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Inheritance

2

X-linked recessive inheritance HP:0001419

This is the authoritative HPO/OMIM inheritance annotation and correctly describes the hemizygous male situation: males carrying a pathogenic KDM5C allele are affected in essentially all reported instances. The classical multiplex XLMR families through which the gene was discovered were maternally transmitted. Contemporary trio-based ascertainment has shifted the picture substantially, with de novo variants now the majority mode. See the companion X-linked inheritance block for the female-manifestation caveat, which this recessive label does not capture.

X-linked recessive inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (2 references)

PMID:15586325 SUPPORT Human Clinical

"In families with nonsyndromic X-linked mental retardation (NS-XLMR), >30% of mutations seem to cluster on proximal Xp and in the pericentric region."

Situates the gene within X-linked intellectual disability discovered through X-linked pedigrees.

PMID:25666439 SUPPORT Human Clinical

"Mutations in KDM5C are an important cause of X-linked intellectual disability in males."

Confirms the male-predominant X-linked transmission.

X-linked inheritance with manifesting heterozygous females HP:0001417

Heterozygous females are frequently affected, which the strict recessive label does not convey. Contemporary series report intellectual disability or learning disability in a majority of heterozygous females, predominantly mild, with behavioural disturbance common and endocrine problems more frequent than in males. A minority of heterozygotes are wholly asymptomatic. The mechanistic basis is that KDM5C escapes X-inactivation, so females normally express it from both X chromosomes and carry a higher baseline dose; heterozygosity therefore produces a partial rather than an all-or-none dose reduction. Skewed X-inactivation is an incomplete explanation - a symptomatic de novo female with no significant XCI skewing is documented. This has direct counselling consequences: a female fetus inheriting the familial variant cannot be described as an unaffected carrier.

X-linked inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (7 references)

PMID:32279304 SUPPORT Human Clinical

"Four heterozygous females were asymptomatic."

Documents that only a minority of the 19 heterozygous females were unaffected.

PMID:32279304 SUPPORT Human Clinical

"our findings provide evidence of the role of KDM5C in ID in females highlighting the increasing implication of XLID genes in females, even in sporadic affected individuals"

Establishes female manifestation as a genuine part of the disease spectrum.

PMID:36831303 SUPPORT Other

"Initially, MRXSCJ was exclusively reported in males, while it is increasingly evident that females with heterozygous KDM5C mutations can show cognitive deficits."

States the historical male-only framing and its correction. Tagged OTHER because this is a literature-summary statement inside a mouse study, not human data generated by that paper.

+ 4 more references

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Mechanistic Hypotheses

3

Transient developmental-window WNT inhibition is disease-modifying

wnt_window_rescue EMERGING

Evidence balance 2 support

Because KDM5C sets neurodevelopmental tempo through WNT output during a circumscribed prenatal window, transient WNT-pathway inhibition confined to that window may be disease-modifying rather than merely symptomatic. The evidence is a single high-quality study in Kdm5c-knockout mice and patient-derived iPSCs. The central translational obstacle is that the window plausibly closes before postnatal molecular diagnosis is achievable.

Show evidence (2 references)

PMID:38383780 SUPPORT In Vitro

"Treatment with WNT signalling modulators at specific times reveal that only a transient alteration of the canonical WNT signalling pathway is sufficient to rescue the transcriptomic and chromatin landscapes in patient-derived cells"

Window-restricted pharmacological rescue in patient-derived iPSC cultures.

PMID:38383780 SUPPORT Model Organism

"WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice."

The in vivo arm of the same result - window-restricted WNT inhibition rescues behaviour in the mouse model.

Rebalancing the KMT2A/KDM5C writer-eraser pair ameliorates the phenotype

h3k4_writer_eraser_rebalancing EMERGING

Evidence balance 1 support 1 partial

KDM5C (eraser) and KMT2A (writer) act on the same H3K4 mark, and their respective loss-of-function mouse models share reduced dendritic spines and increased aggression. Combined loss of both mutually suppresses these phenotypes, suggesting that pharmacological reduction of KMT2A activity could ameliorate KDM5C deficiency. This is a genetic proof of principle in mice only; no pharmacological agent has been tested in this context. Note that KMT2A is the Wiedemann-Steiner syndrome gene - it is cited here purely as a mechanistic counterweight, and Wiedemann-Steiner syndrome is a distinct disease entity, not a synonym or subtype of this disorder.

Show evidence (2 references)

PMID:32483278 SUPPORT Model Organism

"Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes."

Genetic epistasis evidence for mutual suppression between the writer and eraser.

PMID:32483278 PARTIAL Model Organism

"provides a proof of principle for balancing a single writer-eraser pair to ameliorate their associated disorders"

The authors frame this explicitly as a proof of principle, not an established therapy.

HDAC inhibition restores KDM5C expression and H3K4me3 signalling

hdac_inhibition_kdm5c_restoration EMERGING

Evidence balance 2 partial

KDM5C sits at the intersection of transcriptional axes controlled by ARX, ZNF711 and PHF8, all of which are themselves X-linked neurodevelopmental disorder genes. The FDA-approved histone deacetylase inhibitor SAHA (vorinostat) rescued KDM5C depletion, recovered H3K4me3 signalling and improved neuronal differentiation in Arx-knockout mouse embryonic stem-cell-derived neurons, and improved behaviour in ARX-deficient C. elegans. IMPORTANT LIMITATION: this rescue was demonstrated in models where KDM5C is transcriptionally downregulated because its upstream activator ARX is lost, not in models carrying a KDM5C coding variant. Raising expression of a mutant KDM5C allele would not be expected to help in most Claes-Jensen genotypes, so this hypothesis is at best applicable to a hypothetical regulatory-variant subset and should not be read as a therapeutic lead for typical KDM5C loss-of-function disease.

Show evidence (2 references)

PMID:31691806 PARTIAL Model Organism

"In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling and improve neuronal differentiation."

Demonstrates pharmacological restoration of KDM5C level and H3K4me3 signalling, but in an ARX-deficient rather than a KDM5C-mutant model, hence PARTIAL support.

PMID:31691806 PARTIAL Model Organism

"our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy"

The authors' own framing as a potential rather than established strategy.

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Discussions and Knowledge Gaps

3

What determines whether a heterozygous KDM5C female is affected, given that skewed X-inactivation does not reliably explain it?

KNOWLEDGE GAP OPEN kdm5c_female_penetrance_mechanism

Attached to

pathophysiology#Loss of KDM5C H3K4me3/me2 Demethylase Function

Skewed X-inactivation is the conventional explanation for variable expression in X-linked disease, but it is a poor fit here. KDM5C escapes X-inactivation, so the inactive-X allele still contributes, and a symptomatic de novo female with no significant XCI skewing is documented. Meanwhile X-inactivation pattern did correlate with phenotypic expression in another cohort. Without a mechanism, counselling for a female fetus carrying a familial variant cannot be individualised beyond a population-level probability.

