KDM6BLysine (K)-specific demethylase 6B
Autism Reports / Total Reports
12 / 18Rare Variants / Common Variants
57 / 0Chromosome Band
17p13.1Associated Disorders
DD/NDD, ASDGenetic Category
Rare Single Gene Mutation, Syndromic, FunctionalRelevance to Autism
Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). Additional de novo likely gene-disruptive/protein-truncating variants and/or damaging missense variants in KDM6B were identified in ASD probands from the SPARK cohort and the Autism Sequencing Consortium in Feliciano et al., 2019 and Satterstrom et al., 2020, respectively; furthermore, transmission and de novo association (TADA) analysis in both reports identified KDM6B as a candidate gene with a false discovery rate (FDR) 0.01. 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 Zhou et al., 2022 identified KDM6B as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
This gene encodes a histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code. Plays a central role in regulation of posterior development, by regulating HOX gene expression.
External Links
SFARI Genomic Platforms
Reports related to KDM6B (18 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Primary | De novo gene disruptions in children on the autistic spectrum | Iossifov I , et al. (2012) | Yes | - |
| 2 | Recent Recommendation | Synaptic, transcriptional and chromatin genes disrupted in autism | De Rubeis S , et al. (2014) | Yes | - |
| 3 | Recent Recommendation | The contribution of de novo coding mutations to autism spectrum disorder | Iossifov I et al. (2014) | Yes | - |
| 4 | Recent Recommendation | Low load for disruptive mutations in autism genes and their biased transmission | Iossifov I , et al. (2015) | Yes | - |
| 5 | Support | Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability | Lelieveld SH et al. (2016) | No | - |
| 6 | Support | Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders | Reuter MS , et al. (2017) | No | Sleep disturbances, aggressive behavior |
| 7 | Support | Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder | C Yuen RK et al. (2017) | Yes | - |
| 8 | Support | Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands | Jin SC , et al. (2017) | No | Neurodevelopmental disorders (NDD) |
| 9 | Recent recommendation | Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features | Stolerman ES , et al. (2019) | No | ASD |
| 10 | Support | Pathogenicity and functional impact of non-frameshifting insertion/deletion variation in the human genome | Pagel KA , et al. (2019) | Yes | - |
| 11 | Support | Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes | Feliciano P et al. (2019) | Yes | - |
| 12 | Support | Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism | Satterstrom FK et al. (2020) | Yes | - |
| 13 | Support | - | Mahjani B et al. (2021) | Yes | - |
| 14 | Support | - | Singh T et al. (2022) | No | - |
| 15 | Support | - | Gao Y et al. (2022) | Yes | ADHD |
| 16 | Support | - | Hu C et al. (2022) | Yes | - |
| 17 | Support | - | Krgovic D et al. (2022) | No | Autistic behavior, stereotypy |
| 18 | Support | - | Zhou X et al. (2022) | Yes | - |
Rare Variants (57)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.445C>T | p.Arg149Ter | stop_gained | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.4165+5G>A | - | splice_site_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.2851C>T | p.Arg951Ter | stop_gained | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.2134C>T | p.Gln712Ter | stop_gained | Unknown | - | - | 34615535 | Mahjani B et al. (2021) | |
| c.4708G>T | p.Glu1570Ter | stop_gained | De novo | NA | - | 28991257 | Jin SC , et al. (2017) | |
| c.1484G>A | p.Arg495Gln | missense_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.225T>A | p.Tyr75Ter | stop_gained | De novo | NA | - | 31124279 | Stolerman ES , et al. (2019) | |
| c.3529C>T | p.Pro1177Ser | missense_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.4720T>C | p.Tyr1574His | missense_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.1257+2_1257+3del | - | splice_site_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.403C>T | p.Arg135Ter | stop_gained | De novo | NA | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.445C>T | p.Arg149Ter | stop_gained | De novo | NA | - | 31124279 | Stolerman ES , et al. (2019) | |
| c.343C>T | p.Gln115Ter | stop_gained | Unknown | - | Simplex | 28263302 | C Yuen RK et al. (2017) | |
| c.4165+2T>A | - | splice_site_variant | De novo | NA | Multiplex | 35982159 | Zhou X et al. (2022) | |
| c.3730G>T | p.Glu1244Ter | stop_gained | De novo | NA | - | 31124279 | Stolerman ES , et al. (2019) | |
| c.138-2A>G | - | splice_site_variant | De novo | NA | Simplex | 25363768 | Iossifov I et al. (2014) | |
| c.3762_3764del | p.Asp1254del | inframe_deletion | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.4783C>T | p.Arg1595Cys | missense_variant | De novo | NA | - | 31452935 | Feliciano P et al. (2019) | |
| c.4696C>A | p.Arg1566Ser | missense_variant | De novo | NA | - | 27479843 | Lelieveld SH et al. (2016) | |
| c.3992A>G | p.Asn1331Ser | missense_variant | De novo | NA | - | 31124279 | Stolerman ES , et al. (2019) | |
| c.4136A>C | p.Tyr1379Ser | missense_variant | De novo | NA | - | 31124279 | Stolerman ES , et al. (2019) | |
| c.2781_2794del | p.Val928HisfsTer2 | frameshift_variant | Unknown | - | - | 35741772 | Hu C et al. (2022) | |
| c.2331dup | p.Pro778ThrfsTer79 | frameshift_variant | De novo | NA | - | 35982159 | Zhou X et al. (2022) | |
