Human Gene Module / Chromosome 11 / KDM2A

KDM2Alysine demethylase 2A

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
9 / 10
Rare Variants / Common Variants
23 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
11q13.2
Associated Disorders
-
Relevance to Autism

De novo variants in the KDM2A gene have been identified in ASD probands, including a de novo missense variant (p.Arg449Lys) in a proband from the Simons Simplex Collection (Iossifov et al., 2014; Yuen et al., 2016; Yuen et al., 2017; Turner et al., 2017; Satterstrom et al., 2020), while a germline missense variant in this gene was identified in brain tissue from an ASD brain donor from the Harvard Brain Tissue Resource Center (Woodbury-Smith et al., 2022). Functional assessment of the ASD-associated p.Arg449Lys missense variant in Drosophila using an rescue-based strategy in Macrogliese et al., 2020 demonstrated that humanized flies carrying the p.Arg449Lys mutation showed decreased time copulating compared to the humanized reference in a behavioral paradigm.

Molecular Function

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains at least six highly degenerated leucine-rich repeats. This family member plays a role in epigenetic silencing. It nucleates at CpG islands and specifically demethylates both mono- and di-methylated lysine-36 of histone H3.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KDM2A (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
5 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
6 Support - Woodbury-Smith M et al. (2022) Yes -
7 Recent Recommendation - Marcogliese PC et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Zongyao Ren et al. () No ASD
10 Support - Yasser Al-Sarraj et al. (2024) Yes -
Rare Variants   (23)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.958-8C>G - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
G>GAC - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.43-19575G>C - intron_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.1572C>A p.Phe524Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1807T>G p.Ser603Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2875C>T p.Leu959Phe missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.308-193A>G - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.42+4490T>G - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.1480-2739dup - intron_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.307+6396C>G - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.43-20338A>T - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.307+7025A>G - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.43-23144C>T - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.1491G>A p.Glu497%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.732C>A p.Tyr244Ter stop_gained De novo - Simplex 38060137 Zongyao Ren et al. ()
c.308-8869C>T - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.43-25203T>C - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.1479+1611G>C - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.1479+1650C>T - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.955C>T p.Arg319Trp missense_variant De novo - Simplex 38060137 Zongyao Ren et al. ()
c.2988C>G p.Ser996Arg missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1346G>A p.Arg449Lys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2327A>G p.Lys776Arg missense_variant De novo - Unknown 38572415 Yasser Al-Sarraj et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
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.

4/1/2022
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.49239591365253

Ranking 4554/25841 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 0.99999995460364

Ranking 170/18225 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 0.9375909300169

Ranking 13576/18665 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 0.38798644543866

Ranking 1591/20870 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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