KDM6B-Related Neurodevelopmental Disorder

Mendelian MONDO:0032790 Pathograph 20 Show in embeddings browser Neurodevelopmental disorder Chromatinopathy Epigenetic machinery disorder

KDM6B-related neurodevelopmental disorder is a rare, predominantly de novo autosomal dominant chromatinopathy caused by heterozygous loss-of-function or enzymatically disruptive variants in KDM6B (JMJD3), which encodes one of the two mammalian histone H3 lysine 27 (H3K27) di-/tri-demethylases. KDM6B removes the repressive H3K27me2/me3 mark deposited by Polycomb repressive complex 2 (PRC2, catalytic subunit EZH2), and thereby licenses timely de-repression of lineage-specifying genes during neural commitment, neurogenesis, and synaptic maturation. Reduced KDM6B dosage or catalytic activity leaves developmental loci trapped in a Polycomb-repressed, chromatin-inaccessible state, producing a broad neurodevelopmental and behavioral phenotype. The entity is indexed in OMIM (618505) and MONDO (MONDO:0032790) as "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities" (NEDCFSA), a name derived from the original 12-patient series of Stolerman et al. (2019). The definitive 85-individual cohort of Rots et al. (2023) showed that this name is inaccurate and potentially misleading: coarse facies and distal skeletal anomalies are in fact uncommon, whereas cognitive deficits are near-universal and hypotonia and psychosis are unexpectedly frequent. This entry therefore uses the gene-anchored clinical name "KDM6B-related neurodevelopmental disorder" while retaining MONDO:0032790 and the OMIM-derived label as synonyms.

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1
Inheritance
9
Pathophys.
27
Phenotypes
1
Hypotheses
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Gaps
20
Pathograph
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Genes
3
Variants
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Medical Actions
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Differentials
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Trials
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Models
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References
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Deep Research
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Inheritance

1
Autosomal dominant, predominantly de novo HP:0000006
Heterozygous KDM6B variants act in a dominant, dosage-sensitive manner. Expressivity is highly variable: cognitive involvement is consistent, but the severity of intellectual impairment and the presence of behavioral, psychiatric, dysmorphic, and skeletal features differ widely between individuals carrying comparable variants. Because the great majority of variants are de novo, recurrence risk for the siblings of a proband with a confirmed de novo variant is low, with residual risk from parental germline mosaicism. Inheritance from a mildly affected or apparently unaffected parent is documented and implies incomplete penetrance or highly variable expressivity in a minority of families.
Autosomal dominant inheritance Expressivity: VARIABLE De novo rate: Most reported pathogenic KDM6B variants have arisen de novo. The original 12-patient series consisted entirely of de novo alterations, and the 85-individual cohort is described as carrying mostly de novo (likely) pathogenic variants, with a minority inherited from a mildly affected or apparently unaffected parent.
Show evidence (3 references)
PMID:37196654 SUPPORT Human Clinical
"85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants"
Establishes that pathogenic KDM6B variants are mostly de novo in the definitive cohort.
PMID:37196654 SUPPORT Human Clinical
"Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable."
Directly supports the VARIABLE expressivity assignment.
PMID:31124279 SUPPORT Human Clinical
"We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings."
The founding case series established that the causal KDM6B alterations arise de novo.
◈

Mechanistic Hypotheses

1
HOX/Polycomb mis-regulation as the route to the dysmorphic and distal skeletal minority phenotype
patterning_hox_dysmorphology EMERGING
Evidence balance 1 support
The coarse facies and mild distal skeletal anomalies that gave the disorder its OMIM name are hypothesised to arise from failure of KDM6B-dependent de-repression of HOX and related patterning loci during craniofacial and limb development. Supporting evidence is indirect (H3K27me3 control of Hox genes; hox mis-regulation and posterior developmental defects after inhibition of the KDM6 paralogue UTX in zebrafish). No human KDM6B craniofacial or limb developmental study has tested this directly, and the features are uncommon in the largest cohort.
Pathograph links
Unopposed PRC2-Mediated Polycomb Repression -> Disrupted Craniofacial and Distal Skeletal Patterning INDIRECT UNKNOWN INTERMEDIATES Polycomb and H3K27me3 control of HOX and other patterning loci provides a plausible but not directly demonstrated route from KDM6B loss to the dysmorphic and distal limb features seen in a minority of patients.
Disrupted Craniofacial and Distal Skeletal Patterning -> Neurodevelopmental and Behavioral Phenotype INDIRECT UNKNOWN INTERMEDIATES Contributes the dysmorphic and distal skeletal component of the composite clinical phenotype.
Show evidence (1 reference)
PMID:17851529 SUPPORT Model Organism
"Importantly, morpholino oligonucleotide inhibition of a zebrafish UTX homologue resulted in mis-regulation of hox genes and a striking posterior developmental defect"
Establishes an evolutionarily conserved developmental-patterning role for the KDM6 demethylase family, the premise of this hypothesis.
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Discussions and Knowledge Gaps

6
Does KDM6B loss block neural differentiation or accelerate it? Both are reported, and the reconciliation determines which cellular node actually drives the human cognitive phenotype.
OPEN QUESTION OPEN kdm6b_commitment_direction_paradox
Attached to
pathophysiology#Impaired Neural Commitment and Neurogenesis pathophysiology#Precocious Neural Stem Cell Differentiation and Pool Depletion
Human embryonic stem cell-derived progenitors lacking KDM6 enzymes fail to differentiate into neurons and glia, and Jmjd3 deletion in subventricular zone neural stem cells impairs neuronal differentiation. In the hippocampal dentate gyrus, by contrast, Kdm6b deletion causes precocious neuronal differentiation that exhausts the stem cell pool. These are opposite directions of effect on the same cell-fate decision. Plausible reconciliations include regional specialisation (dentate gyrus versus subventricular zone and cortex), developmental timing, differing degrees of KDM6A compensation, or partial versus complete loss of KDM6 activity; the entry currently models both as separate nodes rather than forcing one. A further open strand is whether some of KDM6B's requirement is catalytic-independent, which would mean H3K27me3 demethylase activity alone does not account for the disorder; the abstracts available here do not settle that.
Proposed experiments
Region-matched conditional Kdm6b deletion comparison
exp_kdm6b_region_matched_deletion_comparison
Delete Kdm6b at matched developmental timepoints in dentate gyrus, subventricular zone, and cortical progenitors in the same study and score differentiation direction with common markers, to test whether the discrepancy is regional or methodological.
Catalytically dead KDM6B rescue
exp_kdm6b_catalytic_dead_rescue
Rescue KDM6B-null human neural progenitors with wild-type versus catalytically dead KDM6B and compare differentiation, proliferation, and H3K27me3 landscape, to quantify how much of the requirement is demethylase-dependent.
Show evidence (2 references)
DOI:10.1101/2024.02.20.581302 Preprint · not peer-reviewed SUPPORT Model Organism
"causes precocious neuronal differentiation, and the NSC population fails to become established in the postnatal DG."
The precocious-differentiation arm of the paradox.
PMID:31959746 SUPPORT In Vitro
"However, KDM6-deficient NPCs exhibit poor proliferation and a failure to differentiate into neurons and glia."
The differentiation-block arm of the paradox, in human cells.
Can the per-feature frequencies from the Rots et al. 2023 cohort be brought into this entry as snippet-verified evidence, so that FrequencyEnum bands can be assigned?
CURATION TODO OPEN kdm6b_uncacheable_cohort_frequencies
Attached to
phenotypes#Hypotonia phenotypes#Psychosis phenotypes#Feeding difficulties phenotypes#Coarse facial features
PMID:37196654 is the definitive 85-individual cohort and its tables carry denominators for every recurrent manifestation, including several that this entry curates without a frequency band and at least two that it cannot curate at all. The publisher blocks full-text download, so `just fetch-reference PMID:37196654` yields an abstract-only cache, and PMC10257005 is not fetchable through the current reference sources. Per the project rule that snippets must be exact quotes from the cached reference, those numbers cannot be used here yet, and this entry deliberately leaves the bands off rather than transcribing figures it cannot verify. Two manifestations are consequently absent from `phenotypes` rather than merely unbanded, because no cacheable source documents them in this disorder: sleep disturbance (recorded only as a bare table row in the PMID:31124279 full text) and macrocephaly or postnatal overgrowth (no narrative statement in any cached source; the founding series reports only individual head-circumference centiles in a table). The overgrowth question matters disproportionately, because it is the phenotypic hinge against the Weaver, Sotos, and Cohen-Gibson differentials that this entry lists: if a substantial minority of KDM6B patients are macrocephalic, the clean "eraser loss gives no overgrowth" contrast drawn in those differentials needs qualifying.
Proposed experiments
Ingest the Rots 2023 cohort tables through a cacheable route
exp_kdm6b_cohort_fulltext_ingest
Obtain the cohort frequency tables through a source the reference validator can cache (author-deposited accepted manuscript, a PMC route once available, or supplementary data with a citable identifier), then assign FrequencyEnum bands to hypotonia, psychosis, feeding difficulty, autism, intellectual disability, and the skeletal features, and add macrocephaly and sleep disturbance as phenotypes.
Should the OMIM and MONDO label "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities" be retired in favour of a gene-anchored name, given that the two features in the name are uncommon?
CONTROVERSY OPEN kdm6b_omim_name_mismatch
Attached to
pathophysiology#Disrupted Craniofacial and Distal Skeletal Patterning
The syndrome name derives from a 12-patient ascertainment series. The 85-individual cohort found coarse facies and distal skeletal anomalies to be rare while hypotonia and psychosis are unexpectedly common, and stated explicitly that the OMIM description is inaccurate and potentially misleading. Retaining the name risks misdirecting clinical suspicion away from patients who lack dysmorphism. This entry uses the gene-anchored name while preserving MONDO:0032790 and the OMIM label as synonyms.
Show evidence (1 reference)
PMID:37196654 SUPPORT Human Clinical
"Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading."
Direct source of the naming controversy recorded here.
By what mechanism does reduced KDM6B activity produce coarse facies and mild distal skeletal anomalies in the minority of patients who have them?
KNOWLEDGE GAP OPEN kdm6b_dysmorphology_mechanism_gap
Attached to
pathophysiology#Disrupted Craniofacial and Distal Skeletal Patterning
The neural arm of the mechanism is well supported by human stem cell, mouse, and fly data, but no study has connected KDM6B loss to human craniofacial or limb patterning. The HOX/Polycomb route is inferred from work on the paralogue UTX in zebrafish. Whether the dysmorphic minority reflects a distinct variant class, a modifier, or simply ascertainment bias is unknown.
Proposed experiments
Genotype-stratified dysmorphology analysis of the published cohort
exp_kdm6b_genotype_dysmorphology_stratification
Test within the 85-individual cohort whether coarse facies and distal skeletal features segregate with catalytic-domain missense variants versus truncating variants, or are distributed at random with respect to variant class.
KDM6B-null neural crest and limb bud differentiation with chromatin profiling
exp_kdm6b_neural_crest_limb_differentiation
Differentiate KDM6B-null human induced pluripotent stem cells along neural crest and limb bud trajectories and profile H3K27me3 and chromatin accessibility at HOX clusters to test the patterning hypothesis directly in human cells.
DNA methylation episignature stratified by dysmorphism
exp_kdm6b_episignature_stratified
Derive a peripheral-blood DNA methylation episignature in KDM6B variant carriers and test whether carriers with and without dysmorphism separate, which would indicate a distinct molecular subgroup.
What is the true prevalence, age-of-onset distribution, and natural history of psychosis in KDM6B-related neurodevelopmental disorder?
KNOWLEDGE GAP OPEN kdm6b_psychosis_frequency
Attached to
phenotypes#Psychosis
Psychosis is one of the most clinically actionable features of this disorder, yet the available published characterisations are qualitative and not obviously concordant: OMIM records psychosis in a small percentage of individuals over age 12, while the largest cohort lists it among features that are unexpectedly common. The cohort denominator for individuals aged 12 or older is small. No frequency band can responsibly be assigned from the retrievable abstracts, so none is asserted on the phenotype record.
Proposed experiments
Prospective psychiatric follow-up of the published cohort
exp_kdm6b_prospective_psychiatric_followup
Follow cohort members prospectively from age 10 with standardised psychosis screening instruments to establish incidence and age of onset rather than cross-sectional prevalence in an ascertainment-enriched sample.
Age-stratified reanalysis of the 85-individual cohort
exp_kdm6b_age_stratified_reanalysis
Re-report psychiatric outcomes with explicit age-stratified denominators so that a defensible FrequencyEnum band can be assigned.
Do the available Kdm6b mouse models reproduce the non-neural (craniofacial and distal skeletal) arm of the human phenotype, or only the behavioral arm?
HUMAN MODEL MISMATCH OPEN kdm6b_mouse_human_dysmorphology_mismatch
Attached to
pathophysiology#Disrupted Craniofacial and Distal Skeletal Patterning
The heterozygous and mosaic-brain-knockout mouse models are reported in terms of sociability, memory, hyperactivity, impulsivity, and hippocampal synaptic physiology. The mosaic model is brain-restricted by construction and cannot address craniofacial or limb development at all. Evidence therefore exists in a model system but its fidelity to the dysmorphic component of the human disorder is untested rather than absent, which is the defining situation for a HUMAN_MODEL_MISMATCH rather than a plain knowledge gap.
Proposed experiments
Craniofacial and skeletal morphometry of Kdm6b heterozygous mice
exp_kdm6b_het_mouse_craniofacial_morphometry
Perform skeletal preparations and micro-CT craniofacial morphometry on constitutive Kdm6b heterozygous mice against wild-type littermates to test whether the dysmorphic arm of the human phenotype is modelled at all.
Lineage-restricted conditional Kdm6b deletion
exp_kdm6b_lineage_conditional_deletion
Delete Kdm6b conditionally in neural crest and limb bud lineages to test tissue-autonomous requirements for craniofacial and distal limb patterning.
Show evidence (1 reference)
PMID:39223259 SUPPORT Model Organism
"Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits."
Illustrates that the available mouse characterisation is brain- and behavior-focused, leaving the dysmorphic arm of the human phenotype unmodelled.
⚙