Proposed experiments

Allele-specific KDM5C expression versus XCI in heterozygous females

xci_allele_specific_expression

Quantify allele-specific KDM5C expression in accessible tissues from affected versus unaffected heterozygous females, paired with a quantitative X-chromosome inactivation assay, to test whether residual KDM5C dose rather than XCI pattern predicts phenotype.

Decision criterion

Allele-specific KDM5C expression separates affected from unaffected heterozygotes more cleanly than the XCI ratio does.

Would support

KDM5C dose, not XCI skewing per se, determines female manifestation.

Would refute

XCI skewing remains the dominant determinant and the escape-from-XCI argument is not phenotypically relevant.

Single-cell profiling of heterozygous female patient-derived neurons

xci_single_cell_mosaic

Single-cell transcriptomic profiling of patient-derived neurons from heterozygous females to test whether mosaic cell-by-cell KDM5C dose, rather than tissue-average dose, predicts the phenotype.

Decision criterion

The fraction of neurons falling below a KDM5C expression threshold correlates with clinical severity better than mean expression.

Would support

A cellular-mosaic threshold model of female manifestation.

Would refute

A simple average-dose model of female manifestation.

Show evidence (2 references)

PMID:36536324 SUPPORT Human Clinical

"X-chromosome inactivation (XCI) analysis showed no significant skewed X-inactivation."

A symptomatic heterozygous female without XCI skewing shows the conventional explanation is insufficient.

PMID:36434256 REFUTE Human Clinical

"The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort."

A contrary cohort finding in which XCI pattern did track phenotypic expression, making this an unresolved conflict rather than a settled question.

Is the WNT-dependent developmental window that permits phenotypic rescue in Kdm5c-knockout mice still open at the age at which human patients are diagnosed?

HUMAN MODEL MISMATCH OPEN kdm5c_wnt_window_translatability

Attached to

pathophysiology#Mistimed Canonical WNT Signalling and Progenitor Transition

The rescue result is strong but window-bounded: only transient WNT modulation during a specific developmental period rescues transcriptomic, chromatin and behavioural phenotypes. In humans, KDM5C-related disease is typically diagnosed postnatally after developmental delay becomes apparent, by which time the corticogenesis window that the mouse experiment targets has almost certainly closed. Whether any residual window exists in humans, and whether the mouse window maps onto a human developmental stage at all, is unresolved and determines whether this mechanism is therapeutically reachable or only explanatory.

Proposed experiments

Map the human WNT-sensitive window in cortical organoids

wnt_window_organoid_mapping

Define the developmental interval during which WNT modulation rescues transcriptomic and chromatin phenotypes in KDM5C patient-derived human cortical organoids, and align it against the equivalent mouse corticogenesis stages.

Decision criterion

A WNT-sensitive interval is identifiable in human organoids and can be mapped onto a defined human gestational stage.

Would support

The mouse rescue window has a definable human counterpart.

Would refute

The rescue window is a mouse-specific developmental feature without a human analogue.

Postnatal-equivalent WNT modulation in Kdm5c-knockout mice

wnt_postnatal_modulation

Test whether WNT modulation delivered after the previously defined embryonic window confers any partial behavioural or transcriptomic benefit in Kdm5c-knockout mice.

Decision criterion

Any statistically significant behavioural improvement after postnatal dosing relative to vehicle.

Would support

A residual therapeutic window exists after the age at which human diagnosis is realistic.

Would refute

The mechanism is explanatory only and not therapeutically reachable postnatally.

Show evidence (1 reference)

PMID:38383780 SUPPORT In Vitro

"only a transient alteration of the canonical WNT signalling pathway is sufficient to rescue the transcriptomic and chromatin landscapes in patient-derived cells"

The rescue is explicitly time-restricted, which is precisely what makes human translatability uncertain.

Which specific neuronal subtypes and brain regions mediate the cognitive and behavioural phenotype of KDM5C loss?

KNOWLEDGE GAP OPEN kdm5c_single_cell_gap

Attached to

pathophysiology#Reduced Dendritic Arborisation and Spine Density

Mouse data show strongly region-specific consequences, with the amygdala considerably more affected than the frontal cortex in both transcriptome and dendritic morphology. No single-cell or spatial transcriptomic dataset specific to this disorder has been published, so the cell types that actually mediate the phenotype remain inferred rather than identified. This limits both mechanistic understanding and the design of any cell-type-directed therapy.

Proposed experiments

Single-nucleus and spatial transcriptomics of Kdm5c-knockout brain

kdm5c_snrnaseq_spatial_atlas

Single-nucleus RNA-seq and spatial transcriptomics across amygdala, hippocampus and cortex in Kdm5c-knockout versus wild-type mice at multiple developmental stages, to identify which neuronal subtypes carry the transcriptional lesion.

Decision criterion

One or a small number of neuronal subtypes account for the majority of differentially expressed genes.

Would support

A cell-type-restricted mechanism amenable to targeted intervention.

Would refute

A pan-neuronal mechanism with no privileged cell-type target.

Cell-type-restricted conditional Kdm5c deletion

kdm5c_celltype_conditional_ko

Conditional Kdm5c deletion restricted to defined excitatory and inhibitory neuronal subtypes to test which population is sufficient to produce the behavioural phenotype.

Decision criterion

Deletion in a single defined subtype reproduces the social, memory or aggression phenotype of the global knockout.

Would support

Sufficiency of a specific neuronal population for the behavioural phenotype.

Would refute

A requirement for distributed loss across multiple neuronal populations.

Show evidence (1 reference)

PMID:26804915 SUPPORT Model Organism

"our findings suggest that loss of KDM5C function may impact gene expression in multiple regulatory pathways relevant to the clinical phenotypes"

The authors themselves leave open which pathways and cell types are the operative ones.

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Pathophysiology

8

Pathogenic KDM5C Variant

A hemizygous (males) or heterozygous (females) pathogenic variant in KDM5C is the shared upstream lesion from which the two mechanistic arms of this disorder diverge. Most reported variants reduce or abolish JmjC-domain catalytic output, engaging the demethylase arm. However, catalytic loss is not required: the R1115H substitution leaves both enzymatic activity and protein stability intact yet still fails to repress KDM5C target genes, demonstrating that disruption of the non-enzymatic REST/HDAC1-2/G9a scaffolding role is a parallel consequence of the variant rather than a downstream consequence of demethylase loss. The two arms are therefore modelled as siblings fanning out from this node, not as a chain.

Downstream

Loss of KDM5C H3K4me3/me2 Demethylase Function

Loss of Non-Enzymatic KDM5C Scaffolding in the REST Repressor Complex

Show evidence (2 references)

PMID:29670509 SUPPORT In Vitro

"The KDM5C-R1115H substitution does not have an impact on enzymatic activity nor protein stability."

