Human Gene Module / Chromosome 17 / KDM6B

KDM6BLysine (K)-specific demethylase 6B

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
8 / 12
Rare Variants / Common Variants
43 / 0
EAGLE Score
13.75
Strong Learn More
Aliases
KDM6B, JMJD3
Associated Syndromes
-
Chromosome Band
17p13.1
Associated Disorders
DD/NDD, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

Two de novo loss-of-function variants in the KDM6B gene have been identified in ASD probands from the Simons Simplex Collection (refs).

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.

Reports related to KDM6B (12 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 -
Rare Variants   (43)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4708G>T p.Glu1570Ter stop_gained De novo NA - 28991257 Jin SC , et al. (2017)
c.225T>A p.Tyr75Ter stop_gained De novo NA - 31124279 Stolerman ES , et al. (2019)
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.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.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.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.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

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).

Score Delta: Score remained at 3

1

High Confidence

See all Category 1 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.

1/1/2020
3
icon
3

Score remained at 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).

10/1/2019
3
icon
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
icon
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
icon
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).

1/1/2017
3
icon
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
icon
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
icon
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).

10/1/2014
icon
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 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
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.
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
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