KDM6B

protein-coding

lysine demethylase 6B, the group of Lysine demethylases

Gene summary

The protein encoded by this gene is a lysine-specific demethylase that specifically demethylates di- or tri-methylated lysine 27 of histone H3 (H3K27me2 or H3K27me3). H3K27 trimethylation is a repressive epigenetic mark controlling chromatin organization and gene silencing. This protein can also demethylate non-histone proteins such as retinoblastoma protein. Through its demethylation actvity this gene influences cellular differentiation and development, tumorigenesis, inflammatory diseases, and neurodegenerative diseases. This protein has two classical nuclear localization signals at its N-terminus. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]

Previous symbols:

JMJD3

MANE transcript

NM_001348716.2

Inheritance

AD, AR

ClinVar variants

P:123U:495B:225

Top phenotype

Stolerman neurodevelopmental syndrome

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr17:7,834,217-7,854,796

External References & Databases

Ensembl (ENSG00000132510)

Transcript & Mutation Effects

hg38 • Region Span ~20.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032790

Submitter: PanelApp Australia

neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: G2P

neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032790

Submitter: Illumina

syndromic intellectual disabilityLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0000508

Submitter: ClinGen

*KDM6B* encodes a histone demethylase that plays key roles in the regulation of gene expression during development. Homozygous *KDM6B* variants (missense, splice region, and in-frame deletion) have been reported in three consanguineous families with syndromic intellectual disability (ID) (PMIDs: 21937992, 26077850, 28097321). Affected individuals present with moderate to severe ID, dysmorphic facial features, and mild hand and feet anomalies. Functional studies were not performed to assess the pathogenicity of these variants. Heterozygous *de novo KDM6B* variants cause autosomal dominant syndromic ID; this disease association has been curated separately. In summary, there is limited evidence to support the relationship between *KDM6B* and autosomal recessive syndromic ID. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts this gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 19, 2022. It was reevaluated on August 28, 2026. As a result of this reevaluation, no additional patients were identified and the classification did not change. The scoring was updated to be consistent with SOP Version 12.

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

*KDM6B* encodes a histone demethylase that plays key roles in the regulation of gene expression during development. Although *KDM6B* variants were initially observed in large-scale sequencing studies in autism spectrum disorder and intellectual disability (ID) between 2014 and 2017 (PMIDs: 25363760, 25363768, 27479843, 28263302), the first report focusing on variants in *KDM6B* as a cause of autosomal dominant syndromic ID was published in 2019 (PMID: 31124279). Heterozygous *KDM6B* *de novo* truncating variants have been reported in at least 12 individuals (PMIDs: 25363768, 31124279). Affected individuals present with motor and speech delays, ID, and dysmorphic facial features; variable features include autism spectrum disorder and mild hand and feet anomalies (PMID: 31124279). Heterozygous *de novo KDM6B* missense and in-frame variants have also been reported, but no functional studies were performed to assess their pathogenicity (PMIDs: 25363760, 25363768, 27479843, 31124279). According to gnomAD (v2.1.1), *KDM6B* is intolerant to truncating variants (pLI = 1) but not to missense variants (Z = 1.32). Homozygous *KDM6B* variants have been reported in three consanguineous families with syndromic ID (PMIDs: 21937992, 26077850, 28097321); the disease association in these cases is not clear and will be curated separately. In summary, *KDM6B* is definitively associated with autosomal dominant syndromic ID. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 19 2022 (SOP Version 8).

neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032790

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032790

Submitter: G2P

neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032790

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Stolerman neurodevelopmental syndromeAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 31124279

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KDM6B variants in ClinVar

13 Conditions Cataloged

not providedTotal: 413

Inborn genetic diseasesTotal: 297

Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalitiesTotal: 207

KDM6B-related disorderTotal: 102

not specifiedTotal: 96

Intellectual disabilityTotal: 12

See casesTotal: 4

KDM6B-related intellectual developmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001348716.2. 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			7 clinvar	114 clinvar	3 clinvar	124
missense	2 clinvar	14 clinvar	469 clinvar	99 clinvar	9 clinvar	593
nonsense	17 clinvar	22 clinvar	8 clinvar			47
start loss						0
frameshift	24 clinvar	34 clinvar	9 clinvar			67
splice donor/acceptor (+/-2bp)	2 clinvar	8 clinvar	2 clinvar			12
Total	45	78	495	213	12	843

Highest pathogenic variant AF is 0.0007239082

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001348716.2	RefSeq	NP_001335645.1	20	MANE Select
ENST00000448097.7	Ensembl	ENSP00000412513.2	20	MANE Select
NM_001080424.2	RefSeq	NP_001073893.1	19	Standard
ENST00000254846.9	Ensembl	ENSP00000254846.5	19	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kdm6bb	Danio rerio	Structure: definitive hemopoiesis Quality: disrupted abnormal

Gene / Model

Organism

Observed Phenotype

kdm6bb

Danio rerio

Structure: definitive hemopoiesis

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oxidative Stress Induced Senescence
Pathways Affected in Adenoid Cystic Carcinoma
Oxidative Stress Induced Senescence
Cellular Senescence
Cellular responses to stress

Biological Process

inflammatory response to antigenic stimulus
chromatin remodeling
response to activity
hippocampus development
cell fate commitment

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
chromatin binding
protein binding
beta-catenin binding
chromatin DNA binding

Cellular Component

nucleus
nucleoplasm
MLL3/4 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000254846
Coding exons: 19
Length: 14893
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125747
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.32	924	1.04e+3	0.885	0.0000708	10584
Missense (PolyPhen)		59	195.02	0.30253		2094
Synonymous	-5.07	570	435	1.31	0.0000293	3740
Loss of Function	7.02	4	65.2	0.0613	0.00000402	677

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00027	0.00025	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000065	0.000053	rare
South Asian	0.000033	0.000033	rare
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:17825402, PubMed:17851529, PubMed:17713478, PubMed:18003914). Demethylates trimethylated and dimethylated H3 'Lys-27' (PubMed:17825402, PubMed:17851529, PubMed:17713478, PubMed:18003914). Plays a central role in regulation of posterior development, by regulating HOX gene expression (PubMed:17851529). Involved in inflammatory response by participating in macrophage differentiation in case of inflammation by regulating gene expression and macrophage differentiation (PubMed:17825402). Plays a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression by acting as a link between T-box factors and the SMARCA4-containing SWI/SNF remodeling complex (By similarity). {ECO:0000250|UniProtKB:Q5NCY0, ECO:0000269|PubMed:17713478, ECO:0000269|PubMed:17825402, ECO:0000269|PubMed:17851529, ECO:0000269|PubMed:18003914, ECO:0000269|PubMed:28262558}.;

Recessive Scores

pRec: 0.127

Intolerance Scores

LoFtool: 0.200
RVIS EVS: -1.32
RVIS percentile EVS: 4.79

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.609

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High