A pathogenic variant that spares catalytic activity establishes that the scaffolding arm can be engaged independently of demethylase loss, which is what licenses both arms to hang off the variant node in parallel.

PMID:29670509 SUPPORT In Vitro

"These results suggest that KDM5C may have non-enzymatic roles in gene regulation, and alteration of these roles contributes to MRXSCJ in this patient."

Attributes disease causation in this patient to the non-enzymatic role specifically, independent of the catalytic arm.

Loss of KDM5C H3K4me3/me2 Demethylase Function

KDM5C is a JmjC-domain, Fe(II)/2-oxoglutarate-dependent histone demethylase that converts H3K4me3 to H3K4me2 and H3K4me1 (but not to the unmethylated product). Pathogenic variants abolish or reduce this catalytic output by several distinct routes: nonsense/frameshift alleles that eliminate the transcript or protein, missense alleles that destabilise the protein, and missense alleles within or adjacent to the catalytic JmjC/C5HC2 module that directly impair turnover. Variants adjacent to the accessory ARID and PHD1 domains additionally corrupt substrate recognition by enhancing non-specific DNA binding. ClinGen assigns KDM5C a haploinsufficiency score of 3, and the gene is extremely loss-of-function intolerant, consistent with a pure loss-of-function mechanism rather than gain-of-function or dominant-negative action.

Protein demethylation GO:0006482 ↓ DECREASED Chromatin organization GO:0006325 ⚠ ABNORMAL

histone H3K4 demethylase activity GO:0032453 ↓ DECREASED histone H3K4me/H3K4me2/H3K4me3 demethylase activity GO:0034647 ↓ DECREASED

Brain UBERON:0000955

Downstream

Failure of Locus-Specific H3K4me3 Fine-Tuning at CpG-Island Promoters

Show evidence (7 references)

PMID:17320160 SUPPORT In Vitro

"We show that the X-linked mental retardation (XLMR) gene SMCX (JARID1C), which encodes a JmjC-domain protein, reversed H3K4me3 to di- and mono- but not unmethylated products."

Establishes the enzymatic identity and product specificity of the protein whose loss causes this disorder.

PMID:17320160 SUPPORT In Vitro

"Significantly, several XLMR-patient point mutations reduced SMCX demethylase activity and binding to H3K9me3 peptides, respectively."

Directly links patient-derived variants to reduced demethylase activity.

PMID:25666439 SUPPORT In Vitro

"We also characterize two KDM5C missense mutations, c.1439C>T (p.P480L) and c.1204G>T (p.D402Y) that are compatible with protein production, but compromise stability and enzymatic activity."

Documents protein destabilisation as a distinct route to loss of function alongside direct catalytic impairment.

+ 4 more references

Loss of Non-Enzymatic KDM5C Scaffolding in the REST Repressor Complex

KDM5C also acts non-catalytically as a component of a repressor assembly. An SMCX/KDM5C complex contains the histone deacetylases HDAC1 and HDAC2, the H3K9 methyltransferase G9a, and the transcriptional repressor REST, and co-occupies neuron-restrictive silencer elements in the promoters of REST target genes including SCN2A and SYN1. Depleting KDM5C derepresses these targets with a concomitant rise in promoter H3K4me3. Critically, the patient variant R1115H has entirely normal catalytic activity and protein stability yet still fails to suppress target genes, establishing that loss of demethylase activity alone is an incomplete account of the disease and that a scaffolding/recruitment arm exists in parallel.

Neuron CL:0000540

Negative regulation of DNA-templated transcription GO:0045892 ↓ DECREASED Regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL

Downstream

Derepression of Non-Neuronal, Germline and Cryptic Transcriptional Programs

Neuronal Hyperexcitability and Seizure Substrate

Show evidence (5 references)

PMID:17468742 SUPPORT In Vitro

"Chromatin immunoprecipitation reveals that SMCX and REST co-occupy the neuron-restrictive silencing elements in the promoters of a subset of REST target genes."

Establishes physical co-occupancy of KDM5C with REST at neuronal silencer elements.

PMID:17468742 SUPPORT In Vitro

"RNA-interference-mediated depletion of SMCX derepresses several of these targets and simultaneously increases H3K4 trimethylation at the sodium channel type 2A (SCN2A) and synapsin I (SYN1) promoters."

Links KDM5C loss to derepression of SCN2A and SYN1, a direct route from the chromatin lesion to neuronal excitability.

PMID:17468742 SUPPORT In Vitro

"We propose that loss of SMCX activity impairs REST-mediated neuronal gene regulation, thereby contributing to SMCX-associated X-linked mental retardation."

The authors' own causal proposal connecting the complex to the disease.

+ 2 more references

Failure of Locus-Specific H3K4me3 Fine-Tuning at CpG-Island Promoters

In neurons KDM5C is recruited to CpG-island promoters already decorated with high H3K4me3, where it trims rather than erases the mark. The consequence of KDM5C loss is therefore not a bulk collapse of chromatin state but a locus-specific failure of transcriptional fine-tuning, biased toward upregulation of lowly expressed target genes. KDM5C performs the same trimming function at activity-regulated enhancers during neuronal maturation. This distinction matters mechanistically: global H3K4 methylation levels are preserved in patient fibroblasts and in Kdm5c-null neurons, so the pathology arises from mis-set thresholds at specific regulatory elements.

Neuron CL:0000540

Chromatin remodeling GO:0006338 ⚠ ABNORMAL Regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL

Downstream

Derepression of Non-Neuronal, Germline and Cryptic Transcriptional Programs

Mistimed Canonical WNT Signalling and Progenitor Transition

Show evidence (4 references)

PMID:26804915 SUPPORT Model Organism

"In neurons, Kdm5c is recruited to promoters that harbor CpG islands decorated with high levels of H3K4me3, where it fine-tunes H3K4me3 levels."

Defines the locus-specific fine-tuning function at CpG-island promoters.

PMID:26804915 SUPPORT Model Organism

"Kdm5c predominantly represses these genes, which include members of key pathways that regulate the development and function of neuronal circuitries."

Identifies the repressed target class as neuronal circuit development genes.

PMID:28978483 SUPPORT Model Organism

"Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germline genes during cellular differentiation and in fine-tuning activity-regulated enhancers during neuronal maturation."

Extends the fine-tuning role from promoters to activity-regulated enhancers.

+ 1 more reference

Derepression of Non-Neuronal, Germline and Cryptic Transcriptional Programs

The direct transcriptional consequence of failed H3K4me3 trimming is spurious activation of gene programs that should be silent in neurons. In the developing brain this manifests as failure to silence germline genes during differentiation; in the adult brain KDM5C serves an ongoing genome surveillance role, preventing activation of non-neuronal and cryptic promoters. This surveillance function is shared with, and reinforced by, the related demethylase KDM1A: combined forebrain loss of both enzymes produces stronger ectopic expression of non-neuronal genes in hippocampal neurons and thousands of de novo H3K4me3-enriched regions. The net effect is progressive erosion of neuronal transcriptional identity.

