Human Gene Module / Chromosome 19 / KDM4B

KDM4Blysine demethylase 4B

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
24 / 0
Aliases
KDM4B, JMJD2B,  TDRD14B
Associated Syndromes
-
Chromosome Band
19p13.3
Associated Disorders
ADHD, ID, EPS, ASD
Relevance to Autism

Two de novo variants in the KDM4B gene (one nonsense, one damaging missense) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). KDM4B was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Neuron-specific KDM4B-deficient mice exhibited defective spine maturation, hyperactive behavior, deficits in working memory, and spontaneous epileptic-like seizures (Fujiwara et al., 2016). Duncan et al., 2020 presented a cohort of nine individuals with heterozygous de novo or inherited variants in the KDM4B gene presenting with global developmental delay, with language and motor skills most severely affected, and dysmorphic features; autistic features were observed in one individual from this cohort.

Molecular Function

This gene encodes for a histone demethylase that specifically demethylates 'Lys-9' of histone H3 and is involved in chromatin organization and regulation.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KDM4B (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
3 Recent Recommendation Deletion of JMJD2B in neurons leads to defective spine maturation, hyperactive behavior and memory deficits in mouse Fujiwara K , et al. (2016) No -
4 Recent Recommendation Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects Duncan AR et al. (2020) No ID, epilepsy/seizures, ADHD, autistic features
5 Support - Rodin RE et al. (2021) Yes -
6 Support - Zhou X et al. (2022) Yes -
Rare Variants   (24)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.655C>T p.Arg219Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1360C>T p.Arg454Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.312C>T p.Ser104%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2173C>T p.Arg725Ter stop_gained De novo - - 25363760 De Rubeis S , et al. (2014)
c.1248C>T p.Pro416%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1464G>A p.Pro488%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2303A>G p.His768Arg missense_variant De novo - - 33232677 Duncan AR et al. (2020)
c.473T>C p.Leu158Pro missense_variant Unknown - - 25363760 De Rubeis S , et al. (2014)
c.958G>A p.Val320Met missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1907-1G>C - splice_site_variant Familial Maternal - 33232677 Duncan AR et al. (2020)
c.1336C>T p.Arg446Trp missense_variant Unknown - - 25363760 De Rubeis S , et al. (2014)
c.2547G>C p.Lys849Asn missense_variant Unknown - - 25363760 De Rubeis S , et al. (2014)
c.659T>C p.Leu220Pro missense_variant De novo - Simplex 33232677 Duncan AR et al. (2020)
c.664C>T p.Arg222Trp missense_variant De novo - Simplex 33232677 Duncan AR et al. (2020)
c.288C>T p.Gly96%3D synonymous_variant De novo - Simplex 33232677 Duncan AR et al. (2020)
c.3284C>T p.Pro1095Leu missense_variant De novo - Simplex 33232677 Duncan AR et al. (2020)
c.371_374del p.Lys124ThrfsTer48 frameshift_variant De novo - - 33232677 Duncan AR et al. (2020)
c.1688A>G p.Glu563Gly missense_variant Familial Paternal - 25363760 De Rubeis S , et al. (2014)
c.2023G>A p.Ala675Thr missense_variant Familial Maternal - 25363760 De Rubeis S , et al. (2014)
c.2063C>T p.Thr688Met missense_variant Familial Maternal - 25363760 De Rubeis S , et al. (2014)
c.2596T>A p.Cys866Ser missense_variant Familial Paternal - 25363760 De Rubeis S , et al. (2014)
c.2221dup p.Glu741GlyfsTer41 frameshift_variant De novo - Simplex 33232677 Duncan AR et al. (2020)
c.1778_1779del p.Glu593GlyfsTer41 frameshift_variant Familial Paternal - 33232677 Duncan AR et al. (2020)
ENSG00000127663:ENST00000159111:exon15:c.G2257A:p.G753R,ENSG00000127663:ENST00000536461:exon15:c.G23 - missense_variant De novo - - 33432195 Rodin RE et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo variants in the KDM4B gene (one nonsense, one damaging missense) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). KDM4B was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Neuron-specific KDM4B-deficient mice exhibited defective spine maturation, hyperactive behavior, deficits in working memory, and spontaneous epileptic-like seizures (Fujiwara et al., 2016).

Score Delta: Score remained at 2

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Two de novo variants in the KDM4B gene (one nonsense, one damaging missense) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). KDM4B was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Neuron-specific KDM4B-deficient mice exhibited defective spine maturation, hyperactive behavior, deficits in working memory, and spontaneous epileptic-like seizures (Fujiwara et al., 2016).

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

Two de novo variants in the KDM4B gene (one nonsense, one damaging missense) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). KDM4B was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Neuron-specific KDM4B-deficient mice exhibited defective spine maturation, hyperactive behavior, deficits in working memory, and spontaneous epileptic-like seizures (Fujiwara et al., 2016).

Reports Added
[The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing2021]
10/1/2020
3
icon
3

Decreased from 3 to 3

Description

Two de novo variants in the KDM4B gene (one nonsense, one damaging missense) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). KDM4B was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Neuron-specific KDM4B-deficient mice exhibited defective spine maturation, hyperactive behavior, deficits in working memory, and spontaneous epileptic-like seizures (Fujiwara et al., 2016).

Reports Added
[Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two de novo variants in the KDM4B gene (one nonsense, one damaging missense) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). KDM4B was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Neuron-specific KDM4B-deficient mice exhibited defective spine maturation, hyperactive behavior, deficits in working memory, and spontaneous epileptic-like seizures (Fujiwara et al., 2016).

Reports Added
[New Scoring Scheme]
4/1/2016
icon
4

Increased from to 4

Description

Two de novo variants in the KDM4B gene (one nonsense, one damaging missense) were identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014). KDM4B was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Neuron-specific KDM4B-deficient mice exhibited defective spine maturation, hyperactive behavior, deficits in working memory, and spontaneous epileptic-like seizures (Fujiwara et al., 2016).

Krishnan Probability Score

Score 0.49884428142188

Ranking 2208/25841 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 0.99993475714138

Ranking 616/18225 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 0.937

Ranking 99/239 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 0.29790392558882

Ranking 178/18665 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 0.24704362505915

Ranking 3514/20870 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
Submit New Gene

Report an Error