Pathophysiology

9
KDM6B Haploinsufficiency and Catalytic Impairment
Heterozygous de novo truncating variants reduce functional KDM6B dosage, while missense and in-frame indel variants in or near the JmjC catalytic domain and the zinc-binding motif impair the enzyme's demethylase activity or stability. Both routes converge on reduced cellular H3K27me2/me3 demethylase capacity.
KDM6B hgnc:29012 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDM6B (hgnc:29012). hgnc:29012 is a gene from the HUGO Gene Nomenclature Committee.
histone H3K27me2/H3K27me3 demethylase activity GO:0071558 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone H3K27me2/H3K27me3 demethylase activity (GO:0071558). GO:0071558 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
Kdm6b heterozygous mouse Mus musculus partially recapitulates Recapitulates the human heterozygous loss-of-function dosage state.
Drosophila dual gain-of-function KDM6B variant assay Drosophila melanogaster measures Functional readout that classifies patient missense and in-frame indel variants as disruptive.
Downstream
Failure to Remove Repressive H3K27me3 Reduced KDM6B enzyme dosage or catalytic competence directly lowers the rate at which H3K27me2/me3 is erased from target loci.
Show evidence (2 references)
PMID:31124279 SUPPORT Human Clinical
"Lysine-specific demethylase 6B (KDM6B) demethylates trimethylated lysine-27 on histone H3."
Establishes the enzymatic identity of KDM6B whose loss initiates the disease mechanism.
PMID:37196654 SUPPORT Model Organism
"we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B"
Shows that non-truncating disease alleles act by disrupting the catalytic and cofactor-binding regions, that is, by impairing enzyme function.
Failure to Remove Repressive H3K27me3
KDM6B (JMJD3) and its paralogue KDM6A (UTX) are the JmjC-domain enzymes that specifically remove di- and trimethylation from histone H3 lysine 27. When KDM6B activity falls, H3K27me3 accumulates at KDM6B-bound developmental loci. In human neural progenitor cells lacking KDM6 enzymes, H3K27me3 accumulates and DNA accessibility at neural developmental genes is blocked.
chromatin organization GO:0006325 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromatin organization (GO:0006325). GO:0006325 is a biological process from the Gene Ontology. ⚠ ABNORMAL
histone H3K27me2/H3K27me3 demethylase activity GO:0071558 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone H3K27me2/H3K27me3 demethylase activity (GO:0071558). GO:0071558 is a molecular function from the Gene Ontology. ↓ DECREASED
Experimental models
KDM6-deficient human pluripotent stem cell-derived neural progenitor cells OTHER Shows H3K27me3 accumulation and loss of accessibility at neural developmental genes on KDM6 loss, in human cells.
Downstream
Unopposed PRC2-Mediated Polycomb Repression Persistent H3K27me3 at developmental loci means PRC2-deposited repression is no longer counterbalanced by demethylation.
Show evidence (3 references)
PMID:18003914 SUPPORT In Vitro
"Here we show the JmjC domain-containing protein UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome), as well as the related JMJD3 (jumonji domain containing 3), specifically removes methyl marks on H3K27 in vitro."
Identifies JMJD3/KDM6B as an H3K27-specific demethylase, the activity lost in this disorder.
PMID:18003914 SUPPORT In Vitro
"Finally, overexpression of UTX and JMJD3 leads to reduced di- and trimethylation on H3K27 in cells, suggesting that UTX and JMJD3 may function as H3K27 demethylases in vivo."
Demonstrates that cellular H3K27me2/me3 levels are set by KDM6 enzyme dosage, so reduced dosage raises the repressive mark.
PMID:31959746 SUPPORT In Vitro
"Mechanistically, both JMJD3 and UTX are found to be enriched in gene loci essential for neural development in hNPCs, and KDM6 impairment leads to H3K27me3 accumulation and blockade of DNA accessibility at these genes."
Human neural progenitor evidence that loss of KDM6 activity causes H3K27me3 accumulation at neurodevelopmental loci.
Unopposed PRC2-Mediated Polycomb Repression
H3K27me3 is deposited by Polycomb repressive complex 2 (PRC2, catalytic subunit EZH2) and read by Polycomb repressive complex 1 to enforce transcriptional silencing. KDM6B provides the opposing, erasing arm of this switch; its enzymatic activity antagonizes Polycomb regulation and resolves bivalent promoters at the onset of differentiation. With KDM6B activity reduced, developmental promoters and enhancers that should be de-repressed remain Polycomb-silenced. This is the mechanistic mirror image of PRC2 gain-of-function chromatinopathies such as EZH2-related Weaver syndrome, in which the writing arm is overactive.
HOX/Polycomb mis-regulation as the route to the dysmorphic and distal skeletal minority phenotype
negative regulation of transcription by RNA polymerase II GO:0000122 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased negative regulation of transcription by RNA polymerase II (GO:0000122). GO:0000122 is a biological process from the Gene Ontology. ↑ INCREASED chromatin remodeling GO:0006338 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromatin remodeling (GO:0006338). GO:0006338 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Dysregulated Neurodevelopmental Gene Expression Sustained Polycomb repression at lineage-specifying loci prevents their timely activation.
Disrupted Craniofacial and Distal Skeletal Patterning Polycomb and H3K27me3 control of HOX and other patterning loci provides a plausible but not directly demonstrated route from KDM6B loss to the dysmorphic and distal limb features seen in a minority of patients. HOX/Polycomb mis-regulation as the route to the dysmorphic and distal skeletal minority phenotype
Show evidence (4 references)
PMID:18716661 SUPPORT In Vitro
"Our results demonstrate the relevance of an enzymatic activity that antagonizes Polycomb regulation"
Establishes that Jmjd3/KDM6B acts specifically to antagonize Polycomb (PRC2) repression, the activity lost in this disorder.
PMID:17851529 SUPPORT In Vitro
"Histone H3K27 trimethylation (H3K27me3) has been linked to polycomb-group-protein-mediated suppression of Hox genes and animal body patterning, X-chromosome inactivation and possibly maintenance of embryonic stem cell (ESC) identity."
Defines the Polycomb-repressive role of the H3K27me3 mark that KDM6B normally erases.
PMID:17851529 SUPPORT In Vitro
"An imbalance of H3K27 methylation owing to overexpression of the methylase EZH2 has been implicated in metastatic prostate and aggressive breast cancers."
Supports the framing of KDM6B loss and EZH2 gain as opposite perturbations of the same H3K27 methylation balance; the cited disease context is oncological rather than neurodevelopmental, hence PARTIAL.
+ 1 more reference
Dysregulated Neurodevelopmental Gene Expression
KDM6B occupies promoters and neural enhancer elements of genes that specify neural identity, and its demethylase activity converts these elements from a poised or bivalent state to an active one. Loss of KDM6B leaves these regulatory elements enriched for H3K27me3 and inaccessible, so the transcriptional programme for neural commitment is not executed at the right time. The clinical literature describes the same principle as modulation of chromatin accessibility by RNA polymerase.
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology. neural stem cell CL:0000047 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural stem cell (CL:0000047). CL:0000047 is a cell type from the Cell Ontology.
positive regulation of transcription by RNA polymerase II GO:0045944 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased positive regulation of transcription by RNA polymerase II (GO:0045944). GO:0045944 is a biological process from the Gene Ontology. ↓ DECREASED chromatin organization GO:0006325 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromatin organization (GO:0006325). GO:0006325 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Impaired Neural Commitment and Neurogenesis Failure to activate neurogenic regulators blocks progression of progenitors into neurons and glia.
Precocious Neural Stem Cell Differentiation and Pool Depletion In the hippocampal dentate gyrus the same loss of KDM6B-dependent regulation disrupts the transcriptomic signature of neural stem cell maintenance, so progenitors differentiate early instead of being held in reserve.
Show evidence (3 references)
PMID:25176653 SUPPORT Model Organism
"JMJD3 regulates neurogenic gene expression via interaction at not only promoter regions but also neurogenic enhancer elements."
Shows that KDM6B/JMJD3 directly controls the neurodevelopmental transcriptional programme at promoters and enhancers.
PMID:25176653 SUPPORT Model Organism
"In Jmjd3-deleted SVZ cells, I12b remains enriched with H3K27me3 and Dlx2-dependent neurogenesis fails."
Direct demonstration that loss of the demethylase leaves a neurogenic enhancer H3K27me3-marked and its target gene programme unexecuted.
PMID:38326731 SUPPORT Human Clinical
"KDM6B encodes a histone demethylase, expressed in different tissues during development, which regulates gene expression through the modulation of chromatin accessibility by RNA polymerase."
Clinical-genetics framing of the same chromatin-accessibility mechanism in the context of this disorder.
Impaired Neural Commitment and Neurogenesis
KDM6B activity is required for cells to commit to the neural lineage and for neural progenitors to proliferate and differentiate into neurons and glia. Human embryonic stem cell-derived progenitors lacking KDM6 enzymes still form neural progenitors but proliferate poorly and fail to make neurons and glia; in mice, deletion of Jmjd3 in subventricular zone neural stem cells impairs neuronal differentiation in both the developing and the adult brain.
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology. neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
neuron differentiation GO:0030182 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuron differentiation (GO:0030182). GO:0030182 is a biological process from the Gene Ontology. ↓ DECREASED neural precursor cell proliferation GO:0061351 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural precursor cell proliferation (GO:0061351). GO:0061351 is a biological process from the Gene Ontology. ↓ DECREASED cell fate commitment GO:0045165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cell fate commitment (GO:0045165). GO:0045165 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Experimental models
KDM6-deficient human pluripotent stem cell-derived neural progenitor cells OTHER Shows the progenitor proliferation and differentiation block in human cells.
Downstream
Altered Synaptic Transmission and Plasticity Neurons produced from a KDM6B-deficient progenitor pool show downstream deficits in excitatory synaptic transmission and plasticity.
Neurodevelopmental and Behavioral Phenotype Defective neurogenesis and neuronal differentiation underlie the cognitive and developmental features of the disorder.
Show evidence (3 references)
PMID:18716661 SUPPORT In Vitro
"Starting from a comprehensive profiling of JmjC-domain genes, we report here that Jmjd3, recently identified as a H3-K27me3 specific demethylase, controls the expression of key regulators and markers of neurogenesis and is required for commitment to the neural lineage."
Establishes a requirement for KDM6B/Jmjd3 in neural lineage commitment.
PMID:31959746 SUPPORT In Vitro
"However, KDM6-deficient NPCs exhibit poor proliferation and a failure to differentiate into neurons and glia."
Human stem cell evidence that loss of KDM6 demethylases blocks progenitor proliferation and neuronal/glial differentiation.
PMID:25176653 SUPPORT Model Organism
"JMJD3 is upregulated in neuroblasts, and Jmjd3 deletion targeted to SVZ NSCs in both developing and adult mice impairs neuronal differentiation."
In vivo requirement for the demethylase in developmental and adult neurogenesis.
Precocious Neural Stem Cell Differentiation and Pool Depletion
A second, direction-opposite consequence of KDM6B loss in the neural stem cell compartment. In the mouse hippocampal dentate gyrus, KDM6B is required to establish and maintain the neural stem cell pool: conditional deletion in embryonic dentate gyrus precursors causes precocious neuronal differentiation so that the stem cell population never becomes established, leaving the adult hippocampus essentially devoid of neural stem cells, with defective hippocampal-dependent behavior. Deletion in adult dentate gyrus neural stem cells likewise induces early differentiation and failure of pool maintenance. This is deliberately modeled as a node distinct from "Impaired Neural Commitment and Neurogenesis": that node captures a differentiation block (progenitors fail to become neurons), whereas this one captures premature differentiation that exhausts the progenitor reserve. Both are reported for KDM6B loss in different compartments and developmental windows, and reconciling them is an open question recorded in the kdm6b_commitment_direction_paradox discussion. The node is PROVISIONAL because the supporting study is a mouse preprint.
neural stem cell CL:0000047 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural stem cell (CL:0000047). CL:0000047 is a cell type from the Cell Ontology. neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology.
stem cell population maintenance GO:0019827 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased stem cell population maintenance (GO:0019827). GO:0019827 is a biological process from the Gene Ontology. ↓ DECREASED neuron differentiation GO:0030182 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neuron differentiation (GO:0030182). GO:0030182 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Neurodevelopmental and Behavioral Phenotype Loss of the hippocampal neural stem cell reserve is accompanied by defective hippocampal-dependent behavior in the mouse, offering a substrate for the cognitive phenotype that is separate from the synaptic one.
Show evidence (4 references)
DOI:10.1101/2024.02.20.581302 Preprint · not peer-reviewed SUPPORT Model Organism
"Here we show that the chromatin regulator KDM6B is required for both the establishment and maintenance of NSCs in the mouse DG."
Establishes the neural stem cell maintenance requirement that this node asserts. Preprint (bioRxiv), so the node is graded PROVISIONAL.
DOI:10.1101/2024.02.20.581302 Preprint · not peer-reviewed SUPPORT Model Organism
"Conditional deletion of Kdm6b in embryonic DG precursors results in an adult hippocampus that is essentially devoid of NSCs, and hippocampal-dependent behaviors are defective."
Links stem cell pool depletion to a behavioral deficit, the connection this node's downstream edge asserts.
DOI:10.1101/2024.02.20.581302 Preprint · not peer-reviewed SUPPORT Model Organism
"causes precocious neuronal differentiation, and the NSC population fails to become established in the postnatal DG."
Names the precocious-differentiation mechanism that distinguishes this node from the differentiation-block node.
+ 1 more reference
Altered Synaptic Transmission and Plasticity
Beyond its developmental role, KDM6B loss perturbs mature circuit function. Mosaic brain knockout of KDM6B in mice reduces NMDA receptor-mediated excitatory synaptic transmission and plasticity in the hippocampus, providing a cellular substrate for the cognitive and behavioral phenotype. This node is marked provisional because the evidence is currently from rodent and fly models rather than from human tissue.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
synaptic transmission, glutamatergic GO:0035249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased synaptic transmission, glutamatergic (GO:0035249). GO:0035249 is a biological process from the Gene Ontology. ↓ DECREASED regulation of synaptic plasticity GO:0048167 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of synaptic plasticity (GO:0048167). GO:0048167 is a biological process from the Gene Ontology. ⚠ ABNORMAL long-term synaptic potentiation GO:0060291 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased long-term synaptic potentiation (GO:0060291). GO:0060291 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
KDM6B mosaic brain knockout mouse Mus musculus partially recapitulates Provides the electrophysiological readout for this node.
Drosophila dual gain-of-function KDM6B variant assay Drosophila melanogaster partially recapitulates Demonstrates a conserved requirement for the orthologue in memory and behavior.
Downstream
Neurodevelopmental and Behavioral Phenotype Impaired excitatory synaptic transmission and plasticity plausibly contribute to the cognitive deficits and behavioral features.
Show evidence (2 references)
PMID:39223259 SUPPORT Model Organism
"Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity."
Direct electrophysiological evidence linking KDM6B loss to reduced excitatory synaptic transmission and plasticity.
PMID:37196654 SUPPORT Model Organism
"Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior."
Cross-species evidence that the KDM6B orthologue is required for memory and behavior, consistent with a circuit-level function.
Disrupted Craniofacial and Distal Skeletal Patterning
A minority of affected individuals have coarse facial features and mild distal skeletal anomalies (broad hands, syndactyly, clinodactyly). A plausible mechanism is loss of KDM6-dependent de-repression of HOX and other patterning loci, since H3K27me3 controls Hox gene expression and body patterning and inhibition of the KDM6 paralogue UTX in zebrafish causes hox mis-regulation with a posterior developmental defect. This route has not been demonstrated for KDM6B in human craniofacial or limb development, and the 85-individual cohort showed these features to be uncommon, so the node is explicitly hypothetical.
HOX/Polycomb mis-regulation as the route to the dysmorphic and distal skeletal minority phenotype
cell fate commitment involved in pattern specification GO:0060581 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cell fate commitment involved in pattern specification (GO:0060581). GO:0060581 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Neurodevelopmental and Behavioral Phenotype Contributes the dysmorphic and distal skeletal component of the composite clinical phenotype. HOX/Polycomb mis-regulation as the route to the dysmorphic and distal skeletal minority phenotype
Show evidence (2 references)
PMID:17851529 SUPPORT Model Organism
"Importantly, morpholino oligonucleotide inhibition of a zebrafish UTX homologue resulted in mis-regulation of hox genes and a striking posterior developmental defect, which was partially rescued by wild-type, but not by catalytically inactive, human UTX."
Model-organism evidence that loss of KDM6-family H3K27 demethylase activity mis-regulates hox genes and disturbs body patterning; it concerns the paralogue UTX in zebrafish, not KDM6B in human limb or face, hence PARTIAL.
PMID:37196654 SUPPORT Human Clinical
"Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.)."
Establishes that the dysmorphic and skeletal arm of the phenotype exists but is uncommon, justifying the low-confidence, minority-pathway framing of this node.
Neurodevelopmental and Behavioral Phenotype
The convergent organism-level consequence: near-universal cognitive involvement with highly variable additional features, including motor and speech delay, hypotonia, autism spectrum disorder, attention deficit hyperactivity disorder, psychosis in older individuals, and, in a minority, coarse facies and mild distal skeletal anomalies.
learning or memory GO:0007611 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased learning or memory (GO:0007611). GO:0007611 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Kdm6b heterozygous mouse Mus musculus partially recapitulates Reproduces the autism- and ADHD-like behavioral output of the mechanism.
Show evidence (1 reference)
PMID:37196654 SUPPORT Human Clinical
"Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable."
Defines the organism-level output of the mechanism: obligate cognitive involvement on a variable background.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for KDM6B-Related Neurodevelopmental Disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

27
Digestive 3
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
The Rots et al. cohort reports a denominator for neonatal feeding difficulty or gastroesophageal reflux, but that figure is in the full text, which the publisher does not release into the reference cache, so no frequency band is asserted. See the kdm6b_uncacheable_cohort_frequencies discussion.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"There was a history of hypotonia and feeding difficulties in the neonatal period requiring a nasogastric tube."
Documents neonatal feeding difficulty requiring tube feeding in a KDM6B variant carrier.
Gastroesophageal reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"There was a surgery for gastroesophageal reflux at 5 years of age."
Documents clinically significant gastroesophageal reflux in a KDM6B variant carrier.
Constipation HP:0002019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"There was constipation with some subsequent bladder compression."
Documents constipation, with a secondary urological consequence, in a KDM6B variant carrier.
Ear 1
Macrotia HP:0000400 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrotia (HP:0000400). HP:0000400 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"Dysmorphic facial features that were reported included coarse features, a prominent forehead, broad mouth, large and prominent ears, a round face, prognathism, and epicanthal folds."
Lists large and prominent ears in the summary of dysmorphic facial features across the cohort.
Genitourinary 1
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"Other features that were reported were hypoplastic nipples, pectus excavatum, laryngomalacia, and cryptorchidism."
Lists cryptorchidism among the additional features of the KDM6B cohort.
Head and Neck 3
Coarse facial features HP:0000280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarse facial features (HP:0000280). HP:0000280 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31124279 SUPPORT Human Clinical
"dysmorphic facial features including a prominent nasal bridge or nose, coarse features, as well as widened hands and syndactyly"
Original description of the coarse facial features in KDM6B variant carriers.
PMID:37196654 SUPPORT Human Clinical
"Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort"
Qualifies the feature as present but uncommon once ascertainment bias is removed. No frequency band is asserted because the abstract gives no numerator.
Nonspecific dysmorphism without a recognisable gestalt Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38326731 SUPPORT Human Clinical
"characterized by non-pathognomonic facial and body dysmorphisms, a wide range of neurodevelopmental and behavioral disorders and nonspecific neuroradiological findings"
States directly that the dysmorphism is non-pathognomonic and the neuroradiology nonspecific.
Prominent forehead HP:0011220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent forehead (HP:0011220). HP:0011220 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"Dysmorphic facial features that were reported included coarse features, a prominent forehead, broad mouth, large and prominent ears, a round face, prognathism, and epicanthal folds."
Lists a prominent forehead in the summary of dysmorphic facial features across the cohort.
Limbs 2
Broad hands Broad palm HP:0001169 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad palm (HP:0001169). HP:0001169 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"as well as widened hands and syndactyly with de novo variants in the KDM6B gene"
Reports widened hands as a recurrent distal skeletal feature in the original cohort.
Syndactyly HP:0001159 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syndactyly (HP:0001159). HP:0001159 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"as well as widened hands and syndactyly with de novo variants in the KDM6B gene"
Reports syndactyly among the distal limb findings of the original cohort.
Musculoskeletal 3
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37196654 SUPPORT Human Clinical
"Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.)."
Identifies hypotonia as an unexpectedly common feature of the expanded cohort. The statement is qualitative, so no FrequencyEnum band is assigned.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"The proband had a pectus excavatum, a torticollis with a right head deviation, scoliosis, and an extra rib on each side."
Documents scoliosis, alongside other axial skeletal anomalies, in a KDM6B variant carrier.
Joint hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"widened and thickened hands and fingers, joint hypermobility, clinodactyly of the fifth fingers, and toe syndactyly"
Names joint hypermobility among the musculoskeletal features present in a subset of the cohort.
Nervous System 9
Cognitive deficits VERY_FREQUENT Cognitive impairment HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37196654 SUPPORT Human Clinical
"Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable."
The 85-individual cohort reports cognitive deficits in every affected individual, which maps to the VERY_FREQUENT (80-100%) band.
Impaired intellectual development Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings"
Intellectual disability was one of the defining features of the founding case series.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings."
Developmental delay was the presenting feature of all 12 patients in the founding series.
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"In this study, we report a case series of 12 patients presenting with neurodevelopmental delays in speech and motor development"
Explicitly names speech delay as a defining feature of the reported cohort.
Motor delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"In this study, we report a case series of 12 patients presenting with neurodevelopmental delays in speech and motor development"
Explicitly names motor delay as a defining feature of the reported cohort.
Psychosis HP:0000709 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Psychosis (HP:0000709). HP:0000709 is a phenotype from the Human Phenotype Ontology.
Psychiatric surveillance from adolescence onward is the practical implication of this finding. The cohort tables (full text of PMID:37196654, which the publisher does not release into the reference cache) report the psychotic-disorder denominator as a small number of individuals aged 12 years or older; because that figure cannot be quoted here it is not converted into a frequency band. Resolving it is tracked in the kdm6b_psychosis_frequency discussion.
Show evidence (1 reference)
PMID:37196654 SUPPORT Human Clinical
"Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.)."
The definitive cohort explicitly names psychosis as a feature of the KDM6B-related NDD phenotype, contradicting its omission from the OMIM-derived syndrome name.
Autism spectrum disorder HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:38326731 SUPPORT Human Clinical
"behavioral traits relatable to oppositional defiant, autism spectrum, and attention deficit hyperactivity disorders"
Human case with a de novo pathogenic KDM6B variant showing autism spectrum behavioral traits.
PMID:35711692 SUPPORT Other
"Recent genetic and clinical studies report that KDM6B, a gene encoding a histone H3 lysine 27-specific demethylase, is one of the highest ASD risk genes."
Reports the standing of KDM6B among autism risk genes. Tagged OTHER rather than HUMAN_CLINICAL because this is a background statement in the introduction of a mouse study, not human clinical data generated by the cited publication; the primary human sequencing studies it refers to do not name KDM6B in their abstracts, so no quotable human-genetic source could be substituted.
PMID:35711692 SUPPORT Model Organism
"Here we use an animal model to show that genetic deletion of one Kdm6b allele in mice leads to autistic-like impaired sociability and object recognition memory."
Heterozygous, dosage-matched mouse model reproduces autistic-like behavior, supporting causality of KDM6B haploinsufficiency.
Attention deficit hyperactivity disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35840288 SUPPORT Human Clinical
"The case was oriented as a neurodevelopmental disorder secondary to a genetic alteration and a comorbid Attention Deficit Hyperactivity Disorder (ADHD)."
Human case with a KDM6B frameshift variant and formally assessed comorbid ADHD.
PMID:35711692 SUPPORT Model Organism
"In addition, the mutant mice display markedly increased locomotor activity and impulsivity, two ADHD-like behavioral traits that are ameliorated by methylphenidate treatment."
Mouse haploinsufficiency model reproduces ADHD-like hyperactivity and impulsivity.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38326731 SUPPORT Human Clinical
"exhibiting facial dysmorphisms, dysgraphia, behavioral traits relatable to oppositional defiant, autism spectrum, and attention deficit hyperactivity disorders, a single seizure episode"
Documents a seizure episode in a genetically confirmed patient.
Other 5
Prominent nasal bridge HP:0000426 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent nasal bridge (HP:0000426). HP:0000426 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"dysmorphic facial features including a prominent nasal bridge or nose"
Directly reports the prominent nasal bridge or nose in the KDM6B cohort.
Gray matter heterotopia HP:0002282 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar heterotopic nodule, annotated with Gray matter heterotopia (HP:0002282). HP:0002282 is a phenotype from the Human Phenotype Ontology.
Single case report. Retained because it is the only structural brain finding specifically attributed to this disorder to date.
Show evidence (1 reference)
PMID:38326731 SUPPORT Human Clinical
"a neuroimaging finding of a single cerebellar heterotopic nodule, never described to date in this genetic condition"
Single-patient observation, explicitly novel and therefore not generalisable, so no frequency is asserted.
Patent foramen ovale HP:0001655 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent foramen ovale (HP:0001655). HP:0001655 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"The patient also had a patent foramen ovale and some jaundice."
Documents a congenital cardiac anomaly in a KDM6B variant carrier. Curated at this specific level because the cited case names the specific defect.
Clinodactyly of the 5th finger HP:0004209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clinodactyly of the 5th finger (HP:0004209). HP:0004209 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"widened and thickened hands and fingers, joint hypermobility, clinodactyly of the fifth fingers, and toe syndactyly"
Names fifth-finger clinodactyly among the musculoskeletal features present in a subset of the cohort.
Mandibular prognathia HP:0000303 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mandibular prognathia (HP:0000303). HP:0000303 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"Dysmorphic facial features that were reported included coarse features, a prominent forehead, broad mouth, large and prominent ears, a round face, prognathism, and epicanthal folds."
Lists prognathism in the summary of dysmorphic facial features across the cohort.
🧬

Genetic Associations

1
KDM6B
Gene: KDM6B hgnc:29012 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KDM6B (hgnc:29012). hgnc:29012 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (3 references)
PMID:31124279 SUPPORT Human Clinical
"The KDM6B protein consists of the JmjC catalytic domain and C-terminal helix and zinc motifs which are important in cofactor binding and protein stability"
Defines the functional domain architecture in which the disease-associated missense and in-frame variants cluster.
PMID:31124279 SUPPORT Computational
"indicating that haploinsufficiency of the KDM6B gene is not tolerated"
Population-constraint evidence (gnomAD observed/expected loss-of-function score) that KDM6B is dosage sensitive, the premise of the haploinsufficiency mechanism. Tagged COMPUTATIONAL because the claim comes from a population-database constraint metric rather than a patient observation.
PMID:37196654 SUPPORT Model Organism
"Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B."
Functional assay evidence that disease-associated missense/in-frame variants in the catalytic and zinc-binding regions are damaging. Tagged MODEL_ORGANISM because the assay is a whole-organism Drosophila gain-of-function experiment; the same sentence also reports a computational 3D structure analysis, which is not separately curated here.
🔬

Variants

3
KDM6B truncating variants Pathogenic
Gene: KDM6B hgnc:29012 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in KDM6B (hgnc:29012). hgnc:29012 is a gene from the HUGO Gene Nomenclature Committee. Loss of function
Nonsense and frameshift variants distributed across KDM6B, reported de novo in the founding case series (for example p.Tyr75X, p.Arg149X, p.Glu1244X and several frameshifts), consistent with a haploinsufficiency mechanism.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings."
Source of the de novo truncating and frameshift alleles reported in the original cohort.
KDM6B catalytic-domain missense and in-frame indel variants Pathogenic
Gene: KDM6B hgnc:29012 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in KDM6B (hgnc:29012). hgnc:29012 is a gene from the HUGO Gene Nomenclature Committee. Missense / in-frame indel
Missense substitutions and in-frame insertions or deletions located in or near the JmjC catalytic domain or the Zn-containing domain. Eleven such variants were shown to be functionally disruptive using 3D protein structure analysis combined with a dual Drosophila gain-of-function assay.
Show evidence (1 reference)
PMID:37196654 SUPPORT Model Organism
"we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B"
Direct functional demonstration that these non-truncating alleles impair KDM6B function.
Copy-number deletions encompassing KDM6B Uncertain Significance
Gene: KDM6B hgnc:29012 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in KDM6B (hgnc:29012). hgnc:29012 is a gene from the HUGO Gene Nomenclature Committee. Copy number loss
Chromosomal microarray has identified 17p13.1 deletions that encompass KDM6B in individuals with overlapping features (developmental delay, intellectual disability, speech delay). These are curated as a separate, weaker variant class rather than as established pathogenic alleles, because every reported deletion also removes neighbouring genes, so the phenotype cannot be attributed to KDM6B alone. Chromosomal microarray therefore remains appropriate when a copy-number disorder is suspected, but a deletion finding does not by itself establish this diagnosis.
Show evidence (1 reference)
PMID:31124279 SUPPORT Human Clinical
"However, it is important to note that all seven of these deletions also encompass neighboring genes the effects of which are uncertain."
Directly states the attribution limitation that makes this a PARTIAL, uncertain-significance variant class rather than a pathogenic one.
💊

