Human Gene Module / Chromosome 17 / KDM6B

KDM6BLysine (K)-specific demethylase 6B

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
27 / 0
Aliases
KDM6B, JMJD3
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
17p13.1
Associated Disorders
DD/NDD
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 (8 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)
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.575delG p.Arg192fs frameshift_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.4174G>A p.Glu1392Lys missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.28G>A p.Ala10Thr missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.596G>A p.Arg199Gln 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.3626G>A p.Arg1209Gln 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.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.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.4571A>T p.Thr1524Met missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.325C>T p.Leu109Phe 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.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.1069G>A p.Gly357Arg 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.4571C>T p.Thr1524Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.138-2A>G p.? splice_site_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
delCTT - inframe_deletion De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.4696C>A p.Arg1566Ser missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.[1668_1673del];[1668_1673del] p.[Asn557_Ser558del];[Asn557_Ser558del] inframe_deletion;inframe_deletion Familial Both parents Multiplex 28097321 Reuter MS , et al. (2017)
c.343C>T p.Gln115Ter stop_gained Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
G>T p.Glu1570Ter stop_gained De novo - - 28991257 Jin SC , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

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

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.

10/1/2017
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).

1/1/2017
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).

7/1/2016
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).

1/1/2016
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).

10/1/2014
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.
CNVs associated with KDM6B(1 CNVs)
17p13.1 26 Deletion-Duplication 40  /  153
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
Submit New Gene

Report an Error