Human Gene Module / Chromosome 1 / KDM5B

KDM5BLysine (K)-specific demethylase 5B

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
12 / 18
Rare Variants / Common Variants
51 / 0
EAGLE Score
2.8
Limited Learn More
Aliases
KDM5B, CT31,  JARID1B,  PLU-1,  PLU1,  PPP1R98,  PUT1,  RBBP2H1A
Associated Syndromes
Tourette syndrome
Chromosome Band
1q32.1
Associated Disorders
DD/NDD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

Two de novo loss-of-function variants in the KDM5B gene have been identified in ASD probands from the Simons Simplex Collection (refs).

Molecular Function

This gene encodes a histone demethylase that demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBase
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KDM5B (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
4 Recent Recommendation De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies Homsy J , et al. (2016) No DD, learning disabilities
5 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
6 Support Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism Chen R , et al. (2017) Yes -
7 Positive Association De Novo Coding Variants Are Strongly Associated with Tourette Disorder Willsey AJ , et al. (2017) No -
8 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No -
9 Support Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families Al-Mubarak B , et al. (2017) Yes -
10 Support Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders Faundes V , et al. (2017) No -
11 Support Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences Lebrun N , et al. (2018) Yes -
12 Support Drosophila Histone Demethylase KDM5 Regulates Social Behavior through Immune Control and Gut Microbiota Maintenance Chen K , et al. (2019) No -
13 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
14 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
15 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
16 Support - Alonso-Gonzalez A et al. (2021) Yes -
17 Support - Lebon S et al. (2021) No -
18 Support - Mahjani B et al. (2021) Yes -
Rare Variants   (51)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - frameshift_variant De novo NA Simplex 28472652 Willsey AJ , et al. (2017)
c.529C>T p.Arg177Ter stop_gained De novo NA - 26785492 Homsy J , et al. (2016)
c.3058C>T p.Arg1020Ter stop_gained De novo NA - 26785492 Homsy J , et al. (2016)
TG>TGG - frameshift_variant De novo NA Simplex 28263302 C Yuen RK et al. (2017)
c.3835C>T p.Arg1279Ter stop_gained Unknown - - 28554332 Bowling KM , et al. (2017)
c.1816C>T p.Arg606Ter stop_gained De novo NA Simplex 28344757 Chen R , et al. (2017)
c.4189C>T p.Arg1397Ter stop_gained Unknown - Simplex 32094338 Husson T , et al. (2020)
c.577-28A>T - intron_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.*18C>A - 3_prime_UTR_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.208T>A p.Trp70Arg missense_variant De novo NA Simplex 25961944 Krumm N , et al. (2015)
c.3139C>T p.Arg1047Ter stop_gained De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.4627C>T p.Arg1543Ter stop_gained De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.4000C>T p.Arg1334Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1903G>A p.Ala635Thr missense_variant Unknown - Multiplex 34573379 Lebon S et al. (2021)
c.4548dup p.Glu1517Ter frameshift_variant De novo NA - 31452935 Feliciano P et al. (2019)
c.2243T>C p.Leu748Pro missense_variant De novo NA Simplex 25961944 Krumm N , et al. (2015)
c.2265C>A p.Tyr755Ter stop_gained De novo NA Simplex 28720891 Al-Mubarak B , et al. (2017)
c.299G>A p.Arg100His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.304C>T p.Arg102Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.532A>G p.Ile178Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.541C>G p.Pro181Ala missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3634dup p.Ile1212AsnfsTer18 frameshift_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1100A>G p.Asp367Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2444A>G p.Gln815Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.515G>C p.Arg172Thr missense_variant De novo NA Simplex 25363760 De Rubeis S , et al. (2014)
c.3391G>C p.Asp1131His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3650T>C p.Leu1217Pro missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.292C>T p.Arg98Cys missense_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.1816C>T p.Arg606Ter stop_gained De novo NA Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.520C>T p.His174Tyr stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1052G>A p.Cys351Tyr splice_site_variant De novo NA Multiplex 30217758 Lebrun N , et al. (2018)
c.3802C>T p.Gln1268Ter stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4661T>G p.Val1554Gly missense_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.895C>T p.Pro299Ser stop_gained Familial Maternal and paternal - 29276005 Faundes V , et al. (2017)
c.4109T>G p.Leu1370Ter stop_gained Familial Both parents Simplex 29276005 Faundes V , et al. (2017)
c.249A>G p.Ile87Val missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.593G>C p.Gly198Ala missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.622G>A p.Val208Met missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.772A>T p.Asn258Tyr missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1157C>G p.Ala386Gly missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2386G>A p.Val796Met missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2386G>A p.Val796Met missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3004A>T p.Thr1002Ser missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2818C>T p.Leu940Phe splice_site_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1182dup p.Asn395GlnfsTer13 frameshift_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.576+2T>C - splice_site_variant De novo NA Multiplex (monozygotic twins) 30217758 Lebrun N , et al. (2018)
c.3463del p.Ala1155ProfsTer22 frameshift_variant Familial Maternal Multiplex 34573379 Lebon S et al. (2021)
c.2473A>G p.Lys825Glu splice_site_variant Familial Maternal and paternal - 29276005 Faundes V , et al. (2017)
c.1534_1535insG p.Thr512SerfsTer3 frameshift_variant De novo NA Simplex 25363760 De Rubeis S , et al. (2014)
c.622dup p.Tyr208LeufsTer5 frameshift_variant Familial Maternal and paternal - 29276005 Faundes V , et al. (2017)
c.3907del p.Gln1303SerfsTer80 frameshift_variant Familial Maternal and paternal - 29276005 Faundes V , 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 criteria
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.