Hippocampal pyramidal neuron CL:1001571

Negative regulation of DNA-templated transcription GO:0045892 ↓ DECREASED Neuron differentiation GO:0030182 ⚠ ABNORMAL

Hippocampal formation UBERON:0002421

Downstream

Reduced Dendritic Arborisation and Spine Density

Show evidence (3 references)

PMID:28978483 SUPPORT Model Organism

"Kdm5c retains an important genome surveillance role preventing the incorrect activation of non-neuronal and cryptic promoters in adult neurons."

Establishes lifelong genome surveillance as a second, post-developmental KDM5C function.

PMID:40864554 SUPPORT Model Organism

"including stronger ectopic expression of non-neuronal genes in hippocampal neurons and thousands of de novo H3K4me3-enriched regions, indicating synergistic disruption of repressive chromatin states"

Confirms ectopic non-neuronal gene expression as the readout of failed H3K4me3 restraint.

PMID:26804915 SUPPORT Model Organism

"Kdm5c-knockout brains exhibit abnormal dendritic arborization, spine anomalies, and altered transcriptomes."

Links the transcriptomic derangement to the structural neuronal phenotype.

Mistimed Canonical WNT Signalling and Progenitor Transition

During a defined prenatal window of corticogenesis, KDM5C directly controls canonical WNT output to set the timing of the primary-to-intermediate neural progenitor transition and therefore the tempo of neurogenesis. Loss of KDM5C removes this timing safeguard. The deficit is developmental-window dependent and, in mice and patient-derived induced pluripotent stem cells, transiently reversible: WNT-pathway modulation restricted to that window rescues the transcriptomic and chromatin landscapes in patient-derived cells and rescues behavioural abnormalities in Kdm5c-knockout mice. Conversely, a single WNT3A injection into wild-type embryonic mouse brain produces anxiety and memory changes. This is the most therapeutically actionable mechanism identified to date, but the window may close before postnatal molecular diagnosis is possible.

Neural progenitor cell CL:0011020

Canonical Wnt signaling pathway GO:0060070 ⚠ ABNORMAL Cerebral cortex neuron differentiation GO:0021895 ⚠ ABNORMAL

Cerebral cortex UBERON:0000956

Downstream

Reduced Dendritic Arborisation and Spine Density

Intellectual Disability

Show evidence (3 references)

PMID:38383780 SUPPORT In Vitro

"KDM5C is identified as a safeguard to ensure that neurodevelopment occurs at an appropriate timescale, the disruption of which leads to intellectual disability."

States the developmental-timing safeguard role established in patient-derived iPSCs and mice.

PMID:38383780 SUPPORT In Vitro

"there is a developmental window during which KDM5C directly controls WNT output to regulate the timely transition of primary to intermediate progenitor cells and consequently neurogenesis"

Specifies the WNT-dependent progenitor transition as the mechanism.

PMID:38383780 SUPPORT Model Organism

"WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice."

Demonstrates window-restricted pharmacological reversibility in a mouse model.

Reduced Dendritic Arborisation and Spine Density

The convergent structural endpoint of the transcriptional lesion is a hypoplastic dendritic tree with reduced spine density and immature spine morphology, most pronounced in amygdalar and cortical pyramidal neurons. Reduced dendritic development is seen with KDM5C knockdown in primary mammalian neurons and in zebrafish, and dendritic spine loss is a shared feature of Kdm5c-null and Kmt2a-null mice - the eraser and writer of the same mark - indicating that spine density is set by the balance of the H3K4-methylation writer-eraser pair rather than by either enzyme alone. There is no neurodegeneration, gliosis or tissue destruction; the adult Kdm5c-knockout cortex, hippocampus and amygdala are cytoarchitecturally normal.

Pyramidal neuron CL:0000598 Glutamatergic neuron CL:0000679

Dendrite development GO:0016358 ↓ DECREASED Regulation of dendritic spine development GO:0060998 ⚠ ABNORMAL Regulation of neuron projection development GO:0010975 ⚠ ABNORMAL

Amygdala UBERON:0001876 Cerebral cortex UBERON:0000956

Downstream

Intellectual Disability

Aggressive Behavior

Show evidence (3 references)

PMID:26804915 SUPPORT Model Organism

"Kdm5c-knockout brains exhibit abnormal dendritic arborization, spine anomalies, and altered transcriptomes."

Documents the dendritic and spine phenotype in the mouse model of the disorder.

PMID:17320160 SUPPORT Model Organism

"studies in zebrafish and primary mammalian neurons demonstrated a role for SMCX in neuronal survival and dendritic development and a link to the demethylase activity"

Independently ties dendritic development to KDM5C demethylase function.

PMID:32483278 SUPPORT Model Organism

"Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression."

Shows spine loss is a shared consequence of perturbing either side of the H3K4 writer-eraser pair.

Neuronal Hyperexcitability and Seizure Substrate

Seizures affect roughly a third to a half of individuals and arise from a cell-intrinsic neuronal requirement for KDM5 activity. Two convergent lines define the substrate. First, KDM5C loss derepresses REST targets including the sodium channel gene SCN2A, itself a major epilepsy gene, with increased promoter H3K4me3. Second, combined KDM1A/KDM5C forebrain loss alters hippocampal ion channel expression and increases the intrinsic excitability of CA1 pyramidal neurons. In Drosophila, reducing Kdm5 in neurons but not in glia is sufficient to produce spontaneous and stimulus-induced seizures, establishing that the requirement is neuron-autonomous.

CA1 pyramidal neuron CL:4023060

Regulation of membrane potential GO:0042391 ⚠ ABNORMAL

Hippocampal formation UBERON:0002421

Downstream

Seizures

Show evidence (3 references)

PMID:41537560 SUPPORT Model Organism

"Reducing the expression of its single Kdm5 gene in neurons, but not glia, led to spontaneous and stimulus-induced seizures, underscoring a cell-intrinsic requirement for KDM5 in maintaining neuronal stability."

Establishes a neuron-autonomous, glia-independent requirement for KDM5 in seizure protection.

PMID:40864554 SUPPORT Model Organism

"dKDM-ifKOs display more severe behavioral impairments than the single ifKOs along with altered hippocampal expression of ion channels and increased excitability of CA1 pyramidal neurons"

Provides the cellular electrophysiological substrate for the seizure phenotype.