| c.325C>T | p.Leu109Phe | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.1069G>A | p.Gly357Arg | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.1105C>T | p.Arg369Trp | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.2626G>A | p.Gly876Arg | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.4468+5G>C | - | splice_region_variant | De novo | NA | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.3478C>T | p.Leu1160Phe | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.3626G>A | p.Arg1209Gln | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.4369C>G | p.Arg1457Gly | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.4420G>A | p.Ala1474Thr | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.4571C>T | p.Thr1524Met | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
| c.4174G>A | p.Glu1392Lys | missense_variant | De novo | NA | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.2685del | p.Thr896ProfsTer19 | frameshift_variant | De novo | NA | - | 31124279 | Stolerman ES , et al. (2019) | |
| c.3085dup | p.Gln1029ProfsTer4 | frameshift_variant | De novo | NA | - | 31124279 | Stolerman ES , et al. (2019) | |
| c.4590del | p.Asp1531ThrfsTer5 | frameshift_variant | De novo | NA | - | 31124279 | Stolerman ES , et al. (2019) | |
| c.4186T>A | p.Phe1396Ile | missense_variant | De novo | NA | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.28G>A | p.Ala10Thr | missense_variant | Familial | Maternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.3196_3199dup | p.Ala1067ValfsTer31 | frameshift_variant | De novo | NA | - | 35813072 | Krgovic D et al. (2022) | |
| c.259C>T | p.His87Tyr | missense_variant | Familial | Paternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.578del | p.Gly193GlufsTer5 | frameshift_variant | De novo | NA | Simplex | 22542183 | Iossifov I , et al. (2012) | |
| c.596G>A | p.Arg199Gln | missense_variant | Familial | Maternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.982C>T | p.Arg328Trp | missense_variant | Familial | Paternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.1039C>T | p.His347Tyr | missense_variant | Familial | Maternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.1120G>A | p.Val374Ile | missense_variant | Familial | Maternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.2171C>T | p.Pro724Leu | missense_variant | Familial | Maternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.3532C>T | p.Arg1178Trp | missense_variant | Familial | Paternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.3626G>A | p.Arg1209Gln | missense_variant | Familial | Maternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.4571A>T | p.Thr1524Met | missense_variant | Familial | Maternal | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
| c.3334_3335del | p.Ser1112TrpfsTer2 | frameshift_variant | De novo | NA | - | 31124279 | Stolerman ES , et al. (2019) | |
| c.1085_1088del | p.Glu362AlafsTer124 | frameshift_variant | De novo | NA | - | 31124279 | Stolerman ES , et al. (2019) | |
| c.3862_3865del | p.Phe1288ArgfsTer60 | frameshift_variant | De novo | NA | - | 31124279 | Stolerman ES , et al. (2019) | |
| c.4795del | p.Leu1599TrpfsTer39 | frameshift_variant | De novo | NA | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.3251_3261delinsCCAG | p.Val1084AlafsTer5 | frameshift_variant | De novo | NA | - | 31124279 | Stolerman ES , et al. (2019) | |
| c.4184_4186del | p.Asn1395_Phe1396delinsIle | inframe_deletion | De novo | NA | Simplex | 25363768 | Iossifov I et al. (2014) | |
| c.1668_1673del | p.Asn557_Ser558del | inframe_deletion | Familial | Both parents | Multiplex | 28097321 | Reuter MS , et al. (2017) |
Common Variants
No common variants reported.
SFARI Gene score
1
High Confidence
Score Delta: Score remained at 1
criteria met
See SFARI Gene'scoring criteriaWe 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.
1/1/2020
1
1
Score remained at 1
Description
Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).
10/1/2019
3
1
Decreased from 3 to 1
New Scoring Scheme
Description
Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).
7/1/2019
3
3
Decreased from 3 to 3
Description
Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).
10/1/2017
3
3
Decreased from 3 to 3
Description
Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).
4/1/2017
3
3
Decreased from 3 to 3
Description
Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).
Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.2017] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]1/1/2017
3
3
Decreased from 3 to 3
Description
Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).
7/1/2016
3
3
Decreased from 3 to 3
Description
Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).
1/1/2016
3
3
Decreased from 3 to 3
Description
Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).
Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]10/1/2014
3
Increased from to 3
Description
Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).
Krishnan Probability Score
Score 0.56737413909039
Ranking 1182/25841 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.
ExAC Score
Score 0.99999442492111
Ranking 408/18225 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
Iossifov Probability Score
Score 0.996
Ranking 14/239 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 Washingtonâs 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
Sanders TADA Score
Score 0.013306460468598
Ranking 30/18665 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).
Larsen Cumulative Evidence Score
Score 39
Ranking 52/461 scored genes
[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available
ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size,
and variant frequency in the general population. The approach was first presented in Mol Autism
7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from
that paper.
Zhang D Score
Score 0.43427469541995
Ranking 1078/20870 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.
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
| Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
|---|---|---|---|---|---|
| KMT2B | Mouse | Protein Binding | Q6PDK2 | ||
| WAS | Wiskott-Aldrich syndrome protein | Human | Protein Binding | 7454 | P42768 |