Human Gene Module / Chromosome X / KDM6A

KDM6Alysine demethylase 6A

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 14
Rare Variants / Common Variants
16 / 0
Aliases
KDM6A, KABUK2,  UTX,  bA386N14.2
Associated Syndromes
Kabuki syndrome 2
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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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Zebrafish
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SFARI Genomic Platforms
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Reports related to KDM6A (14 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 2 clinical units and 216 patients Chrot E , et al. (2017) No -
7 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Munnich A , et al. (2019) Yes -
8 Support - Kritioti E et al. (2021) No -
9 Support - Marwaha A et al. (2022) No Epilepsy/seizures
10 Support - Brea-Fernández AJ et al. (2022) No -
11 Support - Zhou X et al. (2022) Yes -
12 Support - Li S et al. (2023) No -
13 Support - Sanchis-Juan A et al. (2023) No -
14 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (16)
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 Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.2988+1G>C - splice_site_variant De novo - - 28708303 Chrot E , et al. (2017)
c.975-1G>A - splice_site_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.445G>C p.Ala149Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_gain Familial Maternal Simplex 35043535 Marwaha A et al. (2022)
c.1192C>T p.Gln398Ter stop_gained De novo - - 34324503 Kritioti E et al. (2021)
G>A p.? splice_site_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.2944G>T p.Gly982Ter stop_gained De novo - Simplex 31406558 Munnich A , et al. (2019)
c.3219dup p.His1074AlafsTer3 frameshift_variant De novo - Simplex 36625521 Li S et al. (2023)
c.2150A>C p.Glu717Ala missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.3730C>T p.Leu1244Phe missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.3217dup p.Trp1073LeufsTer4 frameshift_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.2791_2794dup p.Gln932ProfsTer27 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3669dup p.Gly1224ArgfsTer8 frameshift_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.1070_1076delinsCTGGATT p.Asp357_Gly359delinsAlaGlyPhe missense_variant De novo - - 35982159 Zhou X et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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. A third de novo LoF variant in this gene was identified in a male ASD proband from a day-care hospital in the Greater Paris region in Munnich et al., 2019. 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).

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.

10/1/2019
2
icon
2

Score remained at 2

New Scoring Scheme
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. A third de novo LoF variant in this gene was identified in a male ASD proband from a day-care hospital in the Greater Paris region in Munnich et al., 2019. 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).

Reports Added
[New Scoring Scheme]
7/1/2019
2
icon
2

Score remained at 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. A third de novo LoF variant in this gene was identified in a male ASD proband from a day-care hospital in the Greater Paris region in Munnich et al., 2019. 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).

Reports Added
[Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019]
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.
Original Source
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
Original Source
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).
Original Source
Zhang D Score

Score 0.28258297185278

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.
Original Source
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