Medical Actions

3
Multidisciplinary developmental and supportive care
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No disease-modifying therapy exists. Management is supportive and anticipatory: early intervention with physical, occupational, and speech therapy for developmental delay and hypotonia, educational support for learning difficulties, and coordinated follow-up across genetics, neurology, and psychiatry. Psychiatric surveillance from adolescence is warranted given the reported psychosis risk.
Mechanism Target:
Neurodevelopmental and Behavioral Phenotype — Supportive care addresses the organism-level developmental and behavioral consequences rather than the underlying chromatin lesion.
Show evidence (1 reference)
PMID:35840288 SUPPORT Human Clinical
"It is highly probable that the complexity of these cases requires an approach by a multidisciplinary team"
Explicit clinical recommendation for multidisciplinary management of KDM6B-related disease. The quote is trimmed to the last complete word before the cached abstract itself is truncated.
Genetic counseling
Category: Counseling / Informational Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counseling covers the autosomal dominant, predominantly de novo mechanism, the low but non-zero sibling recurrence risk from parental germline mosaicism, the possibility of a mildly affected transmitting parent, and the wide variability of the phenotype. Establishing the molecular diagnosis also resolves the differential with lysosomal storage and overgrowth chromatinopathies.
Show evidence (1 reference)
PMID:38326731 SUPPORT Human Clinical
"These findings expand the phenotypic spectrum of this syndrome, highlighting the potential role for KDM6B in cerebellar development and providing valuable insights for genetic counseling."
The clinical literature frames phenotype delineation in this disorder as directly serving genetic counseling.
Stimulant pharmacotherapy for ADHD symptoms
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: methylphenidate CHEBI:6887 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses methylphenidate (CHEBI:6887). CHEBI:6887 is a therapeutic agent from Chemical Entities of Biological Interest.
Standard ADHD pharmacotherapy is used symptomatically when attention deficit and hyperactivity are impairing. Direct human trial evidence in KDM6B-related NDD is absent; the mechanistic rationale is supported by rescue of hyperactivity and impulsivity by methylphenidate in the heterozygous Kdm6b mouse. This is preclinical support only and must not be read as disease-specific efficacy evidence.
Target Phenotypes: Attention deficit hyperactivity disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35711692 SUPPORT Model Organism
"In addition, the mutant mice display markedly increased locomotor activity and impulsivity, two ADHD-like behavioral traits that are ameliorated by methylphenidate treatment."
Model-organism evidence of methylphenidate response in Kdm6b haploinsufficiency; PARTIAL because no human treatment study exists for this disorder.
🔬

Diagnosis

1
Molecular diagnosis by exome or genome sequencing
Because the dysmorphism is mild and non-pathognomonic and there is no recognisable facial gestalt, the diagnosis is made molecularly rather than clinically: exome or genome sequencing, or a neurodevelopmental gene panel that includes KDM6B, with parental testing to establish de novo status. Variant interpretation should be domain-aware, since missense variants outside the JmjC catalytic and Zn-containing domains may be benign.
Show evidence (2 references)
PMID:31124279 SUPPORT Human Clinical
"We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings."
Exome sequencing is the ascertainment route by which this disorder is identified.
PMID:37196654 SUPPORT Model Organism
"we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants"
Establishes a functional testing paradigm as an adjunct to sequence-based variant interpretation in this disorder.
📊

Prevalence

1
Worldwide, individuals ascertained by exome or genome sequencing
Cases In Literature Ultra Rare
No population-based prevalence estimate exists. The largest published series assembled 85 individuals worldwide through international collaboration, an order of magnitude that supports an ultra-rare classification.
Show evidence (1 reference)
PMID:37196654 SUPPORT Human Clinical
"Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading."
Establishes the total published cohort size (85 individuals worldwide), the basis for the ultra-rare prevalence class.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from KDM6B-Related Neurodevelopmental Disorder:

Weaver syndrome MONDO:0010193
Overlapping Features EZH2-related overgrowth and intellectual disability syndrome. EZH2 is the catalytic subunit of PRC2 and writes the very H3K27me3 mark that KDM6B erases, so Weaver syndrome and KDM6B-related NDD are opposite perturbations of the same H3K27 methylation switch. The contrast is worth stating explicitly: the same chromatin axis produces an overgrowth syndrome when the writer is overactive and a non-overgrowth neurobehavioral syndrome when the eraser is lost.
Distinguishing Features
  • Weaver syndrome features pre- and postnatal overgrowth with advanced bone age and a distinctive facial appearance, which are not part of the core KDM6B-related NDD presentation.
  • KDM6B-related NDD is dominated by cognitive, behavioral, and psychiatric features with mild, non-gestalt dysmorphism.
  • Molecular testing distinguishes them unambiguously (EZH2 versus KDM6B).
Show evidence (2 references)
PMID:38015625 SUPPORT Human Clinical
"Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM) caused by germline pathogenic variants in EZH2, which encodes the predominant H3K27 methyltransferase and key enzymatic component of Polycomb repressive complex 2 (PRC2). Weaver syndrome is characterized by striking..."
Defines Weaver syndrome as the EZH2 (H3K27 writer) counterpart disorder and names the overgrowth and advanced bone age that distinguish it from KDM6B-related NDD.
PMID:38015625 SUPPORT Model Organism
"Inhibition of the opposing H3K27 demethylases KDM6A and KDM6B substantially reversed the excessive osteogenesis in Ezh2R684C/+ cells both at the transcriptional and phenotypic levels."
Direct experimental demonstration that KDM6B opposes the EZH2 Weaver variant on the same H3K27 axis, which is exactly the writer/eraser contrast this differential rests on.
Sotos syndrome Not Yet Curated MONDO:0019349
Overlapping Features NSD1-related overgrowth syndrome, the principal clinical mimic of Weaver syndrome and part of the same histone-methylation-machinery differential.
Distinguishing Features
  • Overgrowth with macrocephaly, advanced bone age, and a characteristic facial gestalt.
  • Caused by NSD1 haploinsufficiency (an H3K36 methyltransferase) rather than a KDM6 or PRC2 lesion.
Cohen-Gibson syndrome Not Yet Curated MONDO:0060510
Overlapping Features EED-related overgrowth syndrome. EED is a core non-catalytic PRC2 subunit, making this a further PRC2-axis differential for a suspected H3K27 chromatinopathy.
Distinguishing Features
  • Weaver-like overgrowth with advanced bone age, contrasting with the absence of an overgrowth-defined presentation in KDM6B-related NDD.
Kabuki syndrome MONDO:0016512
Overlapping Features Chromatinopathy caused by KMT2D or KDM6A variants. KDM6A (UTX) is the direct paralogue of KDM6B and the other mammalian H3K27me2/me3 demethylase, so Kabuki syndrome is the closest mechanistic neighbour of this disorder.
Distinguishing Features
  • Kabuki syndrome has a recognisable facial gestalt (long palpebral fissures with eversion of the lateral third of the lower lid), persistent fetal fingertip pads, cleft palate, congenital heart disease, and immune deficiency.
  • KDM6B-related NDD has no recognisable gestalt and is identified molecularly.
Show evidence (1 reference)
PMID:18003914 SUPPORT In Vitro
"Here we show the JmjC domain-containing protein UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome), as well as the related JMJD3 (jumonji domain containing 3), specifically removes methyl marks on H3K27 in vitro."
Establishes UTX/KDM6A and JMJD3/KDM6B as the paralogous H3K27 demethylase pair, the basis for pairing Kabuki syndrome with this disorder.
Mucopolysaccharidosis
Overlapping Features Coarse facial features in an infant or young child with developmental delay commonly prompt a first-line evaluation for a lysosomal storage disorder, and this happened in at least one patient in the founding KDM6B series.
Distinguishing Features
  • Mucopolysaccharidoses show progressive coarsening with organomegaly, dysostosis multiplex, and corneal clouding.
  • Abnormal urinary glycosaminoglycans or deficient lysosomal enzyme activity confirm a storage disorder; KDM6B-related NDD has normal lysosomal biochemistry and non-progressive dysmorphism.
🔬

Clinical Trials

1
NCT01238250 RECRUITING
Simons Searchlight, an international observational online registry that collects longitudinal medical, behavioral, learning, and developmental data from people with rare genetic variants causing neurodevelopmental disorders. For an ultra-rare disorder such as this one, registry data are currently the only realistic route to natural-history and outcome information.
Show evidence (1 reference)
clinicaltrials:NCT01238250 SUPPORT Human Clinical
"Simons Searchlight is an observational, online, international research program for families with rare genetic variants that cause neurodevelopmental disorders and may be associated with autism."
Defines the registry scope, which covers rare genetic neurodevelopmental disorders of this kind. The cached record does not name KDM6B explicitly, so the link to this disorder is by registry scope rather than by an explicit gene listing, hence PARTIAL.
🧫

Experimental Models

1
KDM6-deficient human pluripotent stem cell-derived neural progenitor cells OTHER
Deletion of JMJD3 (KDM6B) and/or UTX (KDM6A) in human embryonic stem cells permits neural progenitor generation but causes poor progenitor proliferation, failure of neuronal and glial differentiation, H3K27me3 accumulation, and loss of DNA accessibility at neural developmental loci. Classified as OTHER because the system is human embryonic stem cell-derived rather than iPSC-derived.
neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:31959746
Pathograph links
Failure to Remove Repressive H3K27me3 recapitulates fidelity: high Shows H3K27me3 accumulation and loss of accessibility at neural developmental genes on KDM6 loss, in human cells.
Impaired Neural Commitment and Neurogenesis recapitulates fidelity: high Shows the progenitor proliferation and differentiation block in human cells.
Limitations: Complete KDM6 deletion rather than the heterozygous KDM6B state of patients, and both paralogues are targeted in the most severe conditions.
Show evidence (1 reference)
PMID:31959746 SUPPORT In Vitro
"However, KDM6-deficient NPCs exhibit poor proliferation and a failure to differentiate into neurons and glia."
Human cellular model of the core differentiation block caused by loss of KDM6 demethylase activity.
🐁

Animal Models

3
Kdm6b heterozygous mouse knockout mouse model
Deletion of one Kdm6b allele in mice, matching the human heterozygous dosage, produces autistic-like impaired sociability and object recognition memory plus ADHD-like hyperactivity and impulsivity that respond to methylphenidate.
Species
Mus musculus
Genotype
Kdm6b heterozygous (one allele deleted)
Genes
KDM6B hgnc:29012 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns KDM6B (hgnc:29012). hgnc:29012 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:35711692
Pathograph links
KDM6B Haploinsufficiency and Catalytic Impairment partially recapitulates fidelity: moderate Recapitulates the human heterozygous loss-of-function dosage state.
Limitations: A whole-gene allele deletion rather than the point and in-frame variants that account for many human cases, and mouse behavior is only a proxy for the human cognitive phenotype.
Neurodevelopmental and Behavioral Phenotype partially recapitulates fidelity: moderate Reproduces the autism- and ADHD-like behavioral output of the mechanism.
Limitations: Does not address the dysmorphic, skeletal, or psychiatric (psychosis) arms of the human phenotype.
Show evidence (1 reference)
PMID:35711692 SUPPORT Model Organism
"Here we use an animal model to show that genetic deletion of one Kdm6b allele in mice leads to autistic-like impaired sociability and object recognition memory."
Establishes the heterozygous mouse as a dosage-matched model of the human disorder.
KDM6B mosaic brain knockout mouse conditional knockout mouse model
Mosaic knockout of KDM6B in the mouse brain produces repetitive behaviors, impaired social interaction, and cognitive deficits, and reduces NMDA receptor-mediated hippocampal excitatory synaptic transmission and plasticity. Being brain-restricted by construction, it cannot address the craniofacial or skeletal arm of the human phenotype.
Species
Mus musculus
Genotype
KDM6B mosaic brain knockout
Genes
KDM6B hgnc:29012 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns KDM6B (hgnc:29012). hgnc:29012 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:39223259
Pathograph links
Altered Synaptic Transmission and Plasticity partially recapitulates fidelity: moderate Provides the electrophysiological readout for this node.
Limitations: Mosaic, brain-restricted somatic knockout rather than constitutional heterozygosity; rodent hippocampal physiology is not human tissue.
Show evidence (1 reference)
PMID:39223259 SUPPORT Model Organism
"Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits."
Behavioral and synaptic characterisation of brain-restricted KDM6B loss.
Drosophila dual gain-of-function KDM6B variant assay invertebrate functional assay
A dual Drosophila gain-of-function assay was used to demonstrate that disease-associated missense and in-frame indel variants in or near the JmjC and Zn-containing domains disrupt KDM6B function. The same system showed a role for the fly KDM6B orthologue in memory and behavior.
Species
Drosophila melanogaster
Genotype
KDM6B orthologue manipulation in a dual gain-of-function assay
Publication
PMID:37196654
Pathograph links
KDM6B Haploinsufficiency and Catalytic Impairment measures fidelity: moderate Functional readout that classifies patient missense and in-frame indel variants as disruptive.
Altered Synaptic Transmission and Plasticity partially recapitulates fidelity: low Demonstrates a conserved requirement for the orthologue in memory and behavior.
Limitations: Invertebrate nervous system; supports conservation of function rather than the specific mammalian synaptic mechanism.
Show evidence (1 reference)
PMID:37196654 SUPPORT Model Organism
"Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior."
Establishes the fly model as a functional readout for KDM6B variant interpretation and for conserved cognitive function.
{ }

Source YAML

click to show 
name: KDM6B-Related Neurodevelopmental Disorder
creation_date: "2026-08-15T00:00:00Z"
category: Mendelian
synonyms:
- neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities
- NEDCFSA
- Stolerman syndrome
- Stolerman neurodevelopmental syndrome
- KDM6B-related NDD
description: >
  KDM6B-related neurodevelopmental disorder is a rare, predominantly de novo
  autosomal dominant chromatinopathy caused by heterozygous loss-of-function or
  enzymatically disruptive variants in KDM6B (JMJD3), which encodes one of the
  two mammalian histone H3 lysine 27 (H3K27) di-/tri-demethylases. KDM6B
  removes the repressive H3K27me2/me3 mark deposited by Polycomb repressive
  complex 2 (PRC2, catalytic subunit EZH2), and thereby licenses timely
  de-repression of lineage-specifying genes during neural commitment,
  neurogenesis, and synaptic maturation. Reduced KDM6B dosage or catalytic
  activity leaves developmental loci trapped in a Polycomb-repressed,
  chromatin-inaccessible state, producing a broad neurodevelopmental and
  behavioral phenotype.

  The entity is indexed in OMIM (618505) and MONDO (MONDO:0032790) as
  "neurodevelopmental disorder with coarse facies and mild distal skeletal
  abnormalities" (NEDCFSA), a name derived from the original 12-patient series
  of Stolerman et al. (2019). The definitive 85-individual cohort of Rots et al.
  (2023) showed that this name is inaccurate and potentially misleading: coarse
  facies and distal skeletal anomalies are in fact uncommon, whereas cognitive
  deficits are near-universal and hypotonia and psychosis are unexpectedly
  frequent. This entry therefore uses the gene-anchored clinical name
  "KDM6B-related neurodevelopmental disorder" while retaining MONDO:0032790 and
  the OMIM-derived label as synonyms.
disease_term:
  preferred_term: KDM6B-related neurodevelopmental disorder
  description: >-
    Chromatinopathy caused by heterozygous KDM6B (H3K27 demethylase) variants;
    the OMIM/MONDO label is "neurodevelopmental disorder with coarse facies and
    mild distal skeletal abnormalities".
  term:
    id: MONDO:0032790
    label: neurodevelopmental disorder with coarse facies and mild distal skeletal
      abnormalities
parents:
- Neurodevelopmental disorder
- Chromatinopathy
- Epigenetic machinery disorder
references:
- reference: PMID:37196654
  title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
    disorder.
- reference: PMID:31124279
  title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
    delays and dysmorphic features.
notes: >-
  No GeneReviews chapter exists for KDM6B or for NEDCFSA as of this curation
  (PubMed searches for "KDM6B GeneReviews" returned no records), so the
  Rots et al. 2023 AJHG cohort (PMID:37196654) serves as the phenotype baseline
  in its place. Only the abstract of that paper is retrievable into the
  reference cache (the publisher blocks full-text download), so the per-feature
  cohort percentages reported in its tables cannot be quoted as evidence
  snippets here; frequency bands are therefore asserted only where the abstract
  itself is quantitative, per docs/frequency-evidence-guidelines.md. A 2025
  erratum to that paper is indexed as PMID:41110445; its cached record carries
  no retrievable content and it is not used as an evidence source.

