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KDM6A
lysine demethylase 6A
KDM6A encodes lysine-specific demethylase 6A, a histone-modifying enzyme essential for regulating gene expression during development and preventing uncontrolled cell growth. The KDM6A gene provides instructions for producing an enzyme that removes methyl groups from histone proteins, thereby controlling which genes are active in cells.
KDM6A is located on the short (p) arm of chromosome X, at band Xp11.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome X in the library →Overview
KDM6A is located on the X chromosome and produces lysine-specific demethylase 6A, an enzyme found throughout the body that plays a central role in controlling gene activity. This protein modifies histones, the structural proteins that package DNA within chromosomes, by removing methyl chemical tags in a process called demethylation. Through this epigenetic mechanism, KDM6A influences which genes are switched on or off during embryonic development and throughout life.
The gene is particularly important for normal development of multiple organ systems. Pathogenic variants in KDM6A can cause Kabuki syndrome, a rare condition characterised by distinctive facial features, intellectual disability, and structural abnormalities affecting the heart, kidneys, and other organs. Additionally, the enzyme functions as a tumour suppressor, and acquired changes in KDM6A have been identified in bladder cancer, breast cancer, and several other malignancies.
What the gene does
Lysine-specific demethylase 6A functions primarily as a histone demethylase, removing methyl groups from histone proteins. This modification is a key epigenetic mark that influences gene activity. By stripping away these methyl tags, the enzyme allows genes to become accessible for transcription, effectively switching them on when needed during development and cellular differentiation.
The protein appears to regulate developmental gene programmes that are critical for proper formation of various tissues and organs during embryonic growth. Research suggests it participates in chromatin remodelling complexes that coordinate large-scale changes in gene expression patterns. Beyond its demethylase activity, KDM6A also functions as a tumour suppressor in adult tissues. The enzyme helps maintain normal controls on cell division and survival, preventing cells from acquiring the uncontrolled growth characteristics typical of cancer. This dual role in development and tumour suppression makes KDM6A essential across the lifespan.
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Chromosome location
KDM6A is located at position p11.3 on the short arm of the X chromosome (Xp11.3). The gene spans a region encoding a 1401-amino-acid protein. Because KDM6A resides on the X chromosome, variant interpretation and inheritance patterns differ between individuals with XX and XY chromosome complements. Unlike most X-linked genes, KDM6A typically escapes X-inactivation in individuals with two X chromosomes, meaning both copies are usually active.
Protein structure
The KDM6A protein comprises 1401 amino acids organised into distinct functional regions. The N-terminal portion contains eight tetratricopeptide repeat (TPR) motifs spanning residues 93-385: TPR 1 (amino acids 93-126), TPR 2 (130-163), TPR 3 (170-199), TPR 4 (205-238), TPR 5 (250-283), TPR 6 (284-317), TPR 7 (318-351), and TPR 8 (352-385). These repeating structural elements typically mediate protein-protein interactions. A large region from amino acids 1-1095 facilitates interaction with SUPT6H, a protein involved in transcription regulation.
The protein contains multiple disordered regions distributed throughout its length, including stretches at amino acids 437-457, 521-541, 624-746, 758-778, 810-864, 914-940, and 1043-1079. These intrinsically disordered segments often provide flexibility for regulatory interactions and post-translational modifications that fine-tune enzyme activity. The C-terminal region contains a JmjC domain (amino acids 1095-1258), which is the catalytic core responsible for the demethylase activity of the enzyme.
