown Not maternal - 33150406 Laura Cif et al. (2020)
c.118del p.Ala40ProfsTer6 frameshift_variant De novo - Multiplex (monozygotic twins) 33150406 Laura Cif et al. (2020)
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.

10/1/2024
3

Initial score established: 3

Krishnan Probability Score

Score 0.49162027608431

Ranking 5336/25841 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 0.99999999745259

Ranking 115/18225 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
Sanders TADA Score

Score 0.90143127642555

Ranking 6525/18665 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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