  Reference-cache scoping: several caches in this PR were fetched during the
  Falcon deep-research reference-validation pass and are deliberately not cited.
  PMID:39767643 reports a bi-allelic KDM6B variant in a consanguineous family,
  which is inconsistent with the established heterozygous dominant mechanism and
  is therefore not used to support any claim here. PMID:41110445 is the
  content-free erratum record. The remaining DOI caches
  (DOI:10.1002/ajmg.a.61173 is the DOI-keyed duplicate of PMID:31124279;
  DOI:10.1016/j.conb.2019.02.009, DOI:10.1016/j.gim.2022.09.006,
  DOI:10.1038/s41598-024-70728-5 and DOI:10.54195/9789493296831) are general
  chromatin or chromatinopathy background rather than KDM6B-specific sources,
  and the entry cites primary KDM6B literature in their place.
  DOI:10.1101/2024.02.20.581302 (Gil et al., bioRxiv preprint) IS cited, on the
  Precocious Neural Stem Cell Differentiation and Pool Depletion node.
prevalence:
- population: Worldwide, individuals ascertained by exome or genome sequencing
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based prevalence estimate exists. The largest published series
    assembled 85 individuals worldwide through international collaboration, an
    order of magnitude that supports an ultra-rare classification.
  evidence:
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, by examining the molecular and clinical spectrum of 85 reported
      individuals with mostly de novo (likely) pathogenic KDM6B variants, we
      demonstrate that this description is inaccurate and potentially
      misleading.
    explanation: >-
      Establishes the total published cohort size (85 individuals worldwide),
      the basis for the ultra-rare prevalence class.
inheritance:
- name: Autosomal dominant, predominantly de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  de_novo_rate: >-
    Most reported pathogenic KDM6B variants have arisen de novo. The original
    12-patient series consisted entirely of de novo alterations, and the
    85-individual cohort is described as carrying mostly de novo (likely)
    pathogenic variants, with a minority inherited from a mildly affected or
    apparently unaffected parent.
  expressivity: VARIABLE
  description: >-
    Heterozygous KDM6B variants act in a dominant, dosage-sensitive manner.
    Expressivity is highly variable: cognitive involvement is consistent, but the
    severity of intellectual impairment and the presence of behavioral,
    psychiatric, dysmorphic, and skeletal features differ widely between
    individuals carrying comparable variants. Because the great majority of
    variants are de novo, recurrence risk for the siblings of a proband with a
    confirmed de novo variant is low, with residual risk from parental germline
    mosaicism. Inheritance from a mildly affected or apparently unaffected parent
    is documented and implies incomplete penetrance or highly variable
    expressivity in a minority of families.
  evidence:
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      85 reported individuals with mostly de novo (likely) pathogenic KDM6B
      variants
    explanation: >-
      Establishes that pathogenic KDM6B variants are mostly de novo in the
      definitive cohort.
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cognitive deficits are seen consistently in all individuals, but the
      overall phenotype is highly variable.
    explanation: >-
      Directly supports the VARIABLE expressivity assignment.
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a number of de novo alterations in the KDM6B gene via
      whole exome sequencing (WES) in a cohort of 12 unrelated patients with
      developmental delay, intellectual disability, dysmorphic facial features,
      and other clinical findings.
    explanation: >-
      The founding case series established that the causal KDM6B alterations
      arise de novo.
genetic:
- name: KDM6B
  gene_term:
    preferred_term: KDM6B
    term:
      id: hgnc:29012
      label: KDM6B
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  features: >-
    Pathogenic alleles include nonsense, frameshift, and splice variants
    distributed across the gene (consistent with haploinsufficiency) as well as
    missense and in-frame indel variants clustered in or near the catalytic JmjC
    domain and the Zn-containing domain required for cofactor binding and
    protein stability.
  notes: >-
    KDM6B (lysine demethylase 6B, also known as JMJD3) encodes a JmjC
    domain-containing histone H3K27me2/me3 demethylase at 17p13.1. Inheritance
    is autosomal dominant with the great majority of variants arising de novo;
    see the disease-level inheritance block.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The KDM6B protein consists of the JmjC catalytic domain and C-terminal
      helix and zinc motifs which are important in cofactor binding and protein
      stability
    explanation: >-
      Defines the functional domain architecture in which the disease-associated
      missense and in-frame variants cluster.
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      indicating that haploinsufficiency of the KDM6B gene is not tolerated
    explanation: >-
      Population-constraint evidence (gnomAD observed/expected loss-of-function
      score) that KDM6B is dosage sensitive, the premise of the
      haploinsufficiency mechanism. Tagged COMPUTATIONAL because the claim comes
      from a population-database constraint metric rather than a patient
      observation.
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using 3D protein structure analysis and an innovative dual Drosophila
      gain-of-function assay, we demonstrated a disruptive effect of 11
      missense/in-frame indels located in or near the enzymatic JmJC or
      Zn-containing domain of KDM6B.
    explanation: >-
      Functional assay evidence that disease-associated missense/in-frame
      variants in the catalytic and zinc-binding regions are damaging. Tagged
      MODEL_ORGANISM because the assay is a whole-organism Drosophila
      gain-of-function experiment; the same sentence also reports a
      computational 3D structure analysis, which is not separately curated here.
variants:
- name: KDM6B truncating variants
  gene:
    preferred_term: KDM6B
    term:
      id: hgnc:29012
      label: KDM6B
  type: Loss of function
  clinical_significance: PATHOGENIC
  description: >-
    Nonsense and frameshift variants distributed across KDM6B, reported de novo
    in the founding case series (for example p.Tyr75X, p.Arg149X, p.Glu1244X and
    several frameshifts), consistent with a haploinsufficiency mechanism.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a number of de novo alterations in the KDM6B gene via
      whole exome sequencing (WES) in a cohort of 12 unrelated patients with
      developmental delay, intellectual disability, dysmorphic facial features,
      and other clinical findings.
    explanation: >-
      Source of the de novo truncating and frameshift alleles reported in the
      original cohort.
- name: KDM6B catalytic-domain missense and in-frame indel variants
  gene:
    preferred_term: KDM6B
    term:
      id: hgnc:29012
      label: KDM6B
  type: Missense / in-frame indel
  clinical_significance: PATHOGENIC
  description: >-
    Missense substitutions and in-frame insertions or deletions located in or
    near the JmjC catalytic domain or the Zn-containing domain. Eleven such
    variants were shown to be functionally disruptive using 3D protein structure
    analysis combined with a dual Drosophila gain-of-function assay.
  evidence:
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we demonstrated a disruptive effect of 11 missense/in-frame indels located
      in or near the enzymatic JmJC or Zn-containing domain of KDM6B
    explanation: >-
      Direct functional demonstration that these non-truncating alleles impair
      KDM6B function.
- name: Copy-number deletions encompassing KDM6B
  gene:
    preferred_term: KDM6B
    term:
      id: hgnc:29012
      label: KDM6B
  type: Copy number loss
  clinical_significance: UNCERTAIN_SIGNIFICANCE
  description: >-
    Chromosomal microarray has identified 17p13.1 deletions that encompass
    KDM6B in individuals with overlapping features (developmental delay,
    intellectual disability, speech delay). These are curated as a separate,
    weaker variant class rather than as established pathogenic alleles, because
    every reported deletion also removes neighbouring genes, so the phenotype
    cannot be attributed to KDM6B alone. Chromosomal microarray therefore
    remains appropriate when a copy-number disorder is suspected, but a deletion
    finding does not by itself establish this diagnosis.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, it is important to note that all seven of these deletions also
      encompass neighboring genes the effects of which are uncertain.
    explanation: >-
      Directly states the attribution limitation that makes this a PARTIAL,
      uncertain-significance variant class rather than a pathogenic one.
pathophysiology:
- name: KDM6B Haploinsufficiency and Catalytic Impairment
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Epigenetic Machinery Component Haploinsufficiency"
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  role: trigger
  description: >
    Heterozygous de novo truncating variants reduce functional KDM6B dosage,
    while missense and in-frame indel variants in or near the JmjC catalytic
    domain and the zinc-binding motif impair the enzyme's demethylase activity
    or stability. Both routes converge on reduced cellular H3K27me2/me3
    demethylase capacity.
  genes:
  - preferred_term: KDM6B
    term:
      id: hgnc:29012
      label: KDM6B
  molecular_functions:
  - preferred_term: histone H3K27me2/H3K27me3 demethylase activity
    term:
      id: GO:0071558
      label: histone H3K27me2/H3K27me3 demethylase activity
    modifier: DECREASED
  downstream:
  - target: Failure to Remove Repressive H3K27me3
    causal_link_type: DIRECT
    description: >-
      Reduced KDM6B enzyme dosage or catalytic competence directly lowers the
      rate at which H3K27me2/me3 is erased from target loci.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lysine-specific demethylase 6B (KDM6B) demethylates trimethylated
      lysine-27 on histone H3.
    explanation: >-
      Establishes the enzymatic identity of KDM6B whose loss initiates the
      disease mechanism.
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we demonstrated a disruptive effect of 11 missense/in-frame indels located
      in or near the enzymatic JmJC or Zn-containing domain of KDM6B
    explanation: >-
      Shows that non-truncating disease alleles act by disrupting the catalytic
      and cofactor-binding regions, that is, by impairing enzyme function.
- name: Failure to Remove Repressive H3K27me3
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >
    KDM6B (JMJD3) and its paralogue KDM6A (UTX) are the JmjC-domain enzymes that
    specifically remove di- and trimethylation from histone H3 lysine 27. When
    KDM6B activity falls, H3K27me3 accumulates at KDM6B-bound developmental
    loci. In human neural progenitor cells lacking KDM6 enzymes, H3K27me3
    accumulates and DNA accessibility at neural developmental genes is blocked.
  molecular_functions:
  - preferred_term: histone H3K27me2/H3K27me3 demethylase activity
    term:
      id: GO:0071558
      label: histone H3K27me2/H3K27me3 demethylase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  downstream:
  - target: Unopposed PRC2-Mediated Polycomb Repression
    causal_link_type: DIRECT
    description: >-
      Persistent H3K27me3 at developmental loci means PRC2-deposited repression
      is no longer counterbalanced by demethylation.
  evidence:
  - reference: PMID:18003914
    reference_title: Identification of JmjC domain-containing UTX and JMJD3 as histone
      H3 lysine 27 demethylases.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we show the JmjC domain-containing protein UTX (ubiquitously
      transcribed tetratricopeptide repeat, X chromosome), as well as the
      related JMJD3 (jumonji domain containing 3), specifically removes methyl
      marks on H3K27 in vitro.
    explanation: >-
      Identifies JMJD3/KDM6B as an H3K27-specific demethylase, the activity lost
      in this disorder.
  - reference: PMID:18003914
    reference_title: Identification of JmjC domain-containing UTX and JMJD3 as histone
      H3 lysine 27 demethylases.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, overexpression of UTX and JMJD3 leads to reduced di- and
      trimethylation on H3K27 in cells, suggesting that UTX and JMJD3 may
      function as H3K27 demethylases in vivo.
    explanation: >-
      Demonstrates that cellular H3K27me2/me3 levels are set by KDM6 enzyme
      dosage, so reduced dosage raises the repressive mark.
  - reference: PMID:31959746
    reference_title: JMJD3 and UTX determine fidelity and lineage specification of
      human neural progenitor cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistically, both JMJD3 and UTX are found to be enriched in gene loci
      essential for neural development in hNPCs, and KDM6 impairment leads to
      H3K27me3 accumulation and blockade of DNA accessibility at these genes.
    explanation: >-
      Human neural progenitor evidence that loss of KDM6 activity causes
      H3K27me3 accumulation at neurodevelopmental loci.
- name: Unopposed PRC2-Mediated Polycomb Repression
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Permissive-Repressive Chromatin State Imbalance"
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >
    H3K27me3 is deposited by Polycomb repressive complex 2 (PRC2, catalytic
    subunit EZH2) and read by Polycomb repressive complex 1 to enforce
    transcriptional silencing. KDM6B provides the opposing, erasing arm of this
    switch; its enzymatic activity antagonizes Polycomb regulation and resolves
    bivalent promoters at the onset of differentiation. With KDM6B activity
    reduced, developmental promoters and enhancers that should be de-repressed
    remain Polycomb-silenced. This is the mechanistic mirror image of PRC2
    gain-of-function chromatinopathies such as EZH2-related Weaver syndrome, in
    which the writing arm is overactive.
  biological_processes:
  - preferred_term: negative regulation of transcription by RNA polymerase II
    term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    modifier: INCREASED
  - preferred_term: chromatin remodeling
    term:
      id: GO:0006338
      label: chromatin remodeling
    modifier: ABNORMAL
  downstream:
  - target: Dysregulated Neurodevelopmental Gene Expression
    causal_link_type: DIRECT
    description: >-
      Sustained Polycomb repression at lineage-specifying loci prevents their
      timely activation.
  - target: Disrupted Craniofacial and Distal Skeletal Patterning
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - patterning_hox_dysmorphology
    description: >-
      Polycomb and H3K27me3 control of HOX and other patterning loci provides a
      plausible but not directly demonstrated route from KDM6B loss to the
      dysmorphic and distal limb features seen in a minority of patients.
  evidence:
  - reference: PMID:18716661
    reference_title: The histone H3 lysine 27-specific demethylase Jmjd3 is required
      for neural commitment.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our results demonstrate the relevance of an enzymatic activity that
      antagonizes Polycomb regulation
    explanation: >-
      Establishes that Jmjd3/KDM6B acts specifically to antagonize Polycomb
      (PRC2) repression, the activity lost in this disorder.
  - reference: PMID:17851529
    reference_title: A histone H3 lysine 27 demethylase regulates animal posterior
      development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Histone H3K27 trimethylation (H3K27me3) has been linked to
      polycomb-group-protein-mediated suppression of Hox genes and animal body
      patterning, X-chromosome inactivation and possibly maintenance of
      embryonic stem cell (ESC) identity.
    explanation: >-
      Defines the Polycomb-repressive role of the H3K27me3 mark that KDM6B
      normally erases.
  - reference: PMID:17851529
    reference_title: A histone H3 lysine 27 demethylase regulates animal posterior
      development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      An imbalance of H3K27 methylation owing to overexpression of the methylase
      EZH2 has been implicated in metastatic prostate and aggressive breast
      cancers.
    explanation: >-
      Supports the framing of KDM6B loss and EZH2 gain as opposite perturbations
      of the same H3K27 methylation balance; the cited disease context is
      oncological rather than neurodevelopmental, hence PARTIAL.
  - reference: PMID:38015625
    reference_title: "A mouse model of Weaver syndrome displays overgrowth and\
      \ excess osteogenesis reversible with KDM6A/6B inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This supports both the ideas that writers and erasers of histone marks
      exist in a fine balance to maintain epigenome state and that epigenetic
      modulating agents have therapeutic potential for the treatment of MDEMs.
    explanation: >-
      States the writer/eraser balance principle directly, and does so in the
      context of a Mendelian disorder of the epigenetic machinery rather than
      cancer, which is the framing this node asserts.
- name: Dysregulated Neurodevelopmental Gene Expression
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Dysregulated Neurodevelopmental Transcriptional Program"
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >
    KDM6B occupies promoters and neural enhancer elements of genes that specify
    neural identity, and its demethylase activity converts these elements from a
    poised or bivalent state to an active one. Loss of KDM6B leaves these
    regulatory elements enriched for H3K27me3 and inaccessible, so the
    transcriptional programme for neural commitment is not executed at the right
    time. The clinical literature describes the same principle as modulation of
    chromatin accessibility by RNA polymerase.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  biological_processes:
  - preferred_term: positive regulation of transcription by RNA polymerase II
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    modifier: DECREASED
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  downstream:
  - target: Impaired Neural Commitment and Neurogenesis
    causal_link_type: DIRECT
    description: >-
      Failure to activate neurogenic regulators blocks progression of
      progenitors into neurons and glia.
  - target: Precocious Neural Stem Cell Differentiation and Pool Depletion
    causal_link_type: DIRECT
    description: >-
      In the hippocampal dentate gyrus the same loss of KDM6B-dependent
      regulation disrupts the transcriptomic signature of neural stem cell
      maintenance, so progenitors differentiate early instead of being held in
      reserve.
  evidence:
  - reference: PMID:25176653
    reference_title: Activation of neuronal gene expression by the JMJD3 demethylase
      is required for postnatal and adult brain neurogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      JMJD3 regulates neurogenic gene expression via interaction at not only
      promoter regions but also neurogenic enhancer elements.
    explanation: >-
      Shows that KDM6B/JMJD3 directly controls the neurodevelopmental
      transcriptional programme at promoters and enhancers.
  - reference: PMID:25176653
    reference_title: Activation of neuronal gene expression by the JMJD3 demethylase
      is required for postnatal and adult brain neurogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In Jmjd3-deleted SVZ cells, I12b remains enriched with H3K27me3 and
      Dlx2-dependent neurogenesis fails.
    explanation: >-
      Direct demonstration that loss of the demethylase leaves a neurogenic
      enhancer H3K27me3-marked and its target gene programme unexecuted.
  - reference: PMID:38326731
    reference_title: "Cerebellar heterotopia in an 11-year-old child with KDM6B-related\
      \ neurodevelopmental disorder: A case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KDM6B encodes a histone demethylase, expressed in different tissues during
      development, which regulates gene expression through the modulation of
      chromatin accessibility by RNA polymerase.
    explanation: >-
      Clinical-genetics framing of the same chromatin-accessibility mechanism in
      the context of this disorder.
- name: Impaired Neural Commitment and Neurogenesis
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Impaired Neuronal Maturation, Plasticity, and Postnatal Neurogenesis"
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >
    KDM6B activity is required for cells to commit to the neural lineage and for
    neural progenitors to proliferate and differentiate into neurons and glia.
    Human embryonic stem cell-derived progenitors lacking KDM6 enzymes still
    form neural progenitors but proliferate poorly and fail to make neurons and
    glia; in mice, deletion of Jmjd3 in subventricular zone neural stem cells
    impairs neuronal differentiation in both the developing and the adult brain.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neuron differentiation
    term:
      id: GO:0030182
      label: neuron differentiation
    modifier: DECREASED
  - preferred_term: neural precursor cell proliferation
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
    modifier: DECREASED
  - preferred_term: cell fate commitment
    term:
      id: GO:0045165
      label: cell fate commitment
    modifier: ABNORMAL
  downstream:
  - target: Altered Synaptic Transmission and Plasticity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Neurons produced from a KDM6B-deficient progenitor pool show downstream
      deficits in excitatory synaptic transmission and plasticity.
  - target: Neurodevelopmental and Behavioral Phenotype
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Defective neurogenesis and neuronal differentiation underlie the cognitive
      and developmental features of the disorder.
  evidence:
  - reference: PMID:18716661
    reference_title: The histone H3 lysine 27-specific demethylase Jmjd3 is required
      for neural commitment.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Starting from a comprehensive profiling of JmjC-domain genes, we report
      here that Jmjd3, recently identified as a H3-K27me3 specific demethylase,
      controls the expression of key regulators and markers of neurogenesis and
      is required for commitment to the neural lineage.
    explanation: >-
      Establishes a requirement for KDM6B/Jmjd3 in neural lineage commitment.
  - reference: PMID:31959746
    reference_title: JMJD3 and UTX determine fidelity and lineage specification of
      human neural progenitor cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, KDM6-deficient NPCs exhibit poor proliferation and a failure to
      differentiate into neurons and glia.
    explanation: >-
      Human stem cell evidence that loss of KDM6 demethylases blocks progenitor
      proliferation and neuronal/glial differentiation.
  - reference: PMID:25176653
    reference_title: Activation of neuronal gene expression by the JMJD3 demethylase
      is required for postnatal and adult brain neurogenesis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      JMJD3 is upregulated in neuroblasts, and Jmjd3 deletion targeted to SVZ
      NSCs in both developing and adult mice impairs neuronal differentiation.
    explanation: >-
      In vivo requirement for the demethylase in developmental and adult
      neurogenesis.
- name: Precocious Neural Stem Cell Differentiation and Pool Depletion
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >
    A second, direction-opposite consequence of KDM6B loss in the neural stem
    cell compartment. In the mouse hippocampal dentate gyrus, KDM6B is required
    to establish and maintain the neural stem cell pool: conditional deletion in
    embryonic dentate gyrus precursors causes precocious neuronal
    differentiation so that the stem cell population never becomes established,
    leaving the adult hippocampus essentially devoid of neural stem cells, with
    defective hippocampal-dependent behavior. Deletion in adult dentate gyrus
    neural stem cells likewise induces early differentiation and failure of pool
    maintenance.

