KDM6A

protein-coding

lysine demethylase 6A, the group of Lysine demethylases|Tetratricopeptide repeat domain containing

Gene summary

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. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2014]

Previous symbols:

MANE transcript

NM_001291415.2

Inheritance

XL, AD

ClinVar variants

P:186U:810B:287

Top phenotype

Kabuki syndrome 2

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chrX:44,873,188-45,112,779

External References & Databases

Ensembl (ENSG00000147050)

Transcript & Mutation Effects

hg38 • Region Span ~239.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Kabuki syndrome 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010465

Submitter: Ambry Genetics

Kabuki syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016512

Submitter: Orphanet

Kabuki syndrome 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010465

Submitter: Labcorp Genetics (formerly Invitae)

Kabuki syndrome 2DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010465

Submitter: G2P

Kabuki syndrome 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010465

Submitter: PanelApp Australia

Kabuki syndrome 2DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010465

Submitter: ClinGen

KDM6A was first reported in relation to X-linked dominant Kabuki syndrome 2 (KS2) in 2012 (Lederer D et al., PMID: 22197486). Features of KS2 include neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, motor delay, intellectual disability, microcephaly, congenital heart anomalies, palate defects, renal malformations, hearing loss, recurrent infections, joint hypermobility, and gastroesophageal reflux (Faundes V et al., PMID: 33674768). While Kabuki syndrome 1 (KS1) is characterized by distinct facial dysmorphism, facial phenotypes of patients with KS2 and KDM6A variants are highly variable. At least 13 unique variants (missense, nonsense, small insertion, splice site, small deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data: 19.6 Variants in this gene have been reported in at least 13 probands in 6 publications (PMID: 22197486, PMID: 23076834, PMID: 24664873, PMID: 23913813, PMID: 30509212, PMID: 27302555). Summary of Experimental Data: 4.5 This gene-disease association is supported by multiple animal and cell culture models (PMID: 29073101, PMID: 25972376, PMID: 26431949, PMID: 34126175). Van Laarhoven PM et al., (2015) knocked down the expression of KDM6A orthologs in zebrafish (kdm6a and kdm6al). Morphants exhibited severe abnormalities in all tissues examined, presenting with craniofacial phenotypes and defects in heart development. Shpargel KB et al., (2017) demonstrated that mice carrying neural crest deletion of UTX (KDM6A) display craniofacial dysmorphism, cardiac defects, and postnatal growth retardation. Cook KD, et al., (2015) showed UTX-deficient T cells have decreased expression of interleukin-6 receptor-α and identified a critical link between UTX in T cells and immunity to infection. In summary, there is definitive evidence to support the relationship between the KDM6A gene and X-linked dominant Kabuki syndrome 2, however, the variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 are still not fully understood. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date July 15, 2021 (SOP Version 8).

Clinical Genomic Database (CGD)

Kabuki syndrome 2XL

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 22197486; 23076834; 24633898

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KDM6A variants in ClinVar

19 Conditions Cataloged

Kabuki syndrome 2Total: 941

not providedTotal: 427

Inborn genetic diseasesTotal: 110

not specifiedTotal: 102

KDM6A-related disorderTotal: 90

Intellectual disabilityTotal: 11

Kabuki syndrome 1Total: 11

Malignant tumor of urinary bladderTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001291415.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			47 clinvar	184 clinvar	16 clinvar	247
missense	6 clinvar	20 clinvar	657 clinvar	79 clinvar	8 clinvar	770
nonsense	37 clinvar	14 clinvar	17 clinvar			68
start loss						0
frameshift	52 clinvar	19 clinvar	16 clinvar			87
splice donor/acceptor (+/-2bp)	18 clinvar	20 clinvar	73 clinvar			111
Total	113	73	810	263	24	1283

Highest pathogenic variant AF is 0.000008962822

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 64 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001291415.2	RefSeq	NP_001278344.1	30	MANE Select
ENST00000611820.5	Ensembl	ENSP00000483595.2	30	MANE Select
NM_001291416.2	RefSeq	NP_001278345.1	29	Standard
NM_001291417.2	RefSeq	NP_001278346.1	28	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kdm6a	Danio rerio	Structure: ceratobranchial cartilage Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

kdm6a

Danio rerio

Structure: ceratobranchial cartilage

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transcriptional misregulation in cancer - Homo sapiens (human)
Mesodermal Commitment Pathway
Pathways Affected in Adenoid Cystic Carcinoma
HDMs demethylate histones
Chromatin modifying enzymes

Biological Process

in utero embryonic development
neural tube closure
heart morphogenesis
respiratory system process
chromatin remodeling

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
chromatin binding
chromatin DNA binding
histone demethylase activity
identical protein binding

Cellular Component

nucleus
nucleoplasm
histone methyltransferase complex
MLL3/4 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377967
Coding exons: 29
Length: 239091
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125728
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.95	317	503	0.630	0.0000355	9172
Missense (PolyPhen)		45	147.27	0.30556		2860
Synonymous	0.0950	186	188	0.991	0.0000137	2687
Loss of Function	6.51	4	57.0	0.0702	0.00000443	926

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000072	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000050	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone demethylase that specifically demethylates 'Lys- 27' of histone H3, thereby playing a central role in histone code (PubMed:17851529, PubMed:17713478, PubMed:17761849). Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-27' (PubMed:17851529, PubMed:17713478, PubMed:17761849). Plays a central role in regulation of posterior development, by regulating HOX gene expression (PubMed:17851529). Demethylation of 'Lys-27' of histone H3 is concomitant with methylation of 'Lys-4' of histone H3, and regulates the recruitment of the PRC1 complex and monoubiquitination of histone H2A (PubMed:17761849). Plays a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression (By similarity). {ECO:0000250|UniProtKB:O70546, ECO:0000269|PubMed:17713478, ECO:0000269|PubMed:17761849, ECO:0000269|PubMed:17851529, ECO:0000269|PubMed:18003914}.;
Disease: DISEASE: Kabuki syndrome 2 (KABUK2) [MIM:300867]: A congenital mental retardation syndrome with additional features, including postnatal dwarfism, a peculiar facies characterized by long palpebral fissures with eversion of the lateral third of the lower eyelids, a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy. {ECO:0000269|PubMed:22197486}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.168

Intolerance Scores

LoFtool: 0.187
RVIS EVS: -0.07
RVIS percentile EVS: 48.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.897

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium