Human Gene Module / Chromosome X / KDM6A

KDM6Alysine demethylase 6A

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
1 / 6
Rare Variants / Common Variants
7 / 0
Aliases
KDM6A, KABUK2,  UTX,  bA386N14.2
Associated Syndromes
Kabuki syndrome 2
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
Xp11.3
Associated Disorders
-
Relevance to Autism

Two de novo loss-of-function (LoF) variants were identified in ASD probands in Yuen et al., 2017 (one in a proband from a simplex family, the other in a proband from a multiplex family). Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), KDM6A was determined to be an ASD candidate gene in Yuen et al., 2017.

Molecular Function

This gene is located on the X chromosome and is the corresponding locus to a Y-linked gene which encodes a tetratricopeptide repeat (TPR) protein. The encoded protein of this gene contains a JmjC-domain and catalyzes the demethylation of tri/dimethylated histone H3. Mutations in the KDM6A gene are associated with Kabuki syndrome 2 (KABUK2; OMIM 300867), a congenital intellectual disability syndrome with additional features including postnatal dwarfism and distinct facial dysmorphic features.

Reports related to KDM6A (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Lederer D , et al. (2011) No -
2 Support KDM6A point mutations cause Kabuki syndrome. Miyake N , et al. (2012) No -
3 Support A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A. Lederer D , et al. (2014) No -
4 Primary Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
5 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No -
6 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 22197486 Lederer D , et al. (2011)
- - copy_number_loss De novo - - 22197486 Lederer D , et al. (2011)
- - copy_number_loss De novo - - 22197486 Lederer D , et al. (2011)
c.2173dupT;c.2824dupT;c.2926dupT;c.3061dupT;c.3082dupT p.Ile724fs;p.Ile941fs;p.Ile975fs;p.Ile1020fs;p.Ile1027fs frameshift_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
G>A p.? splice_site_variant De novo - Multiplex 28263302 C Yuen RK , et al. (2017)
c.975-1G>A p.? splice_site_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.2988+1G>C p.? splice_site_variant De novo - - 28708303 Chrot E , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

2

Score Delta: Increased from 2 to 3.3 + acc

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.

4/1/2018
2
icon
3.3 + acc

Increased from 2 to 3.3 + acc

Description

2

7/1/2017
2
icon
2

Increased from 2 to 2

Description

Two de novo loss-of-function (LoF) variants were identified in ASD probands in Yuen et al., 2017 (one in a proband from a simplex family, the other in a proband from a multiplex family). Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), KDM6A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in the KDM6A gene are associated with Kabuki syndrome 2 (KABUK2; OMIM 300867), a congenital intellectual disability syndrome with additional features including postnatal dwarfism and distinct facial dysmorphic features (Lederer et al., 2012; Miyake et al., 2013; Lederer et al., 2014).

4/1/2017
icon
2

Increased from to 2

Description

Two de novo loss-of-function (LoF) variants were identified in ASD probands in Yuen et al., 2017 (one in a proband from a simplex family, the other in a proband from a multiplex family). Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), KDM6A was determined to be an ASD candidate gene in Yuen et al., 2017. Mutations in the KDM6A gene are associated with Kabuki syndrome 2 (KABUK2; OMIM 300867), a congenital intellectual disability syndrome with additional features including postnatal dwarfism and distinct facial dysmorphic features (Lederer et al., 2012; Miyake et al., 2013; Lederer et al., 2014).

Krishnan Probability Score

Score 0.49186984233022

Ranking 4975/25841 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 0.99998712052308

Ranking 474/18225 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 0.94471467968293

Ranking 16184/18665 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 0.28258297185277

Ranking 2991/20870 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.
CNVs associated with KDM6A(1 CNVs)
Xp11.3 14 Deletion-Duplication 22  /  44
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