    This is deliberately modeled as a node distinct from "Impaired Neural
    Commitment and Neurogenesis": that node captures a differentiation block
    (progenitors fail to become neurons), whereas this one captures premature
    differentiation that exhausts the progenitor reserve. Both are reported for
    KDM6B loss in different compartments and developmental windows, and
    reconciling them is an open question recorded in the
    kdm6b_commitment_direction_paradox discussion. The node is PROVISIONAL
    because the supporting study is a mouse preprint.
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: stem cell population maintenance
    term:
      id: GO:0019827
      label: stem cell population maintenance
    modifier: DECREASED
  - preferred_term: neuron differentiation
    term:
      id: GO:0030182
      label: neuron differentiation
    modifier: ABNORMAL
  downstream:
  - target: Neurodevelopmental and Behavioral Phenotype
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Loss of the hippocampal neural stem cell reserve is accompanied by
      defective hippocampal-dependent behavior in the mouse, offering a
      substrate for the cognitive phenotype that is separate from the synaptic
      one.
  evidence:
  - reference: DOI:10.1101/2024.02.20.581302
    reference_title: "Chromatin regulator <i>Kdm6b</i> is required for the establishment and maintenance of neural stem cells in mouse hippocampus"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we show that the chromatin regulator KDM6B is required for both the
      establishment and maintenance of NSCs in the mouse DG.
    explanation: >-
      Establishes the neural stem cell maintenance requirement that this node
      asserts. Preprint (bioRxiv), so the node is graded PROVISIONAL.
  - reference: DOI:10.1101/2024.02.20.581302
    reference_title: "Chromatin regulator <i>Kdm6b</i> is required for the establishment and maintenance of neural stem cells in mouse hippocampus"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Conditional deletion of Kdm6b in embryonic DG precursors results in an
      adult hippocampus that is essentially devoid of NSCs, and
      hippocampal-dependent behaviors are defective.
    explanation: >-
      Links stem cell pool depletion to a behavioral deficit, the connection this
      node's downstream edge asserts.
  - reference: DOI:10.1101/2024.02.20.581302
    reference_title: "Chromatin regulator <i>Kdm6b</i> is required for the establishment and maintenance of neural stem cells in mouse hippocampus"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      causes precocious neuronal differentiation, and the NSC population fails
      to become established in the postnatal DG.
    explanation: >-
      Names the precocious-differentiation mechanism that distinguishes this node
      from the differentiation-block node.
  - reference: DOI:10.1101/2024.02.20.581302
    reference_title: "Chromatin regulator <i>Kdm6b</i> is required for the establishment and maintenance of neural stem cells in mouse hippocampus"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using single cell RNA sequencing (scRNA-seq), we observed that Kdm6b
      -deletion disrupts the transcriptomic signature of NSC maintenance.
    explanation: >-
      Single-cell transcriptomic evidence that the neural stem cell maintenance
      programme itself is disrupted, which is what connects this node upstream to
      dysregulated neurodevelopmental gene expression. The space before
      "-deletion" reproduces the cached text, where the italicised gene symbol
      sits on its own line.
- name: Altered Synaptic Transmission and Plasticity
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >
    Beyond its developmental role, KDM6B loss perturbs mature circuit function.
    Mosaic brain knockout of KDM6B in mice reduces NMDA receptor-mediated
    excitatory synaptic transmission and plasticity in the hippocampus,
    providing a cellular substrate for the cognitive and behavioral phenotype.
    This node is marked provisional because the evidence is currently from
    rodent and fly models rather than from human tissue.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: synaptic transmission, glutamatergic
    term:
      id: GO:0035249
      label: synaptic transmission, glutamatergic
    modifier: DECREASED
  - preferred_term: regulation of synaptic plasticity
    term:
      id: GO:0048167
      label: regulation of synaptic plasticity
    modifier: ABNORMAL
  - preferred_term: long-term synaptic potentiation
    term:
      id: GO:0060291
      label: long-term synaptic potentiation
    modifier: DECREASED
  downstream:
  - target: Neurodevelopmental and Behavioral Phenotype
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired excitatory synaptic transmission and plasticity plausibly
      contribute to the cognitive deficits and behavioral features.
  evidence:
  - reference: PMID:39223259
    reference_title: Impact of KDM6B mosaic brain knockout on synaptic function and
      behavior.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Moreover, KDM6B mosaic knockout display abnormalities in hippocampal
      excitatory synaptic transmission decreasing NMDA receptor mediated
      synaptic transmission and plasticity.
    explanation: >-
      Direct electrophysiological evidence linking KDM6B loss to reduced
      excitatory synaptic transmission and plasticity.
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with the role of KDM6B in human cognition, we demonstrated a
      role for the Drosophila KDM6B ortholog in memory and behavior.
    explanation: >-
      Cross-species evidence that the KDM6B orthologue is required for memory
      and behavior, consistent with a circuit-level function.
- name: Disrupted Craniofacial and Distal Skeletal Patterning
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >
    A minority of affected individuals have coarse facial features and mild
    distal skeletal anomalies (broad hands, syndactyly, clinodactyly). A
    plausible mechanism is loss of KDM6-dependent de-repression of HOX and other
    patterning loci, since H3K27me3 controls Hox gene expression and body
    patterning and inhibition of the KDM6 paralogue UTX in zebrafish causes hox
    mis-regulation with a posterior developmental defect. This route has not
    been demonstrated for KDM6B in human craniofacial or limb development, and
    the 85-individual cohort showed these features to be uncommon, so the node
    is explicitly hypothetical.
  biological_processes:
  - preferred_term: cell fate commitment involved in pattern specification
    term:
      id: GO:0060581
      label: cell fate commitment involved in pattern specification
    modifier: ABNORMAL
  downstream:
  - target: Neurodevelopmental and Behavioral Phenotype
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - patterning_hox_dysmorphology
    description: >-
      Contributes the dysmorphic and distal skeletal component of the composite
      clinical phenotype.
  evidence:
  - reference: PMID:17851529
    reference_title: A histone H3 lysine 27 demethylase regulates animal posterior
      development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Importantly, morpholino oligonucleotide inhibition of a zebrafish UTX
      homologue resulted in mis-regulation of hox genes and a striking posterior
      developmental defect, which was partially rescued by wild-type, but not by
      catalytically inactive, human UTX.
    explanation: >-
      Model-organism evidence that loss of KDM6-family H3K27 demethylase
      activity mis-regulates hox genes and disturbs body patterning; it concerns
      the paralogue UTX in zebrafish, not KDM6B in human limb or face, hence
      PARTIAL.
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, coarse facies and distal skeletal anomalies, as defined by OMIM,
      are rare in this expanded cohort while other features are unexpectedly
      common (e.g., hypotonia, psychosis, etc.).
    explanation: >-
      Establishes that the dysmorphic and skeletal arm of the phenotype exists
      but is uncommon, justifying the low-confidence, minority-pathway framing of
      this node.
- name: Neurodevelopmental and Behavioral Phenotype
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  role: consequence
  biological_processes:
  - preferred_term: learning or memory
    term:
      id: GO:0007611
      label: learning or memory
    modifier: DECREASED
  description: >
    The convergent organism-level consequence: near-universal cognitive
    involvement with highly variable additional features, including motor and
    speech delay, hypotonia, autism spectrum disorder, attention deficit
    hyperactivity disorder, psychosis in older individuals, and, in a minority,
    coarse facies and mild distal skeletal anomalies.
  evidence:
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cognitive deficits are seen consistently in all individuals, but the
      overall phenotype is highly variable.
    explanation: >-
      Defines the organism-level output of the mechanism: obligate cognitive
      involvement on a variable background.
mechanistic_hypotheses:
- hypothesis_group_id: patterning_hox_dysmorphology
  hypothesis_label: HOX/Polycomb mis-regulation as the route to the dysmorphic and
    distal skeletal minority phenotype
  status: EMERGING
  description: >-
    The coarse facies and mild distal skeletal anomalies that gave the disorder
    its OMIM name are hypothesised to arise from failure of KDM6B-dependent
    de-repression of HOX and related patterning loci during craniofacial and
    limb development. Supporting evidence is indirect (H3K27me3 control of Hox
    genes; hox mis-regulation and posterior developmental defects after
    inhibition of the KDM6 paralogue UTX in zebrafish). No human KDM6B
    craniofacial or limb developmental study has tested this directly, and the
    features are uncommon in the largest cohort.
  evidence:
  - reference: PMID:17851529
    reference_title: A histone H3 lysine 27 demethylase regulates animal posterior
      development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Importantly, morpholino oligonucleotide inhibition of a zebrafish UTX
      homologue resulted in mis-regulation of hox genes and a striking posterior
      developmental defect
    explanation: >-
      Establishes an evolutionarily conserved developmental-patterning role for
      the KDM6 demethylase family, the premise of this hypothesis.
phenotypes:
- category: Neurologic
  name: Cognitive deficits
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  frequency: VERY_FREQUENT
  description: >-
    Cognitive involvement is the one consistent feature of the disorder,
    reported in every individual in the definitive 85-person cohort. Severity is
    variable and most affected individuals fall in the mild range.
  evidence:
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cognitive deficits are seen consistently in all individuals, but the
      overall phenotype is highly variable.
    explanation: >-
      The 85-individual cohort reports cognitive deficits in every affected
      individual, which maps to the VERY_FREQUENT (80-100%) band.
- category: Neurologic
  name: Impaired intellectual development
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  description: >-
    Formally diagnosed intellectual disability is present in a substantial
    proportion of individuals and is usually mild; learning difficulties without
    a formal ID diagnosis are common in the remainder. No frequency band is
    asserted because the cohort abstract does not quantify the ID subset
    separately from the broader cognitive-deficit statement.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a cohort of 12 unrelated patients with developmental delay, intellectual
      disability, dysmorphic facial features, and other clinical findings
    explanation: >-
      Intellectual disability was one of the defining features of the founding
      case series.
- category: Neurologic
  name: Global developmental delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: >-
    Developmental delay affecting multiple streams, typically recognised in
    infancy or early childhood, was present in all 12 patients of the founding
    series.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a number of de novo alterations in the KDM6B gene via
      whole exome sequencing (WES) in a cohort of 12 unrelated patients with
      developmental delay, intellectual disability, dysmorphic facial features,
      and other clinical findings.
    explanation: >-
      Developmental delay was the presenting feature of all 12 patients in the
      founding series.
- category: Neurologic
  name: Delayed speech and language development
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  description: >-
    Speech and language delay is one of the two developmental streams
    highlighted in the original description of the syndrome.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we report a case series of 12 patients presenting with
      neurodevelopmental delays in speech and motor development
    explanation: >-
      Explicitly names speech delay as a defining feature of the reported
      cohort.
- category: Neurologic
  name: Motor delay
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  description: >-
    Delayed acquisition of gross motor milestones, commonly delayed independent
    walking.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we report a case series of 12 patients presenting with
      neurodevelopmental delays in speech and motor development
    explanation: >-
      Explicitly names motor delay as a defining feature of the reported cohort.
- category: Neurologic
  name: Hypotonia
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  description: >-
    Hypotonia is described by the largest cohort as unexpectedly common relative
    to the original OMIM-derived description of the syndrome, and can be marked
    enough to prompt a neuromuscular workup. No numeric frequency is quoted in
    the retrievable abstract, so no frequency band is asserted here.
  evidence:
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, coarse facies and distal skeletal anomalies, as defined by OMIM,
      are rare in this expanded cohort while other features are unexpectedly
      common (e.g., hypotonia, psychosis, etc.).
    explanation: >-
      Identifies hypotonia as an unexpectedly common feature of the expanded
      cohort. The statement is qualitative, so no FrequencyEnum band is
      assigned.
- category: Psychiatric
  name: Psychosis
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  description: >-
    Psychosis is a distinctive and clinically actionable feature of this
    chromatinopathy, and its omission from the OMIM-derived syndrome name is one
    of the reasons that name is considered misleading. OMIM records psychosis in
    a small percentage of individuals older than 12 years, and the 85-individual
    cohort lists psychosis among the features that are unexpectedly common
    relative to the original syndrome description. Because the retrievable
    abstract characterises this only qualitatively, no frequency band is
    asserted (see docs/frequency-evidence-guidelines.md).
  evidence:
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, coarse facies and distal skeletal anomalies, as defined by OMIM,
      are rare in this expanded cohort while other features are unexpectedly
      common (e.g., hypotonia, psychosis, etc.).
    explanation: >-
      The definitive cohort explicitly names psychosis as a feature of the
      KDM6B-related NDD phenotype, contradicting its omission from the
      OMIM-derived syndrome name.
  notes: >-
    Psychiatric surveillance from adolescence onward is the practical
    implication of this finding. The cohort tables (full text of PMID:37196654,
    which the publisher does not release into the reference cache) report the
    psychotic-disorder denominator as a small number of individuals aged 12 years
    or older; because that figure cannot be quoted here it is not converted into
    a frequency band. Resolving it is tracked in the kdm6b_psychosis_frequency
    discussion.
- category: Behavioral
  name: Autism spectrum disorder
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  description: >-
    Autism spectrum disorder is a common behavioral feature. KDM6B is among the
    highest-confidence autism risk genes in large sequencing studies, and
    autistic-like phenotypes are reproduced by Kdm6b loss in mice.
  evidence:
  - reference: PMID:38326731
    reference_title: "Cerebellar heterotopia in an 11-year-old child with KDM6B-related\
      \ neurodevelopmental disorder: A case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      behavioral traits relatable to oppositional defiant, autism spectrum, and
      attention deficit hyperactivity disorders
    explanation: >-
      Human case with a de novo pathogenic KDM6B variant showing autism spectrum
      behavioral traits.
  - reference: PMID:35711692
    reference_title: Kdm6b Haploinsufficiency Causes ASD/ADHD-Like Behavioral Deficits
      in Mice.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recent genetic and clinical studies report that KDM6B, a gene encoding a
      histone H3 lysine 27-specific demethylase, is one of the highest ASD risk
      genes.
    explanation: >-
      Reports the standing of KDM6B among autism risk genes. Tagged OTHER rather
      than HUMAN_CLINICAL because this is a background statement in the
      introduction of a mouse study, not human clinical data generated by the
      cited publication; the primary human sequencing studies it refers to do
      not name KDM6B in their abstracts, so no quotable human-genetic source
      could be substituted.
  - reference: PMID:35711692
    reference_title: Kdm6b Haploinsufficiency Causes ASD/ADHD-Like Behavioral Deficits
      in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we use an animal model to show that genetic deletion of one Kdm6b
      allele in mice leads to autistic-like impaired sociability and object
      recognition memory.
    explanation: >-
      Heterozygous, dosage-matched mouse model reproduces autistic-like
      behavior, supporting causality of KDM6B haploinsufficiency.
- category: Behavioral
  name: Attention deficit hyperactivity disorder
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  description: >-
    ADHD-type inattention, hyperactivity, and impulsivity are recurrent
    behavioral features, documented in individual patients and reproduced in the
    heterozygous mouse model.
  evidence:
  - reference: PMID:35840288
    reference_title: "The KDM6B mutation: Phenotype and clinical characteristics-Report
      of a case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The case was oriented as a neurodevelopmental disorder secondary to a
      genetic alteration and a comorbid Attention Deficit Hyperactivity Disorder
      (ADHD).
    explanation: >-
      Human case with a KDM6B frameshift variant and formally assessed comorbid
      ADHD.
  - reference: PMID:35711692
    reference_title: Kdm6b Haploinsufficiency Causes ASD/ADHD-Like Behavioral Deficits
      in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, the mutant mice display markedly increased locomotor activity
      and impulsivity, two ADHD-like behavioral traits that are ameliorated by
      methylphenidate treatment.
    explanation: >-
      Mouse haploinsufficiency model reproduces ADHD-like hyperactivity and
      impulsivity.
- category: Craniofacial
  name: Coarse facial features
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
  description: >-
    Coarse facies gave the disorder its OMIM name and was prominent in the
    original 12-patient series, but is uncommon in the expanded 85-individual
    cohort. It is non-pathognomonic and can prompt an initial suspicion of a
    lysosomal storage disorder.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dysmorphic facial features including a prominent nasal bridge or nose,
      coarse features, as well as widened hands and syndactyly
    explanation: >-
      Original description of the coarse facial features in KDM6B variant
      carriers.
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, coarse facies and distal skeletal anomalies, as defined by OMIM,
      are rare in this expanded cohort
    explanation: >-
      Qualifies the feature as present but uncommon once ascertainment bias is
      removed. No frequency band is asserted because the abstract gives no
      numerator.
- category: Craniofacial
  name: Prominent nasal bridge
  phenotype_term:
    preferred_term: Prominent nasal bridge
    term:
      id: HP:0000426
      label: Prominent nasal bridge
  description: >-
    A prominent nasal bridge or nose was among the recurring dysmorphic features
    in the founding case series. Like the other dysmorphic features of this
    disorder it is mild and does not amount to a recognisable facial gestalt.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dysmorphic facial features including a prominent nasal bridge or nose
    explanation: >-
      Directly reports the prominent nasal bridge or nose in the KDM6B cohort.
- category: Skeletal
  name: Broad hands
  phenotype_term:
    preferred_term: Broad palm
    term:
      id: HP:0001169
      label: Broad palm
  description: >-
    Widened hands were a recurrent distal limb finding in the founding series and
    contributed the "mild distal skeletal abnormalities" component of the OMIM
    name; like coarse facies, the finding is uncommon in the expanded cohort.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      as well as widened hands and syndactyly with de novo variants in the KDM6B
      gene
    explanation: >-
      Reports widened hands as a recurrent distal skeletal feature in the
      original cohort.
- category: Skeletal
  name: Syndactyly
  phenotype_term:
    preferred_term: Syndactyly
    term:
      id: HP:0001159
      label: Syndactyly
  description: >-
    Syndactyly, most often of the toes, was reported in the founding series and
    in the earliest published individual with a KDM6B variant.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      as well as widened hands and syndactyly with de novo variants in the KDM6B
      gene
    explanation: >-
      Reports syndactyly among the distal limb findings of the original cohort.
- category: Neurologic
  name: Seizures
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  description: >-
    Seizures are an occasional, non-defining feature; reported events include
    febrile seizures, partial seizures with an abnormal EEG, and isolated seizure
    episodes. Routine EEG in an asymptomatic carrier is not indicated.
  evidence:
  - reference: PMID:38326731
    reference_title: "Cerebellar heterotopia in an 11-year-old child with KDM6B-related\
      \ neurodevelopmental disorder: A case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      exhibiting facial dysmorphisms, dysgraphia, behavioral traits relatable to
      oppositional defiant, autism spectrum, and attention deficit hyperactivity
      disorders, a single seizure episode
    explanation: >-
      Documents a seizure episode in a genetically confirmed patient.
- category: Neurologic
  name: Gray matter heterotopia
  phenotype_term:
    preferred_term: Cerebellar heterotopic nodule
    term:
      id: HP:0002282
      label: Gray matter heterotopia
  description: >-
    Neuroimaging findings in this disorder are generally nonspecific. A single
    cerebellar heterotopic nodule has been reported in one patient, the first
    such observation in this condition, suggesting a possible role for KDM6B in
    cerebellar development. HPO has no cerebellum-specific heterotopia term, so
    the general gray matter heterotopia term is used with a more specific
    preferred_term.
  evidence:
  - reference: PMID:38326731
    reference_title: "Cerebellar heterotopia in an 11-year-old child with KDM6B-related\
      \ neurodevelopmental disorder: A case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a neuroimaging finding of a single cerebellar heterotopic nodule, never
      described to date in this genetic condition
    explanation: >-
      Single-patient observation, explicitly novel and therefore not
      generalisable, so no frequency is asserted.
  notes: >-
    Single case report. Retained because it is the only structural brain finding
    specifically attributed to this disorder to date.
- category: Craniofacial
  name: Nonspecific dysmorphism without a recognisable gestalt
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  description: >-
    Facial and body dysmorphisms in this disorder are explicitly
    non-pathognomonic; no diagnostic facial gestalt exists, which is why the
    condition is essentially never recognised clinically without sequencing.
  evidence:
  - reference: PMID:38326731
    reference_title: "Cerebellar heterotopia in an 11-year-old child with KDM6B-related\
      \ neurodevelopmental disorder: A case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by non-pathognomonic facial and body dysmorphisms, a wide
      range of neurodevelopmental and behavioral disorders and nonspecific
      neuroradiological findings
    explanation: >-
      States directly that the dysmorphism is non-pathognomonic and the
      neuroradiology nonspecific.
- category: Gastrointestinal
  name: Feeding difficulties
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  description: >-
    Neonatal feeding difficulty is one of the commonest non-neurological
    manifestations, and in the founding series was severe enough in individual
    patients to require nasogastric feeding, and in another a gastrostomy tube
    with dysphagia.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a history of hypotonia and feeding difficulties in the
      neonatal period requiring a nasogastric tube.
    explanation: >-
      Documents neonatal feeding difficulty requiring tube feeding in a
      KDM6B variant carrier.
  notes: >-
    The Rots et al. cohort reports a denominator for neonatal feeding difficulty
    or gastroesophageal reflux, but that figure is in the full text, which the
    publisher does not release into the reference cache, so no frequency band is
    asserted. See the kdm6b_uncacheable_cohort_frequencies discussion.
- category: Gastrointestinal
  name: Gastroesophageal reflux
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  description: >-
    Gastroesophageal reflux is frequently reported alongside neonatal feeding
    difficulty, and has required surgical management.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a surgery for gastroesophageal reflux at 5 years of age.
    explanation: >-
      Documents clinically significant gastroesophageal reflux in a KDM6B
      variant carrier.
- category: Gastrointestinal
  name: Constipation
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  description: >-
    Constipation is a recurrent and sometimes burdensome gastrointestinal
    feature.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was constipation with some subsequent bladder compression.
    explanation: >-
      Documents constipation, with a secondary urological consequence, in a
      KDM6B variant carrier.
- category: Skeletal
  name: Scoliosis
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  description: >-
    Spinal curvature is part of the skeletal spectrum, reported together with
    other axial anomalies such as pectus excavatum and supernumerary ribs.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband had a pectus excavatum, a torticollis with a right head
      deviation, scoliosis, and an extra rib on each side.
    explanation: >-
      Documents scoliosis, alongside other axial skeletal anomalies, in a
      KDM6B variant carrier.
- category: Cardiovascular
  name: Patent foramen ovale
  phenotype_term:
    preferred_term: Patent foramen ovale
    term:
      id: HP:0001655
      label: Patent foramen ovale
  description: >-
    Congenital heart anomalies occur in a minority of individuals. Reported
    findings in the founding series include a patent foramen ovale, mitral valve
    regurgitation, and a vena cava anomaly.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient also had a patent foramen ovale and some jaundice.
    explanation: >-
      Documents a congenital cardiac anomaly in a KDM6B variant carrier.
      Curated at this specific level because the cited case names the
      specific defect.
- category: Genitourinary
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  description: >-
    Genitourinary anomalies are reported in a minority of affected males, with
    cryptorchidism the specific finding named in the founding series.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other features that were reported were hypoplastic nipples, pectus
      excavatum, laryngomalacia, and cryptorchidism.
    explanation: >-
      Lists cryptorchidism among the additional features of the KDM6B
      cohort.
- category: Skeletal
  name: Clinodactyly of the 5th finger
  phenotype_term:
    preferred_term: Clinodactyly of the 5th finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  description: >-
    Fifth-finger clinodactyly is part of the mild distal limb spectrum that gave
    the disorder its OMIM name, present in some but not all cases.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      widened and thickened hands and fingers, joint hypermobility,
      clinodactyly of the fifth fingers, and toe syndactyly
    explanation: >-
      Names fifth-finger clinodactyly among the musculoskeletal features
      present in a subset of the cohort.
- category: Skeletal
  name: Joint hypermobility
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  description: >-
    Joint hypermobility was recorded in a subset of the founding series, in some
    patients marked enough to be described as hyperextensible joints.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      widened and thickened hands and fingers, joint hypermobility,
      clinodactyly of the fifth fingers, and toe syndactyly
    explanation: >-
      Names joint hypermobility among the musculoskeletal features present
      in a subset of the cohort.
- category: Craniofacial
  name: Macrotia
  phenotype_term:
    preferred_term: Macrotia
    term:
      id: HP:0000400
      label: Macrotia
  description: >-
    Large and prominent ears are among the recurrent, individually
    non-diagnostic dysmorphic features.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic facial features that were reported included coarse
      features, a prominent forehead, broad mouth, large and prominent
      ears, a round face, prognathism, and epicanthal folds.
    explanation: >-
      Lists large and prominent ears in the summary of dysmorphic facial
      features across the cohort.
- category: Craniofacial
  name: Prominent forehead
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  description: >-
    A prominent forehead is among the recurrent, individually non-diagnostic
    dysmorphic features.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic facial features that were reported included coarse
      features, a prominent forehead, broad mouth, large and prominent
      ears, a round face, prognathism, and epicanthal folds.
    explanation: >-
      Lists a prominent forehead in the summary of dysmorphic facial
      features across the cohort.
- category: Craniofacial
  name: Mandibular prognathia
  phenotype_term:
    preferred_term: Mandibular prognathia
    term:
      id: HP:0000303
      label: Mandibular prognathia
  description: >-
    Prognathism is among the recurrent, individually non-diagnostic dysmorphic
    features.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic facial features that were reported included coarse
      features, a prominent forehead, broad mouth, large and prominent
      ears, a round face, prognathism, and epicanthal folds.
    explanation: >-
      Lists prognathism in the summary of dysmorphic facial features across
      the cohort.
diagnosis:
- name: Molecular diagnosis by exome or genome sequencing
  description: >-
    Because the dysmorphism is mild and non-pathognomonic and there is no
    recognisable facial gestalt, the diagnosis is made molecularly rather than
    clinically: exome or genome sequencing, or a neurodevelopmental gene panel
    that includes KDM6B, with parental testing to establish de novo status.
    Variant interpretation should be domain-aware, since missense variants
    outside the JmjC catalytic and Zn-containing domains may be benign.
  evidence:
  - reference: PMID:31124279
    reference_title: Genetic variants in the KDM6B gene are associated with neurodevelopmental
      delays and dysmorphic features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a number of de novo alterations in the KDM6B gene via
      whole exome sequencing (WES) in a cohort of 12 unrelated patients with
      developmental delay, intellectual disability, dysmorphic facial features,
      and other clinical findings.
    explanation: >-
      Exome sequencing is the ascertainment route by which this disorder is
      identified.
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we accurately define the broad clinical spectrum of the KDM6B-related NDD,
      introduce an innovative functional testing paradigm for the assessment of
      KDM6B variants
    explanation: >-
      Establishes a functional testing paradigm as an adjunct to sequence-based
      variant interpretation in this disorder.
differential_diagnoses:
- name: Weaver syndrome
  disease_term:
    preferred_term: Weaver syndrome
    term:
      id: MONDO:0010193
      label: Weaver syndrome
  description: >-
    EZH2-related overgrowth and intellectual disability syndrome. EZH2 is the
    catalytic subunit of PRC2 and writes the very H3K27me3 mark that KDM6B
    erases, so Weaver syndrome and KDM6B-related NDD are opposite perturbations
    of the same H3K27 methylation switch. The contrast is worth stating
    explicitly: the same chromatin axis produces an overgrowth syndrome when the
    writer is overactive and a non-overgrowth neurobehavioral syndrome when the
    eraser is lost.
  distinguishing_features:
  - Weaver syndrome features pre- and postnatal overgrowth with advanced bone age
    and a distinctive facial appearance, which are not part of the core
    KDM6B-related NDD presentation.
  - KDM6B-related NDD is dominated by cognitive, behavioral, and psychiatric
    features with mild, non-gestalt dysmorphism.
  - Molecular testing distinguishes them unambiguously (EZH2 versus KDM6B).
  evidence:
  - reference: PMID:38015625
    reference_title: "A mouse model of Weaver syndrome displays overgrowth and\
      \ excess osteogenesis reversible with KDM6A/6B inhibition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Weaver syndrome is a Mendelian disorder of the epigenetic machinery (MDEM)
      caused by germline pathogenic variants in EZH2, which encodes the
      predominant H3K27 methyltransferase and key enzymatic component of
      Polycomb repressive complex 2 (PRC2). Weaver syndrome is characterized by
      striking overgrowth and advanced bone age, intellectual disability, and
      distinctive facies.
    explanation: >-
      Defines Weaver syndrome as the EZH2 (H3K27 writer) counterpart disorder and
      names the overgrowth and advanced bone age that distinguish it from
      KDM6B-related NDD.
  - reference: PMID:38015625
    reference_title: "A mouse model of Weaver syndrome displays overgrowth and\
      \ excess osteogenesis reversible with KDM6A/6B inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Inhibition of the opposing H3K27 demethylases KDM6A and KDM6B
      substantially reversed the excessive osteogenesis in Ezh2R684C/+ cells
      both at the transcriptional and phenotypic levels.
    explanation: >-
      Direct experimental demonstration that KDM6B opposes the EZH2 Weaver
      variant on the same H3K27 axis, which is exactly the writer/eraser
      contrast this differential rests on.
- name: Sotos syndrome
  disease_term:
    preferred_term: Sotos syndrome
    term:
      id: MONDO:0019349
      label: Sotos syndrome
  description: >-
    NSD1-related overgrowth syndrome, the principal clinical mimic of Weaver
    syndrome and part of the same histone-methylation-machinery differential.
  distinguishing_features:
  - Overgrowth with macrocephaly, advanced bone age, and a characteristic facial
    gestalt.
  - Caused by NSD1 haploinsufficiency (an H3K36 methyltransferase) rather than a
    KDM6 or PRC2 lesion.
- name: Cohen-Gibson syndrome
  disease_term:
    preferred_term: Cohen-Gibson syndrome
    term:
      id: MONDO:0060510
      label: Cohen-Gibson syndrome
  description: >-
    EED-related overgrowth syndrome. EED is a core non-catalytic PRC2 subunit,
    making this a further PRC2-axis differential for a suspected H3K27
    chromatinopathy.
  distinguishing_features:
  - Weaver-like overgrowth with advanced bone age, contrasting with the absence
    of an overgrowth-defined presentation in KDM6B-related NDD.
- name: Kabuki syndrome
  disease_term:
    preferred_term: Kabuki syndrome
    term:
      id: MONDO:0016512
      label: Kabuki syndrome
  description: >-
    Chromatinopathy caused by KMT2D or KDM6A variants. KDM6A (UTX) is the direct
    paralogue of KDM6B and the other mammalian H3K27me2/me3 demethylase, so
    Kabuki syndrome is the closest mechanistic neighbour of this disorder.
  distinguishing_features:
  - Kabuki syndrome has a recognisable facial gestalt (long palpebral fissures
    with eversion of the lateral third of the lower lid), persistent fetal
    fingertip pads, cleft palate, congenital heart disease, and immune
    deficiency.
  - KDM6B-related NDD has no recognisable gestalt and is identified molecularly.
  evidence:
  - reference: PMID:18003914
    reference_title: Identification of JmjC domain-containing UTX and JMJD3 as histone
      H3 lysine 27 demethylases.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we show the JmjC domain-containing protein UTX (ubiquitously
      transcribed tetratricopeptide repeat, X chromosome), as well as the
      related JMJD3 (jumonji domain containing 3), specifically removes methyl
      marks on H3K27 in vitro.
    explanation: >-
      Establishes UTX/KDM6A and JMJD3/KDM6B as the paralogous H3K27 demethylase
      pair, the basis for pairing Kabuki syndrome with this disorder.
- name: Mucopolysaccharidosis
  description: >-
    Coarse facial features in an infant or young child with developmental delay
    commonly prompt a first-line evaluation for a lysosomal storage disorder, and
    this happened in at least one patient in the founding KDM6B series.
  distinguishing_features:
  - Mucopolysaccharidoses show progressive coarsening with organomegaly,
    dysostosis multiplex, and corneal clouding.
  - Abnormal urinary glycosaminoglycans or deficient lysosomal enzyme activity
    confirm a storage disorder; KDM6B-related NDD has normal lysosomal
    biochemistry and non-progressive dysmorphism.
treatments:
- name: Multidisciplinary developmental and supportive care
  description: >-
    No disease-modifying therapy exists. Management is supportive and
    anticipatory: early intervention with physical, occupational, and speech
    therapy for developmental delay and hypotonia, educational support for
    learning difficulties, and coordinated follow-up across genetics, neurology,
    and psychiatry. Psychiatric surveillance from adolescence is warranted given
    the reported psychosis risk.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Neurodevelopmental and Behavioral Phenotype
    description: >-
      Supportive care addresses the organism-level developmental and behavioral
      consequences rather than the underlying chromatin lesion.
  evidence:
  - reference: PMID:35840288
    reference_title: "The KDM6B mutation: Phenotype and clinical characteristics-Report
      of a case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is highly probable that the complexity of these cases requires an
      approach by a multidisciplinary team
    explanation: >-
      Explicit clinical recommendation for multidisciplinary management of
      KDM6B-related disease. The quote is trimmed to the last complete word
      before the cached abstract itself is truncated.
- name: Genetic counseling
  description: >-
    Counseling covers the autosomal dominant, predominantly de novo mechanism,
    the low but non-zero sibling recurrence risk from parental germline
    mosaicism, the possibility of a mildly affected transmitting parent, and the
    wide variability of the phenotype. Establishing the molecular diagnosis also
    resolves the differential with lysosomal storage and overgrowth
    chromatinopathies.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38326731
    reference_title: "Cerebellar heterotopia in an 11-year-old child with KDM6B-related\
      \ neurodevelopmental disorder: A case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings expand the phenotypic spectrum of this syndrome,
      highlighting the potential role for KDM6B in cerebellar development and
      providing valuable insights for genetic counseling.
    explanation: >-
      The clinical literature frames phenotype delineation in this disorder as
      directly serving genetic counseling.
- name: Stimulant pharmacotherapy for ADHD symptoms
  description: >-
    Standard ADHD pharmacotherapy is used symptomatically when attention deficit
    and hyperactivity are impairing. Direct human trial evidence in KDM6B-related
    NDD is absent; the mechanistic rationale is supported by rescue of
    hyperactivity and impulsivity by methylphenidate in the heterozygous Kdm6b
    mouse. This is preclinical support only and must not be read as
    disease-specific efficacy evidence.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methylphenidate
      term:
        id: CHEBI:6887
        label: methylphenidate
  target_phenotypes:
  - preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:35711692
    reference_title: Kdm6b Haploinsufficiency Causes ASD/ADHD-Like Behavioral Deficits
      in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, the mutant mice display markedly increased locomotor activity
      and impulsivity, two ADHD-like behavioral traits that are ameliorated by
      methylphenidate treatment.
    explanation: >-
      Model-organism evidence of methylphenidate response in Kdm6b
      haploinsufficiency; PARTIAL because no human treatment study exists for
      this disorder.
clinical_trials:
- name: NCT01238250
  status: RECRUITING
  description: >-
    Simons Searchlight, an international observational online registry that
    collects longitudinal medical, behavioral, learning, and developmental data
    from people with rare genetic variants causing neurodevelopmental disorders.
    For an ultra-rare disorder such as this one, registry data are currently the
    only realistic route to natural-history and outcome information.
  evidence:
  - reference: clinicaltrials:NCT01238250
    reference_title: "Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Simons Searchlight is an observational, online, international research
      program for families with rare genetic variants that cause
      neurodevelopmental disorders and may be associated with autism.
    explanation: >-
      Defines the registry scope, which covers rare genetic neurodevelopmental
      disorders of this kind. The cached record does not name KDM6B explicitly,
      so the link to this disorder is by registry scope rather than by an
      explicit gene listing, hence PARTIAL.
animal_models:
- name: Kdm6b heterozygous mouse
  species: Mus musculus
  genotype: Kdm6b heterozygous (one allele deleted)
  category: knockout mouse model
  description: >-
    Deletion of one Kdm6b allele in mice, matching the human heterozygous
    dosage, produces autistic-like impaired sociability and object recognition
    memory plus ADHD-like hyperactivity and impulsivity that respond to
    methylphenidate.
  genes:
  - preferred_term: KDM6B
    term:
      id: hgnc:29012
      label: KDM6B
  publication: PMID:35711692
  modeled_mechanisms:
  - target: KDM6B Haploinsufficiency and Catalytic Impairment
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Recapitulates the human heterozygous loss-of-function dosage state.
    limitations: >-
      A whole-gene allele deletion rather than the point and in-frame variants
      that account for many human cases, and mouse behavior is only a proxy for
      the human cognitive phenotype.
  - target: Neurodevelopmental and Behavioral Phenotype
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the autism- and ADHD-like behavioral output of the mechanism.
    limitations: >-
      Does not address the dysmorphic, skeletal, or psychiatric (psychosis) arms
      of the human phenotype.
  evidence:
  - reference: PMID:35711692
    reference_title: Kdm6b Haploinsufficiency Causes ASD/ADHD-Like Behavioral Deficits
      in Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we use an animal model to show that genetic deletion of one Kdm6b
      allele in mice leads to autistic-like impaired sociability and object
      recognition memory.
    explanation: >-
      Establishes the heterozygous mouse as a dosage-matched model of the human
      disorder.
- name: KDM6B mosaic brain knockout mouse
  species: Mus musculus
  genotype: KDM6B mosaic brain knockout
  category: conditional knockout mouse model
  description: >-
    Mosaic knockout of KDM6B in the mouse brain produces repetitive behaviors,
    impaired social interaction, and cognitive deficits, and reduces NMDA
    receptor-mediated hippocampal excitatory synaptic transmission and
    plasticity. Being brain-restricted by construction, it cannot address the
    craniofacial or skeletal arm of the human phenotype.
  genes:
  - preferred_term: KDM6B
    term:
      id: hgnc:29012
      label: KDM6B
  publication: PMID:39223259
  modeled_mechanisms:
  - target: Altered Synaptic Transmission and Plasticity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Provides the electrophysiological readout for this node.
    limitations: >-
      Mosaic, brain-restricted somatic knockout rather than constitutional
      heterozygosity; rodent hippocampal physiology is not human tissue.
  evidence:
  - reference: PMID:39223259
    reference_title: Impact of KDM6B mosaic brain knockout on synaptic function and
      behavior.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we show the impact of KDM6B mosaic brain knockout on the manifestation
      of different autistic-like phenotypes including repetitive behaviors,
      social interaction, and significant cognitive deficits.
    explanation: >-
      Behavioral and synaptic characterisation of brain-restricted KDM6B loss.
- name: Drosophila dual gain-of-function KDM6B variant assay
  species: Drosophila melanogaster
  genotype: KDM6B orthologue manipulation in a dual gain-of-function assay
  category: invertebrate functional assay
  description: >-
    A dual Drosophila gain-of-function assay was used to demonstrate that
    disease-associated missense and in-frame indel variants in or near the JmjC
    and Zn-containing domains disrupt KDM6B function. The same system showed a
    role for the fly KDM6B orthologue in memory and behavior.
  publication: PMID:37196654
  modeled_mechanisms:
  - target: KDM6B Haploinsufficiency and Catalytic Impairment
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Functional readout that classifies patient missense and in-frame indel
      variants as disruptive.
  - target: Altered Synaptic Transmission and Plasticity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Demonstrates a conserved requirement for the orthologue in memory and
      behavior.
    limitations: >-
      Invertebrate nervous system; supports conservation of function rather than
      the specific mammalian synaptic mechanism.
  evidence:
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with the role of KDM6B in human cognition, we demonstrated a
      role for the Drosophila KDM6B ortholog in memory and behavior.
    explanation: >-
      Establishes the fly model as a functional readout for KDM6B variant
      interpretation and for conserved cognitive function.
experimental_models:
- name: KDM6-deficient human pluripotent stem cell-derived neural progenitor cells
  description: >-
    Deletion of JMJD3 (KDM6B) and/or UTX (KDM6A) in human embryonic stem cells
    permits neural progenitor generation but causes poor progenitor
    proliferation, failure of neuronal and glial differentiation, H3K27me3
    accumulation, and loss of DNA accessibility at neural developmental loci.
    Classified as OTHER because the system is human embryonic stem cell-derived
    rather than iPSC-derived.
  experimental_model_type: OTHER
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  publication: PMID:31959746
  modeled_mechanisms:
  - target: Failure to Remove Repressive H3K27me3
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Shows H3K27me3 accumulation and loss of accessibility at neural
      developmental genes on KDM6 loss, in human cells.
  - target: Impaired Neural Commitment and Neurogenesis
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Shows the progenitor proliferation and differentiation block in human
      cells.
    limitations: >-
      Complete KDM6 deletion rather than the heterozygous KDM6B state of
      patients, and both paralogues are targeted in the most severe conditions.
  evidence:
  - reference: PMID:31959746
    reference_title: JMJD3 and UTX determine fidelity and lineage specification of
      human neural progenitor cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, KDM6-deficient NPCs exhibit poor proliferation and a failure to
      differentiate into neurons and glia.
    explanation: >-
      Human cellular model of the core differentiation block caused by loss of
      KDM6 demethylase activity.
discussions:
- discussion_id: kdm6b_commitment_direction_paradox
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Does KDM6B loss block neural differentiation or accelerate it? Both are
    reported, and the reconciliation determines which cellular node actually
    drives the human cognitive phenotype.
  attaches_to:
  - pathophysiology#Impaired Neural Commitment and Neurogenesis
  - pathophysiology#Precocious Neural Stem Cell Differentiation and Pool Depletion
  rationale: >-
    Human embryonic stem cell-derived progenitors lacking KDM6 enzymes fail to
    differentiate into neurons and glia, and Jmjd3 deletion in subventricular
    zone neural stem cells impairs neuronal differentiation. In the hippocampal
    dentate gyrus, by contrast, Kdm6b deletion causes precocious neuronal
    differentiation that exhausts the stem cell pool. These are opposite
    directions of effect on the same cell-fate decision. Plausible
    reconciliations include regional specialisation (dentate gyrus versus
    subventricular zone and cortex), developmental timing, differing degrees of
    KDM6A compensation, or partial versus complete loss of KDM6 activity; the
    entry currently models both as separate nodes rather than forcing one.
    A further open strand is whether some of KDM6B's requirement is
    catalytic-independent, which would mean H3K27me3 demethylase activity alone
    does not account for the disorder; the abstracts available here do not
    settle that.
  proposed_experiments:
  - experiment_id: exp_kdm6b_region_matched_deletion_comparison
    name: Region-matched conditional Kdm6b deletion comparison
    description: >-
      Delete Kdm6b at matched developmental timepoints in dentate gyrus,
      subventricular zone, and cortical progenitors in the same study and score
      differentiation direction with common markers, to test whether the
      discrepancy is regional or methodological.
  - experiment_id: exp_kdm6b_catalytic_dead_rescue
    name: Catalytically dead KDM6B rescue
    description: >-
      Rescue KDM6B-null human neural progenitors with wild-type versus
      catalytically dead KDM6B and compare differentiation, proliferation, and
      H3K27me3 landscape, to quantify how much of the requirement is
      demethylase-dependent.
  evidence:
  - reference: DOI:10.1101/2024.02.20.581302
    reference_title: "Chromatin regulator <i>Kdm6b</i> is required for the establishment and maintenance of neural stem cells in mouse hippocampus"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      causes precocious neuronal differentiation, and the NSC population fails
      to become established in the postnatal DG.
    explanation: >-
      The precocious-differentiation arm of the paradox.
  - reference: PMID:31959746
    reference_title: JMJD3 and UTX determine fidelity and lineage specification of
      human neural progenitor cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, KDM6-deficient NPCs exhibit poor proliferation and a failure to
      differentiate into neurons and glia.
    explanation: >-
      The differentiation-block arm of the paradox, in human cells.
- discussion_id: kdm6b_uncacheable_cohort_frequencies
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Can the per-feature frequencies from the Rots et al. 2023 cohort be brought
    into this entry as snippet-verified evidence, so that FrequencyEnum bands
    can be assigned?
  attaches_to:
  - phenotypes#Hypotonia
  - phenotypes#Psychosis
  - phenotypes#Feeding difficulties
  - phenotypes#Coarse facial features
  rationale: >-
    PMID:37196654 is the definitive 85-individual cohort and its tables carry
    denominators for every recurrent manifestation, including several that this
    entry curates without a frequency band and at least two that it cannot
    curate at all. The publisher blocks full-text download, so `just
    fetch-reference PMID:37196654` yields an abstract-only cache, and
    PMC10257005 is not fetchable through the current reference sources. Per the
    project rule that snippets must be exact quotes from the cached reference,
    those numbers cannot be used here yet, and this entry deliberately leaves
    the bands off rather than transcribing figures it cannot verify.

    Two manifestations are consequently absent from `phenotypes` rather than
    merely unbanded, because no cacheable source documents them in this
    disorder: sleep disturbance (recorded only as a bare table row in the
    PMID:31124279 full text) and macrocephaly or postnatal overgrowth (no
    narrative statement in any cached source; the founding series reports only
    individual head-circumference centiles in a table). The overgrowth question
    matters disproportionately, because it is the phenotypic hinge against the
    Weaver, Sotos, and Cohen-Gibson differentials that this entry lists: if a
    substantial minority of KDM6B patients are macrocephalic, the clean
    "eraser loss gives no overgrowth" contrast drawn in those differentials
    needs qualifying.
  proposed_experiments:
  - experiment_id: exp_kdm6b_cohort_fulltext_ingest
    name: Ingest the Rots 2023 cohort tables through a cacheable route
    description: >-
      Obtain the cohort frequency tables through a source the reference
      validator can cache (author-deposited accepted manuscript, a PMC route
      once available, or supplementary data with a citable identifier), then
      assign FrequencyEnum bands to hypotonia, psychosis, feeding difficulty,
      autism, intellectual disability, and the skeletal features, and add
      macrocephaly and sleep disturbance as phenotypes.
- discussion_id: kdm6b_omim_name_mismatch
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Should the OMIM and MONDO label "neurodevelopmental disorder with coarse
    facies and mild distal skeletal abnormalities" be retired in favour of a
    gene-anchored name, given that the two features in the name are uncommon?
  attaches_to:
  - pathophysiology#Disrupted Craniofacial and Distal Skeletal Patterning
  rationale: >-
    The syndrome name derives from a 12-patient ascertainment series. The
    85-individual cohort found coarse facies and distal skeletal anomalies to be
    rare while hypotonia and psychosis are unexpectedly common, and stated
    explicitly that the OMIM description is inaccurate and potentially
    misleading. Retaining the name risks misdirecting clinical suspicion away
    from patients who lack dysmorphism. This entry uses the gene-anchored name
    while preserving MONDO:0032790 and the OMIM label as synonyms.
  evidence:
  - reference: PMID:37196654
    reference_title: The clinical and molecular spectrum of the KDM6B-related neurodevelopmental
      disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, by examining the molecular and clinical spectrum of 85 reported
      individuals with mostly de novo (likely) pathogenic KDM6B variants, we
      demonstrate that this description is inaccurate and potentially
      misleading.
    explanation: >-
      Direct source of the naming controversy recorded here.
- discussion_id: kdm6b_dysmorphology_mechanism_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what mechanism does reduced KDM6B activity produce coarse facies and mild
    distal skeletal anomalies in the minority of patients who have them?
  attaches_to:
  - pathophysiology#Disrupted Craniofacial and Distal Skeletal Patterning
  rationale: >-
    The neural arm of the mechanism is well supported by human stem cell, mouse,
    and fly data, but no study has connected KDM6B loss to human craniofacial or
    limb patterning. The HOX/Polycomb route is inferred from work on the
    paralogue UTX in zebrafish. Whether the dysmorphic minority reflects a
    distinct variant class, a modifier, or simply ascertainment bias is unknown.
  proposed_experiments:
  - experiment_id: exp_kdm6b_genotype_dysmorphology_stratification
    name: Genotype-stratified dysmorphology analysis of the published cohort
    description: >-
      Test within the 85-individual cohort whether coarse facies and distal
      skeletal features segregate with catalytic-domain missense variants versus
      truncating variants, or are distributed at random with respect to variant
      class.
  - experiment_id: exp_kdm6b_neural_crest_limb_differentiation
    name: KDM6B-null neural crest and limb bud differentiation with chromatin profiling
    description: >-
      Differentiate KDM6B-null human induced pluripotent stem cells along neural
      crest and limb bud trajectories and profile H3K27me3 and chromatin
      accessibility at HOX clusters to test the patterning hypothesis directly in
      human cells.
  - experiment_id: exp_kdm6b_episignature_stratified
    name: DNA methylation episignature stratified by dysmorphism
    description: >-
      Derive a peripheral-blood DNA methylation episignature in KDM6B variant
      carriers and test whether carriers with and without dysmorphism separate,
      which would indicate a distinct molecular subgroup.
- discussion_id: kdm6b_psychosis_frequency
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the true prevalence, age-of-onset distribution, and natural history
    of psychosis in KDM6B-related neurodevelopmental disorder?
  attaches_to:
  - phenotypes#Psychosis
  rationale: >-
    Psychosis is one of the most clinically actionable features of this disorder,
    yet the available published characterisations are qualitative and not
    obviously concordant: OMIM records psychosis in a small percentage of
    individuals over age 12, while the largest cohort lists it among features
    that are unexpectedly common. The cohort denominator for individuals aged 12
    or older is small. No frequency band can responsibly be assigned from the
    retrievable abstracts, so none is asserted on the phenotype record.
  proposed_experiments:
  - experiment_id: exp_kdm6b_prospective_psychiatric_followup
    name: Prospective psychiatric follow-up of the published cohort
    description: >-
      Follow cohort members prospectively from age 10 with standardised psychosis
      screening instruments to establish incidence and age of onset rather than
      cross-sectional prevalence in an ascertainment-enriched sample.
  - experiment_id: exp_kdm6b_age_stratified_reanalysis
    name: Age-stratified reanalysis of the 85-individual cohort
    description: >-
      Re-report psychiatric outcomes with explicit age-stratified denominators so
      that a defensible FrequencyEnum band can be assigned.
- discussion_id: kdm6b_mouse_human_dysmorphology_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Do the available Kdm6b mouse models reproduce the non-neural (craniofacial
    and distal skeletal) arm of the human phenotype, or only the behavioral arm?
  attaches_to:
  - pathophysiology#Disrupted Craniofacial and Distal Skeletal Patterning
  rationale: >-
    The heterozygous and mosaic-brain-knockout mouse models are reported in terms
    of sociability, memory, hyperactivity, impulsivity, and hippocampal synaptic
    physiology. The mosaic model is brain-restricted by construction and cannot
    address craniofacial or limb development at all. Evidence therefore exists in
    a model system but its fidelity to the dysmorphic component of the human
    disorder is untested rather than absent, which is the defining situation for
    a HUMAN_MODEL_MISMATCH rather than a plain knowledge gap.
  proposed_experiments:
  - experiment_id: exp_kdm6b_het_mouse_craniofacial_morphometry
    name: Craniofacial and skeletal morphometry of Kdm6b heterozygous mice
    description: >-
      Perform skeletal preparations and micro-CT craniofacial morphometry on
      constitutive Kdm6b heterozygous mice against wild-type littermates to test
      whether the dysmorphic arm of the human phenotype is modelled at all.
  - experiment_id: exp_kdm6b_lineage_conditional_deletion
    name: Lineage-restricted conditional Kdm6b deletion
    description: >-
      Delete Kdm6b conditionally in neural crest and limb bud lineages to test
      tissue-autonomous requirements for craniofacial and distal limb
      patterning.
  evidence:
  - reference: PMID:39223259
    reference_title: Impact of KDM6B mosaic brain knockout on synaptic function and
      behavior.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we show the impact of KDM6B mosaic brain knockout on the manifestation
      of different autistic-like phenotypes including repetitive behaviors,
      social interaction, and significant cognitive deficits.
    explanation: >-
      Illustrates that the available mouse characterisation is brain- and
      behavior-focused, leaving the dysmorphic arm of the human phenotype
      unmodelled.
📚

References & Deep Research

References

2
PMID:37196654
The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder.
No top-level findings curated for this source.
PMID:31124279
Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
KDM6B-Related Neurodevelopmental Disorder: Comprehensive Research Report
Edison Scientific Literature 27 citations 2026-08-15T08:42:13.045682

KDM6B-Related Neurodevelopmental Disorder: Comprehensive Research Report

Executive summary

KDM6B-related neurodevelopmental disorder (KDM6B-NDD), sometimes called Stolerman syndrome, is a rare Mendelian chromatinopathy caused predominantly by heterozygous loss-of-function or function-impairing variants in KDM6B/JMJD3, an H3K27me2/3 histone demethylase. The best current human dataset comprises 85 individuals carrying 71 likely pathogenic variants. Developmental abnormalities were found in essentially all, with intellectual disability (ID) in 63%, autism spectrum disorder (ASD) in 61%, other behavioral problems in 60%, hypotonia in 57%, and neonatal feeding difficulty or gastroesophageal reflux in 51%. Expression is highly variable; most ID is mild, recognizable facial gestalt is absent, and 11% inherited the variant from a mildly affected or apparently unaffected parent. (rots2024clinicalepigeneticsof pages 85-87, rots2024clinicalepigeneticsof pages 79-82)

Recent 2024 experimental work strengthens the biological model: Kdm6b is required for hippocampal neural-stem-cell maintenance, while brain mosaic knockout disrupts NMDA-receptor-mediated transmission and plasticity and produces cognitive, social, and repetitive-behavior phenotypes in mice. These findings are mechanistically important but do not yet establish a human biomarker or treatment. (brauer2024impactofkdm6b pages 9-10, gil2024chromatinregulatorkdm6b pages 1-5, gil2024chromatinregulatorkdm6b pages 11-14)

Domain Best-supported finding/statistic Suggested ontology terms Evidence type/strength
Identifiers / naming OMIM names the condition “Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities” (OMIM #618505), but the larger 85-person cohort argues coarse facies/distal skeletal findings are rare and not typical; “KDM6B-related neurodevelopmental disorder” is the more accurate disease label. Initial disease-defining report described 12 unrelated patients with de novo KDM6B variants. (stolerman2019geneticvariantsin pages 1-2, rots2024clinicalepigeneticsof pages 85-87) OMIM: 618505; MONDO: not confirmed from available sources; NCIT: neurodevelopmental disorder; HPO: HP:0001263 Global developmental delay; HP:0001249 Intellectual disability Human cohort data; strong for naming revision, moderate for formal identifier set
Genetics / inheritance Disease is caused by heterozygous pathogenic/likely pathogenic KDM6B variants; in the expanded cohort 64/85 (75%) were de novo and 9/85 (11%) inherited from mildly affected or apparently unaffected parents, indicating high but incomplete penetrance/variable expressivity. KDM6B is constrained for LoF (pLI=1, LOEUF=0.14; earlier gnomAD o/e 0.06, 90% CI 0.03–0.14), supporting haploinsufficiency/functional loss. (rots2024clinicalepigeneticsof pages 79-82, rots2024clinicalepigeneticsof pages 85-87, stolerman2019geneticvariantsin pages 10-11) HGNC: KDM6B; inheritance: autosomal dominant; SO: loss_of_function_variant, missense_variant, stop_gained, frameshift_variant Human genetic cohort + population constraint; strong
Variant classes / protein regions 71 different KDM6B variants were considered likely pathogenic across 85 individuals. Pathogenicity is strongest for variants disrupting the JmjC catalytic region or Zn-containing domain; some linker/surface missense changes were reclassified as VUS in functional assays. Truncating variants in the last/penultimate exons may escape NMD yet still cause loss of function by removing the Zn-containing domain. (rots2024clinicalepigeneticsof pages 79-82, rots2024clinicalepigeneticsof pages 85-87, stolerman2019geneticvariantsin pages 10-11) SO: missense_variant, frameshift_variant, nonsense_variant; GO: GO:0032454 histone demethylase activity; protein region terms: JmjC domain, zinc-binding domain Human cohort + Drosophila functional assay; moderate-strong
Core neurodevelopmental phenotype In the 85-person pathogenic/likely pathogenic cohort, neurodevelopmental abnormalities were present in all assessed individuals; developmental delay was present in all except two. ID 63%, usually mild; ASD 61%; other behavioral problems 60%. (rots2024clinicalepigeneticsof pages 79-82) HPO: HP:0001263, HP:0001249, HP:0000717 Autism, HP:0000708 Behavioral abnormality Human cohort; strong
Neurologic features Hypotonia 57%, sleep disturbance 32%, movement disorders 24% (gait abnormality, dystonia-like movements, spasticity, hypertonia, toe walking), seizures 13%. Psychotic disorder was reported in 4/20 (20%) individuals aged ≥12 years. (rots2024clinicalepigeneticsof pages 79-82, rots2024clinicalepigeneticsof pages 85-87) HPO: HP:0001252 Hypotonia; HP:0002360 Sleep disturbance; HP:0100022 Movement disorder; HP:0001250 Seizure; HP:0000709 Psychosis Human cohort; strong for frequencies, moderate for age-related psychiatric risk
Growth / craniofacial / musculoskeletal Postnatal overgrowth features occurred in 30%; macrocephaly 26%, tall stature 8%, increased weight 14%, increased birth weight 16% (10/63). Dysmorphism is usually mild/variable with no recognizable gestalt. Limb/skeletal findings: broad fingers/hands or broad toes/feet 20%, spine curvature 13%, toe syndactyly 9%, short fingers/toes 9%. (rots2024clinicalepigeneticsof pages 79-82, rots2024clinicalepigeneticsof pages 85-87) HPO: HP:0000256 Macrocephaly; HP:0000098 Tall stature; HP:0001159 Syndactyly; HP:0001165 Brachydactyly; HP:0000928 Abnormality of the vertebral column Human cohort; strong
GI / feeding / congenital anomalies Neonatal feeding difficulty or GERD 51%, constipation 18%. Congenital anomalies: heart defects 13%, genitourinary anomalies 10%, cleft lip/palate 4%. (rots2024clinicalepigeneticsof pages 79-82) HPO: HP:0011968 Feeding difficulties; HP:0002019 Gastroesophageal reflux; HP:0002019/HP:0001508 Constipation; HP:0001627 Abnormal heart morphology; HP:0000078 Abnormality of the genital system; HP:0000175 Cleft palate Human cohort; strong
Sex distribution / modifiers Cohort shows a male bias (~75%); authors hypothesize a possible female protective effect and contribution from other genetic/environmental modifiers, but no definitive modifier genes are established. (rots2024clinicalepigeneticsof pages 85-87) PATO: male-biased frequency; HPO: variable expressivity Human cohort observation; moderate
Molecular mechanism KDM6B/JMJD3 is an H3K27me2/3 demethylase that counteracts Polycomb repression to regulate developmental gene expression. Human disorder is best explained by loss of function / reduced function, not a clearly established dominant-negative mechanism. (stolerman2019geneticvariantsin pages 2-2, stolerman2019geneticvariantsin pages 10-11, swahari2019histonedemethylasesin pages 3-4) GO: GO:0032454 histone demethylase activity; GO:0016575 histone deacetylation? not applicable; GO:0045664 regulation of neuron differentiation; GO:0006357 regulation of transcription by RNA polymerase II Human genetics + mechanistic review; strong for upstream mechanism
Cellular / systems pathophysiology Recent models show Kdm6b is required for dentate gyrus neural stem-cell establishment and maintenance; deletion causes precocious neuronal differentiation, depletion of NSCs, and transcriptomic disruption on scRNA-seq. In mosaic brain KO mice, Kdm6b loss causes reduced excitatory synaptic transmission, impaired NMDAR-dependent LTP, altered NR2A/NR2B balance, and autism-like/social/cognitive phenotypes. (gil2024chromatinregulatorkdm6b pages 1-5, gil2024chromatinregulatorkdm6b pages 11-14, brauer2024impactofkdm6b pages 9-10, brauer2024impactofkdm6b pages 1-2) GO: neurogenesis, neuron differentiation, synaptic plasticity, NMDA receptor signaling; CL: neural stem cell, neuroblast, excitatory neuron; UBERON: hippocampus, dentate gyrus, cerebellum Mouse in vivo + scRNA-seq/electrophysiology; moderate-strong
Anatomy most affected Highest-confidence affected system is the central nervous system, especially cortex/hippocampus/dentate gyrus and likely broader neural circuits; secondary involvement includes GI, cardiac, genitourinary, and musculoskeletal systems. (rots2024clinicalepigeneticsof pages 79-82, gil2024chromatinregulatorkdm6b pages 1-5, brauer2024impactofkdm6b pages 9-10) UBERON: brain, hippocampus, dentate gyrus, cerebellum, heart, gastrointestinal tract, urinary system; CL: neural stem cell, cerebellar granule neuron Human phenotype + mouse mechanism; moderate-strong
Diagnostics Current diagnosis is primarily genomic: WES/WGS or NDD/autism/ID panels including KDM6B; CMA, Fragile X testing, and metabolic testing were used in early workups; parental testing is important for de novo status. Disease is unlikely to be recognized clinically alone because dysmorphism is mild/variable. (stolerman2019geneticvariantsin pages 8-9, stolerman2019geneticvariantsin pages 6-7, stolerman2019geneticvariantsin pages 9-10, rots2024clinicalepigeneticsof pages 85-87) NCIT: Whole Exome Sequencing, Chromosomal Microarray Analysis; HPO-based phenotyping; ACMG/AMP variant classification Human clinical cohort; strong for sequencing-based diagnosis
Epigenomic diagnostics A validated KDM6B-specific DNA methylation episignature was not established in the available disease-specific sources. Recent chromatinopathy literature supports episignatures as a general approach for variant interpretation, but this remains an evidence gap for KDM6B in the accessible dataset. (rots2024clinicalepigeneticsof pages 85-87, jaarsveld2023delineationofa pages 6-8) EFO/OBI: DNA methylation profiling; epigenetic biomarker Indirect/general chromatinopathy evidence; weak for KDM6B-specific use
Management / real-world care No disease-modifying therapy is established. Reported care is supportive and multidisciplinary: physical, occupational, and speech therapy, special education, management of constipation/GERD/feeding problems, and treatment of spasticity in some cases (including botulinum toxin in one report). Awareness of adolescent/adult psychiatric risk may affect follow-up. (stolerman2019geneticvariantsin pages 8-9, stolerman2019geneticvariantsin pages 8-8, rots2024clinicalepigeneticsof pages 79-82, rots2024clinicalepigeneticsof pages 85-87) NCIT: Physical Therapy, Occupational Therapy, Speech Therapy, Special Education, Botulinum Toxin Therapy Human case/cohort care data; moderate
Trials / registries No interventional disease-specific trials were identified. Simons Searchlight (NCT01238250) is a recruiting observational registry that explicitly includes KDM6B, collects longitudinal medical/behavioral/developmental data, and aims to improve care for rare genetic NDDs. (NCT01238250 chunk 1, NCT01238250 chunk 2) NCIT: Observational Study; ClinicalTrials.gov: NCT01238250 Registry evidence; strong for data collection, not treatment efficacy
Prognosis / epidemiology Natural history remains incompletely defined. Available evidence supports a lifelong neurodevelopmental disorder with usually mild ID when present, variable ASD/behavioral burden, and possible later psychotic disorders. No robust prevalence, incidence, life-expectancy, or disease-specific mortality estimates were found. Early GeneDx ascertainment found 12/10,619 exomes (0.12%) among tested DD/ID cases, which is not population prevalence. (stolerman2019geneticvariantsin pages 9-10, rots2024clinicalepigeneticsof pages 79-82, rots2024clinicalepigeneticsof pages 85-87) HPO: chronic neurodevelopmental course; epidemiology terms unavailable Limited cohort evidence; moderate for course, weak for prevalence/survival
Prevention / counseling No primary prevention is known for the disorder itself. Best-supported prevention-related measures are genetic counseling, recurrence-risk assessment based on de novo vs inherited status, and consideration of family testing/cascade testing when a familial variant is found. (rots2024clinicalepigeneticsof pages 79-82, rots2024clinicalepigeneticsof pages 85-87) NCIT: Genetic Counseling; prenatal/preimplantation testing terms if familial variant known Inference from Mendelian inheritance pattern; moderate
Major evidence gaps Key gaps: no confirmed population prevalence/incidence; no standardized diagnostic criteria beyond molecular diagnosis; no established KDM6B episignature in the accessible disease-specific literature; no disease-specific biomarkers; no interventional trials; sparse adult outcome, QoL, and survival data; no confirmed modifier genes or protective environmental factors. (rots2024clinicalepigeneticsof pages 85-87, rots2024clinicalepigeneticsof pages 79-82, stolerman2019geneticvariantsin pages 9-10, jaarsveld2023delineationofa pages 6-8) Evidence gap / no ontology term needed Cross-source synthesis; strong as a gap assessment

Table: This table summarizes the most clinically and mechanistically supported findings for KDM6B-related neurodevelopmental disorder, emphasizing quantified human cohort data and clearly marking areas where evidence is still lacking.

1. Disease information

Definition and identifiers

KDM6B-NDD is a congenital-onset, lifelong neurodevelopmental disorder characterized primarily by developmental delay, variable ID, ASD or other behavioral/psychiatric manifestations, and variably associated neurologic, feeding, growth, and congenital abnormalities. It belongs to the Mendelian disorders of the epigenetic machinery/chromatinopathies.

  • OMIM phenotype: 618505, Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities.
  • Gene: KDM6B, also known as JMJD3; gene OMIM 611577.
  • Chromosomal location: 17p13.1.
  • Synonyms: KDM6B-related neurodevelopmental disorder; KDM6B-related NDD; Stolerman syndrome; neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities.
  • MONDO, Orphanet, MeSH, ICD-10/ICD-11: a disease-specific identifier/code could not be verified in the retrieved authoritative literature. Until formally mapped, broader codes for genetic neurodevelopmental disorder, developmental delay, ID, or ASD should not be represented as disease-specific identifiers.

The OMIM title derives from the initial 12-person series. Investigators studying the expanded cohort caution that coarse facies and distal skeletal abnormalities are uncommon and that the title may mislead clinicians; KDM6B-related neurodevelopmental disorder is consequently the preferable descriptive name. (stolerman2019geneticvariantsin pages 1-2, rots2024clinicalepigeneticsof pages 85-87)

Evidence provenance

The foundational report was an international, clinician-assembled series of 12 unrelated individuals identified largely by clinical whole-exome sequencing (WES), with phenotypes abstracted from records, photographs, and clinician correspondence. The expanded analysis comprised 85 molecularly selected individuals—73 newly evaluated and the original 12—with detailed data unavailable for 16 research-cohort participants. Thus, the principal evidence is aggregated disease-level research based on individual clinical records, not a population-based EHR study. (stolerman2019geneticvariantsin pages 2-2, rots2024clinicalepigeneticsof pages 79-82)

Foundational abstract quotation: “We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings.” Stolerman et al., American Journal of Medical Genetics A, July 2019, DOI: 10.1002/ajmg.a.61173. (stolerman2019geneticvariantsin pages 1-2)

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

The established cause is a germline heterozygous pathogenic or likely pathogenic KDM6B variant. Most variants arise de novo, but inherited disease occurs. The dominant mechanism is reduced KDM6B function—usually haploinsufficiency or functional loss from truncating or critical-domain missense variants—rather than infection, toxin exposure, or a demonstrated dominant-negative mechanism. In the 85-person cohort, 64/85 (75%) variants were confirmed de novo and nine were inherited. (rots2024clinicalepigeneticsof pages 85-87, rots2024clinicalepigeneticsof pages 79-82)

Genetic risk factors

  • Protein-truncating variants, including nonsense and frameshift alleles, are strongly implicated.
  • Missense variants require domain-aware interpretation; variants affecting the JmjC catalytic region or core residues of the zinc-containing domain have the strongest functional support.
  • Some late truncations escape nonsense-mediated decay but delete the critical zinc-containing domain and still cause functional loss.
  • Population constraint supports dosage sensitivity: the expanded analysis reports pLI=1 and LOEUF=0.14; the earlier study reported loss-of-function observed/expected ratio 0.06 (90% CI 0.03–0.14). Missense variation overall is less constrained, making functional/domain evidence especially important. (rots2024clinicalepigeneticsof pages 85-87, stolerman2019geneticvariantsin pages 10-11)

Examples from the initial report include c.2684del, c.3085dup, c.3862_3865del, c.1085_1088del, c.3730G>T, and c.3992A>G (p.Asn1331Ser). These examples should not be treated as recurrent hotspots; the expanded cohort contained 71 different variants. (stolerman2019geneticvariantsin pages 6-7, rots2024clinicalepigeneticsof pages 79-82)

Modifiers and environmental factors

No validated modifier gene, protective allele, environmental risk factor, infectious trigger, toxin, diet, or lifestyle factor has been established. The approximately 3:1 male bias prompted a hypothesis of a female protective effect, but this remains inferential. A severe individual carrying pathogenic variants in both KDM6B and HNRNPU illustrates how a second diagnosis may intensify phenotype, but HNRNPU is not an established general modifier. Authors propose that genetic background and environmental factors contribute to expressivity; no specific gene–environment interaction has been demonstrated. (rots2024clinicalepigeneticsof pages 85-87)

3. Phenotypic spectrum

The most reliable frequencies come from the expanded pathogenic/likely pathogenic cohort; denominators vary by available data. Severe ID was reported in only two individuals, one of whom also had an HNRNPU diagnosis. (rots2024clinicalepigeneticsof pages 79-82)

Neurodevelopmental and behavioral phenotypes

  • Developmental delay: 72/77, 94%; speech-language, motor, or global; generally evident in infancy or early childhood. Suggested HPO: HP:0001263 Global developmental delay, HP:0000750 Delayed speech and language development, HP:0001270 Motor delay.
  • Neurodevelopmental problems: 66/74, 89% in the table’s age-qualified analysis.
  • Intellectual disability: 40/64, 63%; usually mild and variable. HPO: HP:0001249.
  • Autism: 46/76, 61%. HPO: HP:0000717 Autism.
  • Other behavioral problems: 44/73, 60%, including attention and social/behavioral difficulties. HPO: HP:0000708 Behavioral abnormality, with ADHD/anxiety terms where clinically diagnosed.
  • Psychotic disorder: 4/20, 20% among those aged ≥12 years. The denominator is small and enriched by ascertainment; this is a surveillance signal, not a population risk estimate. HPO: HP:0000709 Psychosis. (rots2024clinicalepigeneticsof pages 85-87, rots2024clinicalepigeneticsof pages 79-82)

Neurologic phenotypes

  • Hypotonia: 40/70, 57%; occasionally severe enough to prompt muscle biopsy or myopathy-panel testing. HPO: HP:0001252.
  • Sleep disturbance: 21/66, 32%. HPO: HP:0002360.
  • Movement disorder: 16/67, 24%; gait abnormalities, dystonia-like movement, spasticity, hypertonia, and toe walking. Two improved over time; one required botulinum toxin for spasticity. HPO: HP:0100022, HP:0001257 Spasticity, HP:0002066 Gait abnormality, HP:0001332 Dystonia.
  • Seizures: 9/69, 13%. HPO: HP:0001250. EEG abnormalities have been described, but routine EEG is not supported in asymptomatic individuals. (stolerman2019geneticvariantsin pages 8-9, rots2024clinicalepigeneticsof pages 79-82)

Growth, gastrointestinal, and congenital phenotypes

  • Postnatal overgrowth: approximately 30%; macrocephaly 26%, increased weight 14%, tall stature 8%, and increased birth weight 10/63 (16%). Most had normal growth and none had short stature in the expanded cohort. Suggested HPO: HP:0000256 Macrocephaly, HP:0000098 Tall stature, HP:0004324 Increased body weight.
  • Neonatal feeding difficulty or GERD: 33/65, 51%; severe cases required nasogastric feeding or neonatal intensive care. HPO: HP:0011968 Feeding difficulties, HP:0002020 Gastroesophageal reflux.
  • Constipation: 11/61, 18%, sometimes chronic and a major care burden. HPO: HP:0002019.
  • Congenital heart disease: 13%; genitourinary anomalies: 10%; cleft lip/palate: 4%. Suggested HPO: HP:0001627 Abnormal heart morphology, HP:0000078 Genitourinary abnormality, HP:0000175 Cleft palate, HP:0410030 Cleft lip.
  • Musculoskeletal findings include broad hands/fingers or feet/toes (20%), spinal curvature (13%), toe syndactyly (9%), and short digits (9%). HPO: HP:0001159 Syndactyly, HP:0001165 Brachydactyly, HP:0000928 Vertebral-column abnormality. (rots2024clinicalepigeneticsof pages 79-82)

Dysmorphic features are usually mild and inconsistent—prominent forehead/bridge, broad mouth, large ears, round or coarse face, prognathism, and epicanthal folds were reported—but no diagnostic facial gestalt exists. (stolerman2019geneticvariantsin pages 9-10, rots2024clinicalepigeneticsof pages 85-87)

Functional and quality-of-life effects

Speech, learning, adaptive function, social communication, feeding, mobility, sleep, and bowel management can materially affect daily life. Some individuals require special education and lifelong developmental services. Nevertheless, no disease-specific EQ-5D, SF-36, PROMIS, caregiver-burden, or adaptive-function natural-history dataset was found; per-phenotype quality-of-life estimates are unavailable. (stolerman2019geneticvariantsin pages 8-9, stolerman2019geneticvariantsin pages 8-8, rots2024clinicalepigeneticsof pages 79-82)

4. Genetic and molecular information

Gene and protein

KDM6B/JMJD3 encodes a nuclear chromatin regulator that removes di- and trimethyl groups from lysine 27 of histone H3. The gene has 22 exons in the transcript used in the original report (NM_001080424.1). Functionally important C-terminal regions include the JmjC catalytic domain, helical elements, and a zinc-binding motif required for cofactor interaction and protein stability. (stolerman2019geneticvariantsin pages 6-7, stolerman2019geneticvariantsin pages 2-2)

Suggested annotations include GO:0032454 histone demethylase activity, GO:0071558 histone H3-K27 demethylation, nuclear chromatin, and regulation of transcription. The iron/2-oxoglutarate-dependent JmjC reaction implicates iron(II) and 2-oxoglutarate as biochemical cofactors, but no disease-specific cofactor deficiency has been shown.