PMID:17468742 SUPPORT In Vitro

"increases H3K4 trimethylation at the sodium channel type 2A (SCN2A) and synapsin I (SYN1) promoters"

Connects the chromatin lesion to derepression of a major sodium-channel epilepsy gene.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

20

Digestive 1

Gastrointestinal Dysfunction Abnormality of the gastrointestinal tract HP:0011024

Curation note: the registry constipation figure appears only in the paper's result tables, not in any cited abstract, so the phenotype is annotated at the evidenced level (gastrointestinal dysfunction) rather than as Constipation (HP:0002019). Re-specialise if a quotable source is found.

Show evidence (2 references)

PMID:41537560 SUPPORT Human Clinical

"participants frequently reported growth abnormalities, vision and digestive issues, behavioral concerns, and seizures in nearly half of the cases"

Digestive issues reported as a frequent systemic feature.

PMID:34089235 SUPPORT Human Clinical

"We find that up to 70% of affected females were reported to display syndromic features including gastrointestinal dysfunction and hearing impairment."

Gastrointestinal dysfunction quantified in affected females.

Ear 1

Hearing Impairment Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:34089235 SUPPORT Human Clinical

"up to 70% of affected females were reported to display syndromic features including gastrointestinal dysfunction and hearing impairment"

Hearing impairment documented as a syndromic feature in affected females.

Head and Neck 2

Microcephaly Microcephaly HP:0000252

Frequency intentionally omitted. The only frequency signal available is the HPO annotation count (7/20, i.e. about 35%, which would be FREQUENT rather than OCCASIONAL), and that count is not quotable from any cited abstract. Per docs/frequency-evidence-guidelines.md the band is omitted rather than guessed; the cited sources support the disease-phenotype association only.

Show evidence (2 references)

PMID:36536324 SUPPORT Human Clinical

"moderate developmental delay, serious expressive language delay, short stature, microcephaly, and typical facial particularities"

Microcephaly documented as part of the Claes-Jensen-type phenotype.

PMID:41743791 SUPPORT Human Clinical

"Affected males presented with short stature, microcephaly, language delay, and intellectual disability"

Independent two-family series listing microcephaly among the core male features, so the association does not rest on a single female case report.

Abnormal Facial Shape FREQUENT Abnormal facial shape HP:0001999

Show evidence (2 references)

PMID:32279304 SUPPORT Human Clinical

"Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity."

Distinctive facial features listed among the core male features.

PMID:29456765 SUPPORT Human Clinical

"Males with hemizygous mutations in KDM5C present with intellectual disability and facial dysmorphism"

Pairs facial dysmorphism with intellectual disability as the male presentation.

Integument 1

Hypertrichosis Hypertrichosis HP:0000998

Show evidence (1 reference)

PMID:36434256 SUPPORT Human Clinical

"other observed clinical manifestations were short stature, obesity and hypertrichosis"

Hypertrichosis documented among the observed manifestations.

Musculoskeletal 1

Spasticity Spasticity HP:0001257

Course: PROGRESSIVE

Show evidence (2 references)

PMID:32279304 SUPPORT Human Clinical

"Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity."

Spasticity is listed among the core male features.

PMID:10982473 SUPPORT Human Clinical

"slowly progressive spastic paraplegia"

Documents the progressive spastic paraplegia phenotype in the index family.

Nervous System 9

Intellectual Disability VERY_FREQUENT Intellectual disability HP:0001249

Show evidence (4 references)

PMID:32279304 SUPPORT Human Clinical

"KDM5C variants are one of the major causes of moderate to severe XLID."

Establishes moderate-to-severe intellectual disability as the core disease feature.

PMID:34089235 SUPPORT Human Clinical

"Previous studies have found that males present with moderate to severe ID with significant syndromic comorbidities such as epilepsy, short stature, and craniofacial abnormalities."

Confirms the severity distribution in males across prior cohorts.

PMID:18697827 SUPPORT Human Clinical

"Clinical findings of the nine affected males from the four different families included mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%)."

Quantitative cohort data giving 100% frequency of intellectual disability in affected males, supporting the VERY_FREQUENT band.

+ 1 more reference

Severe Intellectual Disability Severe intellectual disability HP:0010864

Severity: SEVERE

Show evidence (2 references)

PMID:18697827 SUPPORT Human Clinical

"The degree of mental retardation consisted of mild (25%), moderate (12%) and severe (63%)."

Quantifies the skew toward severe intellectual disability in affected males.

PMID:10982473 SUPPORT Human Clinical

"four males in two generations present severe mental retardation, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasia"

The index family that defines the eponym showed severe intellectual disability.

Delayed Speech and Language Development VERY_FREQUENT Delayed speech and language development HP:0000750

Frequency basis (docs/frequency-evidence-guidelines.md, Patterns C and D-1): no cited abstract reports a percentage for this phenotype. VERY_FREQUENT rests on PMID:36434256 describing the condition as "characterized by ... intellectual disability with speech disorders" - a highly-characteristic wording that maps to the VERY_FREQUENT band - corroborated by the RARE-X 93% communication-challenge figure, which appears in that paper's result tables rather than its abstract and therefore cannot be quoted as a snippet. The 4/19 language-impairment count in PMID:32279304 is a female-only, expression-specific subset and is not a competing overall frequency estimate.

Show evidence (3 references)

PMID:41743791 SUPPORT Human Clinical

"Affected males presented with short stature, microcephaly, language delay, and intellectual disability"

Language delay listed among the core male features in an independent two-family series.

PMID:36434256 SUPPORT Human Clinical

"The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern"

Speech disorder is listed as a core component of the neurodevelopmental presentation in a 30-individual cohort.

PMID:32279304 SUPPORT Human Clinical

"All affected individuals presented with learning disabilities or ID (mostly moderate), and four also had a language impairment mainly affecting expression."

Documents expressive-predominant language impairment in affected heterozygous females.

Global Developmental Delay Global developmental delay HP:0001263

Show evidence (2 references)

PMID:36434256 SUPPORT Human Clinical

"manifested a neurodevelopmental condition characterized by psychomotor delay"

Psychomotor delay is documented as a defining early feature.

PMID:36536324 SUPPORT Human Clinical

"who presented with Claes-Jensen type-like phenotypes, such as moderate developmental delay, serious expressive language delay, short stature, microcephaly, and typical facial particularities"

Developmental delay documented in an affected heterozygous female.

Seizures Seizure HP:0001250

Frequency intentionally omitted. The RARE-X registry meta-analysis gives 35% overall (47% male, 18% female), Ghasemi's literature review gives 64% male / 19% female, and the RARE-X newly recruited female subcohort gives 56%. Registry self-enrolment enriches for symptomatic females while historical XLMR-family literature enriches for severely affected males; per docs/frequency-evidence-guidelines.md the band is omitted rather than guessed. Variants in the catalytic domain appear enriched for seizures.

