Human Gene Module / Chromosome 19 / DOT1L

DOT1LDOT1 like histone lysine methyltransferase

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
30 / 0
Aliases
-
Associated Syndromes
Nil-Deshwan neurodevelopmental syndrome, DD
Chromosome Band
19p13.3
Associated Disorders
-
Relevance to Autism

Maroni et al., 2025 identified a cohort of 16 individuals through collaborating clinicians and GeneMatcher with monoallelic DOT1L variants presenting with a variable neurodevelopmental disorder characterized by language delay (13/16), motor delay (9/16), intellectual disability (4/16), a diagnosis of ASD (4/16), seizures/epilepsy (3/16), and craniofacial anomalies (14/16); additional functional studies in this report identified patient-specific missense variants with either decreased (the newly identified p.Asp157Asn variant) or increased (the previously reported p.Glu123Lys variant) methyltransferase activity, while heterozygous forebrain-specific Dot1l conditional knockout mice demonstrated altered early vocalization development in both male and female pups, as well as a sex-specific sociability deficit in the three-chamber test in female Dot1l cKO mice. A previous study (Nil et al., 2023) had reported nine unrelated individuals with seven different de novo heterozygous missense variants in DOT1L through the Undiagnosed Disease Network (UDN), the SickKids Complex Care genomics project, and GeneMatcher presenting with some degree of global developmental delay/intellectual disability and at least one major congenital anomaly in most individuals; subsequent functional assessment of DOT1L missense variants in Drosophila and human cells in this report demonstrated gain-of-function effects in flies and increased H3K79 methylation levels in flies and human cells. A number of de novo DOT1L variants, including two de novo loss-of-function variants in probands from the Simons Simplex Collection, have been reported in ASD probands (Iossifov et al., 2014; Satterstrom et al., 2020; Zhou et al., 2022; Fu et al., 2022).

Molecular Function

The protein encoded by this gene is a histone methyltransferase that methylates lysine-79 of histone H3. It is inactive against free core histones, but shows significant histone methyltransferase activity against nucleosomes.

External Links
Gene CardPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser
Reports related to DOT1L (6 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 Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
3 Support - Zhou X et al. (2022) Yes -
4 Support - Fu JM et al. (2022) Yes -
5 Support - Zelha Nil et al. (2023) No ASD, epilepsy/seizures
6 Primary - Marissa J Maroni et al. () No ASD, ADHD, ID, epilepsy/seizures
Rare Variants   (30)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1399G>A p.Val467Met missense_variant De novo - - 35982160 Fu JM et al. (2022)
c.133T>G p.Cys45Gly missense_variant De novo - - 37827158 Zelha Nil et al. (2023)
c.1792C>T p.Gln598Ter stop_gained Unknown - - 40494548 Marissa J Maroni et al. ()
c.299C>T p.Thr100Met missense_variant De novo - - 37827158 Zelha Nil et al. (2023)
c.367G>A p.Glu123Lys missense_variant De novo - - 37827158 Zelha Nil et al. (2023)
c.367G>A p.Glu123Lys missense_variant Unknown - - 37827158 Zelha Nil et al. (2023)
c.385G>A p.Glu129Lys missense_variant De novo - - 37827158 Zelha Nil et al. (2023)
c.1348C>T p.Gln450Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.1876C>G p.Leu626Val missense_variant De novo - - 37827158 Zelha Nil et al. (2023)
c.2557C>T p.Arg853Cys missense_variant De novo - - 37827158 Zelha Nil et al. (2023)
c.3074A>T p.Lys1025Met missense_variant De novo - - 37827158 Zelha Nil et al. (2023)
c.121A>T p.Ile41Phe missense_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.123C>G p.Ile41Met missense_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.255C>G p.Ile85Met missense_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.400G>A p.Glu134Lys missense_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.409G>A p.Gly137Arg missense_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.469G>A p.Asp157Asn missense_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.469G>T p.Asp157Tyr missense_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.565G>A p.Asp189Asn missense_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.806C>T p.Ser269Leu missense_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.995C>G p.Pro332Arg missense_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.1262A>G p.Asn421Ser missense_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.2075T>G p.Leu692Arg missense_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.1822C>T p.Gln608Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
- p.Leu1067AspfsTer66 frameshift_variant Unknown - - 40494548 Marissa J Maroni et al. ()
c.2822G>C p.Gly941Ala missense_variant De novo - Unknown 35982159 Zhou X et al. (2022)
c.2610G>A p.Pro870= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4432C>T p.Pro1478Ser missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1344A>C p.Ser448= synonymous_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.1624_1626del p.Glu542del inframe_deletion Unknown - - 40494548 Marissa J Maroni et al. ()
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2025
2S

Initial score established: 2S

Krishnan Probability Score

Score 0.44737272223479

Ranking 12553/25841 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 0.99998896175721

Ranking 464/18225 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 0.973

Ranking 53/239 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 0.55866687457047

Ranking 587/18665 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
Zhang D Score

Score 0.32963205743714

Ranking 2299/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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