Key variants
Pathogenic variants in KDM6A encompass a range of change types, with many resulting in premature termination of protein synthesis. Deletions removing genetic material within the gene sequence and nonsense variants that introduce early stop signals are frequently observed in individuals with Kabuki syndrome. These changes typically produce a shortened, non-functional enzyme unable to perform histone demethylation. Somatic variants acquired during an individual's lifetime have been identified in tumour samples from bladder, breast, oesophageal, colorectal, kidney, and brain cancers, as well as myeloid leukaemia and multiple myeloma. The specific functional consequences depend on which protein domain is affected and whether any residual enzyme activity remains.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1711C>T | p.Arg571Ter | Pathogenic | ★★☆☆ | Kabuki syndrome 2 |
c.1990C>T | p.Arg664Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.2128C>T | p.Arg710Ter | Pathogenic | ★★☆☆ | Neurodevelopmental disorder |
c.2482_2485del | p.Asp828fs | Pathogenic | ★★☆☆ | not provided |
c.2597_2598del | p.Ser866fs | Pathogenic | ★★☆☆ | Kabuki syndrome 2 |
c.2988+1G>A | - | Pathogenic | ★★☆☆ | not provided |
c.3172C>T | p.Gln1058Ter | Pathogenic | ★★☆☆ | Kabuki syndrome 2 |
c.3341_3344del | p.Asp1114fs | Pathogenic | ★★☆☆ | not provided |
c.3793C>T | p.Arg1265Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Kabuki syndrome 2 |
c.3919C>T | p.Arg1307Trp | Pathogenic | ★★☆☆ | Kabuki syndrome 2 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Germline pathogenic variants in KDM6A cause Kabuki syndrome 2 (KDM6A), typically following an X-linked dominant inheritance pattern. Affected individuals present with characteristic facial features including long palpebral fissures and eversion of the lateral lower eyelid, intellectual disability of variable severity, postnatal growth deficiency, and structural anomalies that may affect the heart, kidneys, palate, and skeleton. Kabuki syndrome can also result from variants in the KMT2D gene, referred to as Kabuki syndrome (AD) when caused by autosomal dominant inheritance.
Somatic variants in KDM6A contribute to cancer development across multiple tissue types. Loss of functional KDM6A protein disrupts normal tumour suppressor mechanisms, potentially allowing cells to evade growth controls and accumulate additional oncogenic changes.
Inheritance pattern
Conditions caused by pathogenic KDM6A variants typically follow x-linked dominant inheritance.
X-linked dominant: all daughters of an affected father inherit the altered X and are affected. Sons receive the father's Y and are unaffected.
UK clinical status
KDM6A is included on multiple NHS Genomic Medicine Service gene panels with green classification, indicating strong evidence for clinical validity. The gene appears on panels for Kabuki syndrome, intellectual disability (R29), DDG2P (developmental disorders), Fetal anomalies (R21), and several organ-specific panels including CAKUT (congenital anomalies of kidney and urinary tract), clefting, deafness and congenital structural abnormalities, structural eye disease (R36), congenital hyperinsulinism (R144), and primary immunodeficiency or monogenic inflammatory bowel disease (R15). This broad panel representation reflects the multisystem nature of KDM6A-related developmental conditions and supports diagnostic genomic testing in relevant clinical presentations.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is KDM6A inheritance different from typical X-linked conditions?
KDM6A follows X-linked dominant inheritance, meaning a single pathogenic variant can cause Kabuki syndrome regardless of the individual's chromosome complement. Unlike many X-linked genes, KDM6A typically escapes X-inactivation, so individuals with two X chromosomes usually express both copies, which influences the inheritance pattern and clinical severity.
Why is KDM6A associated with both developmental conditions and cancer?
KDM6A performs two critical roles: regulating developmental gene programmes during embryonic growth and functioning as a tumour suppressor in adult tissues. Germline variants disrupt early development, causing Kabuki syndrome, whilst somatic variants acquired later in life can contribute to cancer by removing normal growth controls.
What does histone demethylation mean for gene activity?
Histone demethylation is the removal of methyl chemical groups from histone proteins that package DNA. KDM6A specifically removes methyl marks that silence genes, thereby switching genes on and making them available for the cell to use. This epigenetic mechanism allows cells to control which genes are active without changing the underlying DNA sequence.
References
- Robertson AG, Kim J, Al-Ahmadie H. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2018. PMID: 30096301
- Banka S, Lederer D, Benoit V. Novel KDM6A (UTX) mutations and a clinical and molecular review of the X-linked Kabuki syndrome (KS2). Clinical genetics. 2015. PMID: 24527667
- Micale L, Augello B, Maffeo C. Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Human mutation. 2014. PMID: 24633898
- Miyake N, Mizuno S, Okamoto N. KDM6A point mutations cause Kabuki syndrome. Human mutation. 2013. PMID: 23076834
- Miyake N, Koshimizu E, Okamoto N. MLL2 and KDM6A mutations in patients with Kabuki syndrome. American journal of medical genetics. Part A. 2013. PMID: 23913813
- Lederer D, Grisart B, Digilio MC. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. American journal of human genetics. 2012. PMID: 22197486