Show evidence (3 references)

PMID:41537560 SUPPORT Human Clinical

"Meta-analyses of this data and previously published cases reaffirmed that seizures are a frequent feature in both hemizygous males and heterozygous females with KDM5C variants, with over a third of individuals reporting at least one seizure."

Largest meta-analysis establishing seizures in over a third of individuals of both sexes.

PMID:39835750 SUPPORT Human Clinical

"highlighting the higher manifestation of seizures in males and also addressing the heterogeneity of phenotypes in females"

Documents the male-biased seizure frequency across 175 literature cases.

PMID:18697827 SUPPORT Human Clinical

"mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%)"

Earlier cohort estimate of 33% seizures in affected males.

Hyperreflexia FREQUENT Hyperreflexia HP:0001347

Show evidence (2 references)

PMID:18697827 SUPPORT Human Clinical

"Clinical findings of the nine affected males from the four different families included mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%)."

Gives 78% hyperreflexia in affected males, supporting the FREQUENT band.

PMID:18697827 SUPPORT Human Clinical

"male patients with mental retardation, short stature and hyperreflexia should be considered candidates for mutations in the JARID1C gene"

Establishes hyperreflexia as a gene-prioritising clinical marker.

Aggressive Behavior FREQUENT Aggressive behavior HP:0000718

Show evidence (2 references)

PMID:18697827 SUPPORT Human Clinical

"mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%)"

Gives 44% aggressive behaviour in affected males, within the FREQUENT band.

PMID:26804915 SUPPORT Model Organism

"disruption of the mouse Kdm5c gene recapitulates adaptive and cognitive abnormalities observed in XLID, including impaired social behavior, memory deficits, and aggression"

Aggression is recapitulated in the mouse model, supporting a direct mechanistic link.

Autism Spectrum Disorder Autism HP:0000717

Show evidence (2 references)

PMID:34089235 SUPPORT Human Clinical

"more than half of individuals reported a diagnosis of autism spectrum disorder or described features consistent with this spectrum"

Quantifies autism spectrum diagnoses in the largest caregiver-reported cohort.

PMID:29670509 SUPPORT Other

"KDM5C-deficiency is characterized by frequent autistic and aggressive behaviors"

Literature-summary statement in the same paper tying autistic behaviour specifically to KDM5C deficiency rather than to intellectual disability in general.

Sleep Disturbance Sleep disturbance HP:0002360

Show evidence (1 reference)

PMID:36434256 SUPPORT Human Clinical

"behavioral features with particular disturbed sleep pattern"

Sleep disturbance singled out as a characteristic behavioural feature.

Growth 2

Short Stature FREQUENT Short stature HP:0004322

Show evidence (3 references)

PMID:18697827 SUPPORT Human Clinical

"Clinical findings of the nine affected males from the four different families included mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%)."

Gives 55% short stature in affected males, within the FREQUENT band.

PMID:32279304 SUPPORT Human Clinical

"Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity."

Short stature listed among the core male features.

PMID:40125771 SUPPORT Human Clinical

"An 8-year-old boy with prenatal-onset short stature"

Documents prenatal onset of the growth restriction.

Obesity Obesity HP:0001513

Show evidence (1 reference)

PMID:36434256 SUPPORT Human Clinical

"other observed clinical manifestations were short stature, obesity and hypertrichosis"

Obesity documented among the observed manifestations.

Other 3

Maxillary Hypoplasia Hypoplasia of the maxilla HP:0000327

Show evidence (1 reference)

PMID:10982473 SUPPORT Human Clinical

"four males in two generations present severe mental retardation, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasia"

Maxillary hypoplasia is one of the four defining features of the index family.

Progressive Spastic Paraplegia Progressive spastic paraplegia HP:0007020

Course: PROGRESSIVE

Show evidence (2 references)

PMID:10982473 SUPPORT Human Clinical

"This study presents a family with a syndromic form of X-linked mental retardation in which four males in two generations present severe mental retardation, slowly progressive spastic paraplegia"

Primary description of progressive spastic paraplegia in the family that defines the eponym.

PMID:10982473 SUPPORT Human Clinical

"The two known loci for X-linked mental retardation and spastic paraplegia are excluded: proteolipid protein in Xp21 and L1 cell adhesion molecule in Xq28."

Documents the exclusion of PLP1 and L1CAM, establishing this as a distinct entity.

Ophthalmological Abnormality Abnormality of the eye HP:0000478

Curation note: HPO annotates Strabismus (HP:0000486) to this disorder and the RARE-X registry reports abnormal eye movement in the great majority of respondents with vision problems, but those figures appear only in HPO annotation files and paper result tables, not in any cited abstract. Per the evidence SOP the specific strabismus claim is therefore not asserted here; re-specialise this phenotype to HP:0000486 if a quotable source is found. The strabismus-specific surgical target is retained on the ophthalmological treatment entry, where the cited description covers it.

Show evidence (2 references)

PMID:41537560 SUPPORT Human Clinical

"participants frequently reported growth abnormalities, vision and digestive issues, behavioral concerns, and seizures in nearly half of the cases"

Vision problems reported as a frequent systemic feature in the registry cohort.

PMID:40125771 SUPPORT Human Clinical

"An 8-year-old boy with prenatal-onset short stature, ophthalmological abnormalities, and dysmorphic features had a KDM5C variant typically linked to Claes-Jensen syndrome"

Documents ophthalmological abnormalities in a molecularly confirmed KDM5C patient.

🧬

Genetic Associations

1

KDM5C (Causative)

Gene: KDM5C hgnc:11114 variant_origin: GERMLINE

Show evidence (4 references)

PMID:15586325 SUPPORT Human Clinical

"Our results suggest that JARID1C mutations are a relatively common cause of XLMR and that this gene might play an important role in human brain function."

Gene-discovery paper establishing JARID1C/KDM5C as the causative gene.

PMID:29670509 SUPPORT Human Clinical

"Mutations in KDM5C cause Mental Retardation, X-linked, Syndromic, Claes-Jensen type (MRXSCJ, OMIM #300534) and are one of the most common causes of X-linked ID."

Explicitly binds KDM5C to the MRXSCJ/OMIM 300534 entity curated here.

PMID:25666439 SUPPORT Human Clinical

"Mutations in KDM5C are an important cause of X-linked intellectual disability in males."

Independent confirmation of the gene-disease relationship.

+ 1 more reference

💊

Medical Actions

7

Multidisciplinary Supportive and Developmental Care

Action: Supportive care Ontology label: Supportive Care NCIT:C15747

There is no disease-modifying therapy, no approved drug, no gene therapy and no interventional clinical trial for this disorder. Management is entirely symptomatic and supportive, centred on early developmental intervention and coordinated multidisciplinary follow-up covering development, growth, seizures, vision, behaviour, mobility and bowel function.

Show evidence (1 reference)

PMID:34089235 SUPPORT Human Clinical

"As a rare disorder, its etiology and natural history remain an area of active investigation, with treatment limited to symptom management."