4/1/2022
2
icon
1

Decreased from 2 to 1

1/1/2021
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the KDM5B gene (two nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A fourth de novo LoF variant in this gene was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017.

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021]
1/1/2020
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the KDM5B gene (two nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A fourth de novo LoF variant in this gene was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]
10/1/2019
2
icon
2

Decreased from 2 to 2

New Scoring Scheme
Description

Two de novo LoF variants in the KDM5B gene (two nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A fourth de novo LoF variant in this gene was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
4/1/2019
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the KDM5B gene (two nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A fourth de novo LoF variant in this gene was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017.

Reports Added
[Drosophila Histone Demethylase KDM5 Regulates Social Behavior through Immune Control and Gut Microbiota Maintenance.2019]
10/1/2018
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the KDM5B gene (two nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A fourth de novo LoF variant in this gene was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017.

Reports Added
[Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences.2018]
7/1/2017
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the KDM5B gene (two nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A fourth de novo LoF variant in this gene was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017.

Reports Added
[Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families.2017]
4/1/2017
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the KDM5B gene (two nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A fourth de novo LoF variant in this gene was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017.

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Excess of rare, inherited truncating mutations in autism.2015] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.2017] [De Novo Coding Variants Are Strongly Associated with Tourette Disorder.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
1/1/2016
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the KDM5B gene (two nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760).

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Excess of rare, inherited truncating mutations in autism.2015] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016]
4/1/2015
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the KDM5B gene (two nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760).

Reports Added
[Excess of rare, inherited truncating mutations in autism.2015]
10/1/2014
icon
2

Increased from to 2

Description

Two de novo LoF variants in the KDM5B gene (two nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760).

Krishnan Probability Score

Score 0.49587907608577

Ranking 2764/25841 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 5.0942014234463E-5

Ranking 13445/18225 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 2.2857808817364E-5

Ranking 9/18665 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
Larsen Cumulative Evidence Score

Score 52

Ranking 30/461 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.
Original Source
Zhang D Score

Score 0.50791540770519

Ranking 468/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
AKR1C1 aldo-keto reductase family 1, member C1 Human Direct Regulation 1645 Q04828
ETS1 Protein C-ets-1 Human Protein Binding 2113 P14921
FAM90A1 Protein FAM90A1 Human Protein Binding 55138 Q86YD7
Hoxa7 homeobox A7 Mouse DNA Binding 15404 P02830
LMO2 Rhombotin-2 Human Protein Binding 4005 P25791
PLIN2 perilipin 2 Human Direct Regulation 123 Q99541
SLITRK3 SLIT and NTRK-like protein 3 Human Protein Binding 22865 O94933
TFAP2C Transcription factor AP-2 gamma Human Protein Binding 7022 Q92754
TSPYL6 Testis-specific Y-encoded-like protein 6 Human Protein Binding 388951 Q8N831
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