Human Gene Module / Chromosome 9 / KDM4C

KDM4Clysine demethylase 4C

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 3
Rare Variants / Common Variants
10 / 0
Aliases
KDM4C, GASC1,  JHDM3C,  JMJD2C,  TDRD14C
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
9p24.1
Associated Disorders
-
Relevance to Autism

CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the KDM4C gene was observed in a combined cohort of ASD and SCZ cases compared to controls [3 CNVs from ASD cases and 6 CNVs from SCZ cases (9 total) vs. 0 CNVs in controls (Odds ratio 10.46, P = 8.6E-03)]. In a follow-up CNV analysis in a Japanese sample set of 2,605 schizophrenia cases, 1,141 ASD cases, and 2,310 controls, Kato et al., 2020 found evidence for significant associations between CNVs affecting KDM4C and ASD (p = 0.04) and schizophrenia (p=0.003).

Molecular Function

This gene is a member of the Jumonji domain 2 (JMJD2) family. The encoded protein is a trimethylation-specific demethylase, and converts specific trimethylated histone residues to the dimethylated form. This enzymatic action regulates gene expression and chromosome segregation.

Reports related to KDM4C (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights Kushima I , et al. (2018) Yes -
2 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
3 Support Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder Kato H et al. (2020) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - Simplex 33279929 Kato H et al. (2020)
- - copy_number_gain Unknown - Unknown 33279929 Kato H et al. (2020)
- - copy_number_gain Unknown - Simplex 30208311 Kushima I , et al. (2018)
- - copy_number_loss Unknown - Simplex 30208311 Kushima I , et al. (2018)
- - copy_number_gain Unknown - Unknown 30208311 Kushima I , et al. (2018)
- - copy_number_loss Unknown - Unknown 30208311 Kushima I , et al. (2018)
- - copy_number_loss Unknown - Multiplex 30208311 Kushima I , et al. (2018)
- - copy_number_loss Familial Maternal Simplex 33279929 Kato H et al. (2020)
- - copy_number_loss Familial Paternal Simplex 30208311 Kushima I , et al. (2018)
c.2557T>G p.Trp853Gly missense_variant De novo NA - 31452935 Feliciano P et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the KDM4C gene was observed in a combined cohort of ASD and SCZ cases compared to controls [3 CNVs from ASD cases and 6 CNVs from SCZ cases (9 total) vs. 0 CNVs in controls (Odds ratio 10.46, P = 8.6E-03)].

Score Delta: Score remained at 3

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.

10/1/2020
3
icon
3

Score remained at 3

Description

CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the KDM4C gene was observed in a combined cohort of ASD and SCZ cases compared to controls [3 CNVs from ASD cases and 6 CNVs from SCZ cases (9 total) vs. 0 CNVs in controls (Odds ratio 10.46, P = 8.6E-03)].

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the KDM4C gene was observed in a combined cohort of ASD and SCZ cases compared to controls [3 CNVs from ASD cases and 6 CNVs from SCZ cases (9 total) vs. 0 CNVs in controls (Odds ratio 10.46, P = 8.6E-03)].

10/1/2018
icon
3

Increased from to 3

Description

CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the KDM4C gene was observed in a combined cohort of ASD and SCZ cases compared to controls [3 CNVs from ASD cases and 6 CNVs from SCZ cases (9 total) vs. 0 CNVs in controls (Odds ratio 10.46, P = 8.6E-03)].

Krishnan Probability Score

Score 0.49192458415654

Ranking 4920/25841 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 0.0007587346026227

Ranking 11960/18225 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
Sanders TADA Score

Score 0.94566687863515

Ranking 16561/18665 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).
Zhang D Score

Score 0.48587120147617

Ranking 613/20870 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.
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