States directly that treatment is limited to symptom management.

Speech and Language Therapy

Action: Speech and language therapy Ontology label: Speech Language Therapy NCIT:C159273

Speech and language impairment is near-universal and expressive language is disproportionately affected, so early speech therapy with augmentative and alternative communication where needed is a core intervention.

Target Phenotypes: Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:32279304 PARTIAL Human Clinical

"four also had a language impairment mainly affecting expression"

Documents the expressive language impairment this intervention targets; no trial evidence exists for the intervention itself in this disorder.

Physical Therapy and Spasticity Management

Action: Physical therapy Ontology label: Physical Therapy NCIT:C15302

Physiotherapy, stretching and orthotics target the spasticity, hyperreflexia and progressive spastic paraplegia seen in a subset, aiming to preserve gait and prevent contractures. Pharmacological adjuncts used in general practice include baclofen and botulinum toxin; there is no disorder-specific evidence base for either.

Target Phenotypes: Spasticity HP:0001257

Show evidence (1 reference)

PMID:10982473 PARTIAL Human Clinical

"slowly progressive spastic paraplegia"

Documents the progressive motor target of this intervention; the intervention itself is standard practice, not disorder-specific evidence.

Antiseizure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Standard antiseizure medication selected by seizure semiology. Seizures affect roughly a third to a half of individuals with a median first-seizure age of about 2 years, so EEG at diagnosis and ongoing seizure review are indicated. No disorder-specific antiseizure agent or regimen has been studied; there is no evidence favouring any particular drug in KDM5C-related disease.

Mechanism Target:

INHIBITS Neuronal Hyperexcitability and Seizure Substrate

Target Phenotypes: Seizure HP:0001250

Show evidence (1 reference)

PMID:41537560 PARTIAL Human Clinical

"seizures are a frequent feature in both hemizygous males and heterozygous females with KDM5C variants, with over a third of individuals reporting at least one seizure"

Establishes the seizure burden that justifies antiseizure therapy; no trial evidence exists for any specific agent in this disorder.

Ophthalmological Assessment and Correction

Action: Surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Formal ophthalmological examination at diagnosis and periodically thereafter. Strabismus and abnormal eye movements are common and frequently under-recognised, and untreated strabismus carries a preventable amblyopia risk, making this one of the highest-yield underused assessments in the disorder. Management is refractive correction and, where indicated, strabismus surgery.

Target Phenotypes: Strabismus HP:0000486

Show evidence (1 reference)

PMID:40125771 SUPPORT Human Clinical

"This atypical presentation highlights the importance of ophthalmological assessments in X-linked syndromes with variable expressivity, even without classic features."

Explicit recommendation for ophthalmological assessment in this disorder.

Behavioural Support and Psychotropic Management

Action: Behavioral counseling Ontology label: Behavioral Counseling NCIT:C181743

Behavioural intervention is first-line for the aggression, impulsivity, anxiety and autism-spectrum features that caregivers consistently rate as the greatest burden, with psychotropic medication reserved for when behavioural approaches are insufficient. Polypharmacy is a recognised iatrogenic risk in this population.

Target Phenotypes: Aggressive behavior HP:0000718 Autism HP:0000717

Show evidence (1 reference)

PMID:34089235 PARTIAL Human Clinical

"more than half of individuals reported a diagnosis of autism spectrum disorder or described features consistent with this spectrum"

Quantifies the behavioural burden this intervention targets; the intervention itself is standard practice.

Genetic Counseling and Cascade Testing

Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counselling must be updated for current evidence. De novo variants are now the majority mode, so recurrence risk in an apparently sporadic family is far lower than the classic X-linked-recessive family framing implies (with an empiric allowance for gonadal mosaicism). Crucially, a daughter who inherits the familial variant cannot be counselled as an unaffected carrier: a majority of heterozygous females have learning disability or intellectual disability, and a substantial minority have seizures. Cascade testing of at-risk female relatives is therefore both a reproductive and a diagnostic intervention. The DNA methylation episignature independently identifies carriers. Prenatal diagnosis and preimplantation genetic testing are available once the familial variant is known.

Show evidence (2 references)

PMID:32279304 SUPPORT Human Clinical

"Disease expression of XLID in females should be taken into consideration for genetic counseling."

Direct recommendation that female disease expression change counselling practice.

PMID:29456765 SUPPORT Human Clinical

"can be used for molecular diagnosis and carrier identification"

Supports episignature-based carrier identification as an adjunct to cascade testing.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Claes-Jensen Type X-Linked Intellectual Disability:

Wiedemann-Steiner syndrome MONDO:0011518

Overlapping Features The mechanistic mirror image of this disorder: KMT2A writes the same H3K4 methyl mark that KDM5C erases, and the two mouse models share reduced dendritic spines and increased aggression. Because KMT2A is frequently discussed in KDM5C mechanism papers, this pairing is a recognised source of entity confusion; the two are distinct diseases with distinct genes, and a KDM5C entry must not absorb Wiedemann-Steiner content.

Distinguishing Features

Caused by autosomal dominant KMT2A variants, not X-linked KDM5C variants
Hypertrichosis cubiti and a distinct facial gestalt
No sex-biased severity, unlike the male-predominant severity of Claes-Jensen type

Show evidence (1 reference)

PMID:32483278 SUPPORT Model Organism

"we show functional interactions of a writer-eraser duo, KMT2A and KDM5C, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively"

Explicitly separates the two gene-disease pairs while documenting their mechanistic relationship.

Fragile X syndrome MONDO:0010383

Overlapping Features The most common inherited cause of intellectual disability in males and a routine exclusion in any X-linked intellectual disability work-up. The testicular finding usefully discriminates: macroorchidism is characteristic of fragile X, whereas decreased testicular size is the annotated finding in Claes-Jensen type.

Distinguishing Features

CGG repeat expansion in FMR1 rather than a KDM5C sequence variant
Macroorchidism, in contrast to decreased testicular size in Claes-Jensen type
Long face and large ears
Requires repeat-expansion testing rather than sequencing

{ }

Source YAML

click to show

name: Claes-Jensen Type X-Linked Intellectual Disability
creation_date: '2026-07-31T00:00:00Z'
category: Genetic
parents:
- Neurodevelopmental Disorder
- X-linked Disorder
- Chromatinopathy
disease_term:
  preferred_term: syndromic X-linked intellectual disability Claes-Jensen type
  term:
    id: MONDO:0010355
    label: syndromic X-linked intellectual disability Claes-Jensen type
synonyms:
- MRXSCJ
- MRXSJ
- Claes-Jensen syndrome
- KDM5C-related syndromic X-linked intellectual disability
- syndromic X-linked intellectual disability JARID1C-related
- KDM5C neurodevelopmental disorder
description: >
  Claes-Jensen type syndromic X-linked intellectual disability (MRXSCJ; OMIM
  300534; ORPHA:85279) is a rare X-linked chromatinopathy caused by
  loss-of-function variants in KDM5C at Xp11.22. KDM5C (formerly JARID1C/SMCX)
  encodes a JmjC-domain histone demethylase that removes di- and tri-methyl
  marks from histone H3 lysine 4 (H3K4me2/me3) at CpG-island promoters and
  activity-regulated enhancers. Hemizygous males present with mild to severe
  intellectual disability (most often moderate to severe) accompanied by short
  stature, microcephaly, maxillary hypoplasia, hyperreflexia and spasticity
  (including slowly progressive spastic paraplegia in the original family),
  seizures, strabismus, and aggressive or disinhibited behaviour. KDM5C is one
  of the more frequently mutated single genes in X-linked intellectual
  disability, accounting for roughly 0.7-2.8% of cases.

