Human Gene Module / Chromosome 12 / KDM5A

KDM5Alysine demethylase 5A

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
10 / 0
Aliases
KDM5A, RBBP-2,  RBBP2,  RBP2
Associated Syndromes
-
Chromosome Band
12p13.33
Associated Disorders
DD/NDD, ID, EPS
Relevance to Autism

Screening of ENU mutagenized mice for ASD-like behavioral phenotypes (deficits in ultrasonic vocalizations (USVs) and nest-building behavior) in El Hayek et al., 2020 identified Kdm5a as a candidate gene; to validate this discovery, the authors generated a Kdm5a knockout mouse model (Kdm5a-/-) and demonstrated Kdm5a-/- mice not only exhibited disrupted ultrasonic vocalizations but also displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Screening of whole exome sequencing and microarray data from a clinical cohort in this report also identified individuals with de novo heterozygous variants and homozygous variants in the KDM5A gene presenting with a phenotype characterized by autism spectrum disorder, developmental delay, intellectual disability, and delayed/absent speech development.

Molecular Function

This gene encodes a member of the Jumonji, AT-rich interactive domain 1 (JARID1) histone demethylase protein family. The encoded protein plays a role in gene regulation through the histone code by specifically demethylating lysine 4 of histone H3. The encoded protein interacts with many other proteins, including retinoblastoma protein, and is implicated in the transcriptional regulation of Hox genes and cytokines.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KDM5A (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary - El Hayek L et al. (2020) Yes DD, ID, epilepsy/seizures
2 Support - Mitani T et al. (2021) No -
3 Support - Krgovic D et al. (2022) Yes DD
4 Support - More RP et al. (2023) Yes -
5 Support - Lauretta El Hayek et al. (2023) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.953A>G p.Tyr318Cys missense_variant Unknown - - 35813072 Krgovic D et al. (2022)
- - copy_number_loss Familial Both parents Simplex 33350388 El Hayek L et al. (2020)
- - copy_number_loss Familial Both parents Multiplex 33350388 El Hayek L et al. (2020)
c.4048C>T p.Arg1350Ter stop_gained De novo - Simplex 33350388 El Hayek L et al. (2020)
c.2510C>T p.Pro837Leu missense_variant Familial - Multiplex 36702863 More RP et al. (2023)
c.1A>T p.Met1? initiator_codon_variant De novo - Simplex 33350388 El Hayek L et al. (2020)
c.4283G>T p.Arg1428Leu missense_variant De novo - Simplex 33350388 El Hayek L et al. (2020)
c.2541+1G>T - splice_site_variant Familial Both parents Multiplex 33350388 El Hayek L et al. (2020)
c.2525A>C p.Gln842Pro missense_variant Familial Both parents Simplex 34582790 Mitani T et al. (2021)
c.1429T>G p.Phe477Val missense_variant Familial Both parents Simplex 33350388 El Hayek L et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.49672073580069

Ranking 2534/25841 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 0.99999482747131

Ranking 401/18225 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 0.94665315622625

Ranking 16957/18665 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 0.38469109983564

Ranking 1632/20870 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
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