Variant interpretation

The initial 2019 variants were conservatively reported as VUS because the gene–disease relationship was new. Subsequent recurrence, de novo enrichment, population constraint, and functional assays established the disorder. Current classification should apply ACMG/AMP criteria with careful attention to de novo status, loss-of-function mechanism, domain location, population frequency, phenotype, and functional data. (stolerman2019geneticvariantsin pages 1-2, rots2024clinicalepigeneticsof pages 85-87)

Functional analysis showed strong loss of function for p.Cys1575Ser, which directly disrupts a zinc-binding cysteine; p.Arg1566Ser and p.Glu1570Gln had moderate effects. Conversely, linker or surface variants with minimal functional effects remained VUS. This demonstrates that not every rare KDM6B missense variant is causal. (rots2024clinicalepigeneticsof pages 85-87)

Pathogenic alleles are expected to be ultra-rare or absent from population databases. Exact gnomAD allele frequencies must be checked by variant and transcript at interpretation time; the cohort sources do not provide a frequency for every allele. Disease-causing variants are usually constitutional germline variants. Somatic KDM6B changes in cancer are outside this disorder’s definition.

Chromosomal abnormalities and epigenetic information

Deletions encompassing KDM6B have been reported, but at least seven described deletions also included neighboring genes, preventing attribution of the full phenotype solely to KDM6B. CMA remains appropriate when a copy-number disorder is suspected. (stolerman2019geneticvariantsin pages 10-11)

KDM6B directly regulates the repressive H3K27me2/3 chromatin state. A clinically validated, disease-specific peripheral-blood DNA-methylation episignature was not established in the retrieved KDM6B literature. Methylation profiling is promising across chromatinopathies but should not currently be presented as a validated KDM6B diagnostic test.

5. Environmental information

No causal environmental exposure, lifestyle behavior, occupational exposure, infectious agent, immune trigger, or nutritional deficiency is recognized. Smoking, alcohol, exercise, and diet have not been linked to penetrance or severity. Standard avoidance of known prenatal neurotoxins is good general health practice but is not KDM6B-specific prevention. The disorder is not infectious or transmissible.

6. Mechanism and pathophysiology

Causal chain

Upstream: germline reduction of KDM6B dosage or catalytic/structural function → abnormal persistence or targeting of repressive H3K27me2/3 and disruption of catalytic-independent protein interactions.

Intermediate: altered developmental transcription in neural progenitors and postmitotic neurons → premature neuronal differentiation and depletion of neural-stem-cell pools, impaired maturation of synaptic gene programs, and altered glutamatergic transmission.

Downstream: disturbed circuit formation and plasticity—particularly hippocampal/dentate-gyrus, cortical, and cerebellar programs → developmental delay, cognitive impairment, ASD/behavioral phenotypes, hypotonia/movement abnormalities, and seizures in a subset. The exact mapping from each cellular defect to each human feature remains incomplete. (brauer2024impactofkdm6b pages 9-10, gil2024chromatinregulatorkdm6b pages 1-5, gil2024chromatinregulatorkdm6b pages 11-14, swahari2019histonedemethylasesin pages 3-4)

Neural differentiation and stem-cell maintenance

KDM6B removes H3K27me3 from bivalent chromatin and facilitates neural-lineage programs; evidence includes cooperation with SMAD3 during TGF-β-dependent differentiation and regulation at promoters and enhancers. Suggested GO terms: neurogenesis, regulation of neuron differentiation, neural stem-cell maintenance, and chromatin organization. Suggested CL terms: CL:0000047 neural stem cell, neural progenitor cell, neuroblast, excitatory neuron, and cerebellar granule neuron. (swahari2019histonedemethylasesin pages 3-4)

A February 2024 mouse preprint used conditional deletion, scRNA-seq, transcriptomics, and CUT&RUN. Embryonic deletion left adult dentate gyri essentially devoid of neural stem cells because of precocious differentiation. Acute adult deletion increased TBR2-positive intermediate progenitors by 28% and neuroblasts by 43%, followed by a 25% reduction in adult neural stem cells at 30 days. Only a subset of downregulated maintenance genes gained promoter H3K27me3, supporting additional catalytic-independent functions. Metabolic expression shifted from glycolytic toward oxidative programs, but no validated human metabolomic signature exists. (gil2024chromatinregulatorkdm6b pages 1-5, gil2024chromatinregulatorkdm6b pages 11-14)

Direct abstract quotation: “Conditional deletion of Kdm6b in embryonic DG precursors results in an adult hippocampus that is essentially devoid of NSCs, and hippocampal-dependent behaviors are defective.” Gil et al., bioRxiv, posted February 2024, DOI: 10.1101/2024.02.20.581302. This was a preprint in the retrieved source and should be weighted accordingly. (gil2024chromatinregulatorkdm6b pages 1-5)

Synaptic function and plasticity

The September 2024 peer-reviewed mosaic knockout study found reduced excitatory postsynaptic-current frequency, impaired NMDA-receptor-mediated transmission and LTP, slower NMDA-current decay, and a shift from NR2A toward NR2B-containing receptors. Proposed downstream nodes include PSD95 and NMDAR localization/composition. Mice showed hyperactivity, repetitive behavior, social deficits, and cognitive impairment. Suggested GO terms: chemical synaptic transmission, regulation of NMDA receptor activity, long-term potentiation, learning or memory, and synapse organization. (brauer2024impactofkdm6b pages 9-10, brauer2024impactofkdm6b pages 1-2)

Direct abstract quotation: “KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity.” Brauer et al., Scientific Reports, September 2024, DOI: 10.1038/s41598-024-70728-5. (brauer2024impactofkdm6b pages 1-2)

Earlier mouse/cell evidence shows that cerebellar Kdm6b loss impairs late expression of glutamate and GABA receptor subunits, while excitatory-neuron deletion dysregulates VGLUT1/2 and synaptic structure. KDM6B is strongly activity inducible and participates in BDNF transcription and neuronal survival. These mechanisms are plausible contributors, not clinical biomarkers. (brauer2024impactofkdm6b pages 1-2, swahari2019histonedemethylasesin pages 4-6, swahari2019histonedemethylasesin pages 7-9)

Immune, metabolic, and tissue-damage mechanisms

KDM6B regulates inflammatory transcription in several contexts, but chronic inflammation, autoimmunity, immunodeficiency, oxidative injury, fibrosis, or a primary metabolic defect has not been demonstrated in KDM6B-NDD. No disease-specific proteomic, metabolomic, or lipidomic signature has been validated. No human single-cell or spatial-transcriptomic study specific to KDM6B-NDD was identified.

7. Anatomical structures affected

The central nervous system is primary. Human manifestations implicate distributed cortical and subcortical networks; mechanistic evidence is strongest for the hippocampus, especially the dentate gyrus, and for cerebellar granule-neuron maturation. Suggested UBERON terms: UBERON:0000955 brain, UBERON:0002421 hippocampal formation, UBERON:0001885 dentate gyrus, UBERON:0002037 cerebellum, and cerebral cortex. (brauer2024impactofkdm6b pages 9-10, gil2024chromatinregulatorkdm6b pages 1-5)

Secondary systems include gastrointestinal tract, heart, genitourinary tract, craniofacial structures, spine, hands, and feet. No consistent lateralization is reported. At the subcellular level, the principal compartment is the nucleus/chromatin, with downstream involvement of excitatory synapses and postsynaptic densities. Suggested GO cellular components: nucleus, chromatin, synapse, postsynaptic density, and glutamatergic synapse.

8. Temporal development and natural history

Onset is congenital or early pediatric and usually insidious: feeding difficulty, hypotonia, or delayed milestones commonly emerge in infancy, followed by speech, learning, ASD, and behavioral manifestations. The condition is chronic and lifelong, not relapsing-remitting. Most cognitive impairment is mild, but expressivity ranges from subtle learning problems to substantial disability. (rots2024clinicalepigeneticsof pages 85-87, rots2024clinicalepigeneticsof pages 79-82)

No formal stages exist. Some movement abnormalities may improve—two cohort members had resolution—whereas developmental and adaptive vulnerabilities generally persist. Psychosis may emerge in adolescence or adulthood; its observed 20% frequency among 20 participants aged ≥12 years requires replication. Critical intervention windows have not been experimentally defined, although standard neurodevelopmental practice favors prompt early therapy. (rots2024clinicalepigeneticsof pages 85-87, rots2024clinicalepigeneticsof pages 79-82)

9. Inheritance and population

Inheritance is autosomal dominant. De novo occurrence predominates, but 9/85 individuals inherited variants maternally (five) or paternally (four) from mildly affected or apparently unaffected parents. This demonstrates reduced penetrance or very subtle expression and mandates parental molecular testing rather than reliance on reported family history. Expressivity is markedly variable. Anticipation, founder variants, and a systematic role for consanguinity are not established. Germline mosaicism was not quantified, but it remains a residual recurrence possibility after an apparently de novo result. (rots2024clinicalepigeneticsof pages 85-87, rots2024clinicalepigeneticsof pages 79-82)

The approximately 75% male proportion may indicate ascertainment effects or female protection. No ethnic, geographic, or founder enrichment is established. A 2024 Pakistani report of a biallelic in-frame duplication is not sufficient to redefine the well-supported dominant disorder model.

Population prevalence and incidence are unknown. The initial GeneDx search identified 12 affected individuals among 10,619 DD/ID-indication exomes (0.12%); this is a diagnostic-cohort yield, not population prevalence. (stolerman2019geneticvariantsin pages 9-10)

10. Diagnostics

Recommended approach

  1. Clinical assessment: developmental, neurologic, behavioral/psychiatric, growth, feeding/GI, congenital anomaly, and three-generation family histories; standardized developmental/IQ and ASD evaluation where indicated.
  2. First-line genomic testing: trio WES or WGS is preferred for unexplained syndromic NDD; alternatively use a comprehensive ID/ASD/developmental-delay panel containing KDM6B. Trio testing materially strengthens de novo evidence.
  3. Copy-number analysis: CMA remains useful, particularly when WES does not reliably detect CNVs. Genome sequencing may unify SNV/indel and structural-variant detection where validated.
  4. Variant confirmation and segregation: orthogonal confirmation according to laboratory policy and parental testing. Interpret against the clinically relevant transcript and current ClinVar/gnomAD evidence.
  5. Phenotype-driven tests: MRI for focal neurologic signs, regression, abnormal head growth, or seizures; EEG for suspected seizures; swallow/feeding assessment, GI evaluation, echocardiography, renal imaging, ophthalmology, or orthopedic evaluation only when clinically indicated.

The original diagnostic workups used WES, CMA, Fragile-X analysis, neurodevelopmental panels, and metabolic screening. One patient was tested for RAI1/Smith–Magenis syndrome, illustrating phenotypic overlap. The broad and mild dysmorphism means molecular testing—not facial recognition—is decisive. (stolerman2019geneticvariantsin pages 9-10, stolerman2019geneticvariantsin pages 6-7, stolerman2019geneticvariantsin pages 8-9, rots2024clinicalepigeneticsof pages 85-87)

Karyotyping and FISH are not routine unless a rearrangement is suspected. Mitochondrial, repeat-expansion, biopsy, proteomic, metabolomic, or liquid-biopsy testing has no established KDM6B-specific role. RNA sequencing may eventually clarify splice or expression VUS, but no validated disease-specific assay was found. A negative methylation assay cannot currently exclude KDM6B-NDD.

Differential diagnosis

The broad differential includes other chromatinopathies and syndromic NDDs, particularly KDM6A-related Kabuki syndrome, KDM2B-related NDD, CHD8-related NDD, SETD1A-related NDD, Kleefstra syndrome/EHMT1, Wiedemann–Steiner syndrome/KMT2A, Coffin–Siris/BAF-complex disorders, DNMT3A-related Tatton-Brown–Rahman syndrome, NSD1-related Sotos syndrome, and EZH2-related Weaver syndrome. RAI1-related Smith–Magenis syndrome, Fragile X syndrome, CNV disorders, and primary neuromuscular disease may be considered according to sleep/behavior, overgrowth, dysmorphism, hypotonia, or movement presentation. Broad sequencing is more efficient than serial phenotype-driven single-gene testing.

Screening

KDM6B-NDD is not part of newborn screening. Population carrier screening is inappropriate for a predominantly de novo dominant condition. Cascade testing is appropriate when a familial pathogenic variant is identified. Prenatal or preimplantation testing is technically possible once the familial variant is known, after counseling regarding variable expressivity and reduced penetrance.

11. Outcome and prognosis

No disease-specific survival rate, mortality rate, or life-expectancy estimate exists. Available reports do not indicate a characteristic degenerative or fatal course, but adult ascertainment is limited. Prognosis is driven principally by cognitive/adaptive level, communication, ASD/behavioral or psychiatric burden, seizures, movement impairment, feeding/GI morbidity, and congenital anomalies. (rots2024clinicalepigeneticsof pages 85-87, rots2024clinicalepigeneticsof pages 79-82)

Most reported ID is mild, and some movement abnormalities improve, but full neurodevelopmental “recovery” should not be expected. Speech, occupational, educational, and behavioral interventions may improve function without correcting the molecular cause. No prognostic biomarker or reliable genotype–phenotype correlation has been identified. (stolerman2019geneticvariantsin pages 8-8, rots2024clinicalepigeneticsof pages 85-87)

12. Treatment and current applications

There is no approved disease-modifying, gene, RNA, cell, or targeted epigenetic therapy. Current real-world care is individualized and multidisciplinary:

  • early developmental intervention; speech-language, occupational, and physical therapy; augmentative communication and special education as needed;
  • evidence-based ASD, ADHD, anxiety, sleep, or psychosis care through developmental pediatrics/psychiatry;
  • standard antiseizure treatment for epilepsy;
  • feeding therapy, nutrition support, reflux treatment, and constipation management;
  • PT/orthopedics/rehabilitation for hypotonia, gait, contracture, scoliosis, or spasticity; botulinum toxin helped one reported patient’s spasticity;
  • routine management of cardiac, genitourinary, palatal, or other congenital anomalies. (stolerman2019geneticvariantsin pages 8-9, stolerman2019geneticvariantsin pages 8-8, rots2024clinicalepigeneticsof pages 85-87, rots2024clinicalepigeneticsof pages 79-82)

Suggested NCIT intervention concepts include Speech Therapy, Occupational Therapy, Physical Therapy, Behavioral Therapy, Special Education, Anticonvulsant Therapy, Nutritional Support, and Botulinum Toxin Therapy. No KDM6B-specific pharmacogenomic guidance or response-rate evidence exists.

Although epigenetic enzymes are pharmacologically tractable, inhibiting KDM6B would be mechanistically concerning in a loss-of-function disorder. Results from other chromatinopathies cannot be directly translated, and broad prenatal/postnatal chromatin manipulation may have cell- and developmental-stage-specific toxicity.

Trials and registries

No interventional KDM6B-specific trial was identified. Simons Searchlight, NCT01238250, explicitly enrolls people with pathogenic/likely pathogenic KDM6B variants. It is a recruiting, prospective, family-based observational registry collecting annual medical, behavioral, learning, developmental, and biospecimen data; it is not a treatment trial. ClinicalTrials.gov: NCT01238250. (NCT01238250 chunk 1, NCT01238250 chunk 2)

13. Prevention

Primary prevention through lifestyle, vaccination, or environmental modification is unavailable. Secondary/tertiary prevention consists of timely molecular diagnosis, early developmental intervention, seizure recognition, feeding and aspiration assessment when indicated, constipation treatment, orthopedic monitoring, and age-appropriate behavioral/psychiatric surveillance. (rots2024clinicalepigeneticsof pages 85-87, rots2024clinicalepigeneticsof pages 79-82)

Genetic counseling should explain dominant inheritance, the predominance of de novo variants, variable expression, and apparently unaffected transmitting parents. For an affected heterozygous individual, each pregnancy has a theoretical 50% transmission probability, but phenotype cannot be predicted reliably. For parents negative in blood after a de novo diagnosis, recurrence is low but not zero because of possible germline mosaicism. Prenatal diagnosis and PGT-M are options when the familial variant is known.

14. Other species and natural disease

No naturally occurring veterinary syndrome confidently equivalent to human KDM6B-NDD was identified, and there is no zoonotic potential or cross-species transmission. Orthologous Kdm6b is evolutionarily conserved in mouse, and functional conservation is also exploited in Drosophila assays. Species taxon suggestions are Homo sapiens NCBI Taxon 9606, Mus musculus 10090, Drosophila melanogaster 7227, and Danio rerio 7955. Exact ortholog NCBI Gene and breed-ontology identifiers should be retrieved from their live databases before knowledge-base ingestion.

15. Model organisms and advanced technologies

Mouse models

  • Constitutive knockout: complete loss is neonatal/embryonic lethal because of respiratory-network deficits, limiting its fidelity for viable heterozygous human disease.
  • Heterozygous models: reproduce hyperactivity and social/cognitive abnormalities but may vary by sex and background.
  • Conditional neural-stem-cell deletion: demonstrates premature differentiation, failure to establish/maintain dentate-gyrus stem cells, and hippocampal behavioral deficits. scRNA-seq, bulk transcriptomics, and CUT&RUN provide cell-state and chromatin evidence. (gil2024chromatinregulatorkdm6b pages 1-5, gil2024chromatinregulatorkdm6b pages 11-14)
  • Postnatal CRISPR mosaic brain knockout: produces repetitive behavior, social and cognitive deficits, and NMDAR/LTP abnormalities. Limitations include broad, non-cell-specific mosaic targeting and incomplete knockout. (brauer2024impactofkdm6b pages 9-10, brauer2024impactofkdm6b pages 1-2)
  • Cerebellar granule-neuron conditional knockout: impairs late maturation and synaptic receptor-gene programs while early neuronal markers are relatively preserved. (swahari2019histonedemethylasesin pages 4-6, swahari2019histonedemethylasesin pages 7-9)

Drosophila and cellular systems

Drosophila gain-of-function assays have been useful for discriminating damaging zinc-domain variants from linker/surface VUS. Their limitation is that overexpression may not reproduce human heterozygous haploinsufficiency, and the assay may miss N-terminal interaction defects. Human patient-derived iPSC neurons or organoids would offer higher translational relevance, but no mature KDM6B-NDD iPSC/organoid platform was identified in the retrieved evidence. (rots2024clinicalepigeneticsof pages 85-87)

2023–2024 developments and expert interpretation

  1. The expanded 85-person analysis replaced a narrow dysmorphology-centered picture with a genotype-first spectrum dominated by developmental delay, mild ID, ASD, behavioral problems, hypotonia, and feeding/GI concerns. It also established inherited disease and highlighted adolescent psychosis surveillance. (rots2024clinicalepigeneticsof pages 85-87, rots2024clinicalepigeneticsof pages 79-82)
  2. The 2024 dentate-gyrus study connected KDM6B to neural-stem-cell maintenance using scRNA-seq and CUT&RUN and suggested both demethylase-dependent and independent functions. (gil2024chromatinregulatorkdm6b pages 1-5, gil2024chromatinregulatorkdm6b pages 11-14)
  3. The 2024 mosaic knockout study provided peer-reviewed electrophysiologic evidence linking KDM6B loss to NMDAR composition, LTP, cognition, and ASD-like behaviors. (brauer2024impactofkdm6b pages 9-10, brauer2024impactofkdm6b pages 1-2)
  4. Experts caution that domain location alone is insufficient for missense classification; functional evidence showed several presumed damaging linker variants had minimal effects and should remain VUS. (rots2024clinicalepigeneticsof pages 85-87)

Evidence limitations and knowledge-base cautions

The disorder remains underascertained and recently defined. Frequencies are referral-cohort estimates with variable denominators, not population risks. Adult natural history, life expectancy, quantitative quality of life, penetrance, sex effects, and variant-specific prognosis are unresolved. No validated KDM6B blood episignature, fluid biomarker, human single-cell atlas, spatial transcriptomic dataset, disease-specific treatment trial, or proven protective factor was identified. Mouse behavioral findings should be annotated as model evidence rather than human clinical manifestations. Finally, the OMIM phenotype name should be retained as an identifier-linked synonym but not used to imply that coarse facies or distal skeletal abnormalities are obligatory.

References

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  3. (brauer2024impactofkdm6b pages 9-10): Bastian Brauer, Carlos Ancatén-González, Constanza Ahumada-Marchant, Rodrigo C. Meza, Nicolas Merino-Veliz, Gino Nardocci, Lorena Varela-Nallar, Gloria Arriagada, Andrés E. Chávez, and Fernando J. Bustos. Impact of kdm6b mosaic brain knockout on synaptic function and behavior. Scientific Reports, Sep 2024. URL: https://doi.org/10.1038/s41598-024-70728-5, doi:10.1038/s41598-024-70728-5. This article has 9 citations and is from a peer-reviewed journal.

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  16. (NCT01238250 chunk 1): Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight. Simons Searchlight. 2010. ClinicalTrials.gov Identifier: NCT01238250

  17. (NCT01238250 chunk 2): Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight. Simons Searchlight. 2010. ClinicalTrials.gov Identifier: NCT01238250

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