Human Gene Module / Chromosome X / KDM6A

KDM6Alysine demethylase 6A

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 16
Rare Variants / Common Variants
19 / 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
Entrez GeneOMIMUniProtHumanBaseVariCarta
Zebrafish
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KDM6A (16 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
15 Support - Ruohao Wu et al. (2024) Yes -
16 Support - Alistair T Pagnamenta et al. (2024) No -
Rare Variants   (19)
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)
- - inversion Unknown - - 38776926 Alistair T Pagnamenta et al. (2024)
- - copy_number_loss Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
- - copy_number_gain Unknown - - 38776926 Alistair T Pagnamenta et al. (2024)
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.3365+2T>C - splice_site_variant Familial Maternal Simplex 38764027 Ruohao Wu et al. (2024)
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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