  IMPORTANT SCOPE NOTE — this entity is defined by KDM5C. It must not be
  conflated with (a) disorders of the KDM5 paralogues KDM5A, KDM5B or KDM5D,
  which are separate genes with separate disease associations; (b)
  Wiedemann-Steiner syndrome (KMT2A), which is the mechanistic writer-side
  mirror image of this eraser-side disorder and is frequently co-cited in KDM5C
  mechanism papers but is a distinct MONDO entity; or (c) other eponymous
  X-linked intellectual disability types such as Siderius type (PHF8) or Lubs
  type (MECP2 duplication).

  The historical "X-linked recessive" label is empirically inaccurate for
  females. KDM5C escapes X-inactivation, so females normally carry a higher
  baseline KDM5C dose; heterozygous females range from fully asymptomatic to
  moderately affected, and contemporary cohorts report intellectual disability
  or learning disability in a majority of heterozygous females. This entry
  therefore models both the recessive-annotated inheritance and the
  manifesting-heterozygote reality.
references:
- reference: PMID:41537560
  title: Individuals with reported and novel KDM5C variants present with seizures,
    a feature recapitulated in a Drosophila model.
  findings: []
- reference: PMID:32279304
  title: 'Further delineation of the female phenotype with KDM5C disease causing variants:
    19 new individuals and review of the literature.'
  findings: []
- reference: PMID:15586325
  title: Mutations in the JARID1C gene, which is involved in transcriptional regulation
    and chromatin remodeling, cause X-linked mental retardation.
  findings: []
notes: >
  GeneReviews baseline: searched PubMed (`GeneReviews[All Fields] AND (KDM5C OR
  JARID1C OR SMCX OR Claes-Jensen)`, `Claes-Jensen[TI] GeneReviews[TI]`) and the
  NCBI Bookshelf `gene` book on 2026-07-31. No GeneReviews chapter exists for
  Claes-Jensen syndrome / KDM5C-related neurodevelopmental disorder; the only
  Bookshelf hits are gene-table fragments inside other GeneReviews chapters.
  In the absence of a GeneReviews baseline, the phenotype list here is anchored
  on the two largest systematic aggregations (PMID:39835750, 175 literature
  cases; PMID:41537560, RARE-X registry meta-analysis to 269 individuals) plus
  the female-specific series PMID:32279304 and the caregiver-reported cohort
  PMID:34089235.
pathophysiology:
- name: Pathogenic KDM5C Variant
  biological_scale: MOLECULAR
  description: >
    A hemizygous (males) or heterozygous (females) pathogenic variant in KDM5C is
    the shared upstream lesion from which the two mechanistic arms of this disorder
    diverge. Most reported variants reduce or abolish JmjC-domain catalytic output,
    engaging the demethylase arm. However, catalytic loss is not required: the
    R1115H substitution leaves both enzymatic activity and protein stability intact
    yet still fails to repress KDM5C target genes, demonstrating that disruption of
    the non-enzymatic REST/HDAC1-2/G9a scaffolding role is a parallel consequence of
    the variant rather than a downstream consequence of demethylase loss. The two
    arms are therefore modelled as siblings fanning out from this node, not as a
    chain.
  evidence:
  - reference: PMID:29670509
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The KDM5C-R1115H substitution does not have an impact on enzymatic activity nor protein stability."
    explanation: >
      A pathogenic variant that spares catalytic activity establishes that the
      scaffolding arm can be engaged independently of demethylase loss, which is
      what licenses both arms to hang off the variant node in parallel.
  - reference: PMID:29670509
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results suggest that KDM5C may have non-enzymatic roles in gene regulation, and alteration of these roles contributes to MRXSCJ in this patient."
    explanation: >
      Attributes disease causation in this patient to the non-enzymatic role
      specifically, independent of the catalytic arm.
  downstream:
  - target: Loss of KDM5C H3K4me3/me2 Demethylase Function
  - target: Loss of Non-Enzymatic KDM5C Scaffolding in the REST Repressor Complex
- name: Loss of KDM5C H3K4me3/me2 Demethylase Function
  biological_scale: MOLECULAR
  description: >
    KDM5C is a JmjC-domain, Fe(II)/2-oxoglutarate-dependent histone demethylase
    that converts H3K4me3 to H3K4me2 and H3K4me1 (but not to the unmethylated
    product). Pathogenic variants abolish or reduce this catalytic output by
    several distinct routes: nonsense/frameshift alleles that eliminate the
    transcript or protein, missense alleles that destabilise the protein, and
    missense alleles within or adjacent to the catalytic JmjC/C5HC2 module that
    directly impair turnover. Variants adjacent to the accessory ARID and PHD1
    domains additionally corrupt substrate recognition by enhancing
    non-specific DNA binding. ClinGen assigns KDM5C a haploinsufficiency score
    of 3, and the gene is extremely loss-of-function intolerant, consistent with
    a pure loss-of-function mechanism rather than gain-of-function or
    dominant-negative action.
  molecular_functions:
  - preferred_term: histone H3K4 demethylase activity
    term:
      id: GO:0032453
      label: histone H3K4 demethylase activity
    modifier: DECREASED
  - preferred_term: histone H3K4me/H3K4me2/H3K4me3 demethylase activity
    term:
      id: GO:0034647
      label: histone H3K4me/H3K4me2/H3K4me3 demethylase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: Protein demethylation
    term:
      id: GO:0006482
      label: protein demethylation
    modifier: DECREASED
  - preferred_term: Chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  locations:
  - preferred_term: Brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:17320160
    reference_title: The X-linked mental retardation gene SMCX/JARID1C defines a family
      of histone H3 lysine 4 demethylases.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that the X-linked mental retardation (XLMR) gene SMCX (JARID1C), which encodes a JmjC-domain protein, reversed H3K4me3 to di- and mono- but not unmethylated products."
    explanation: Establishes the enzymatic identity and product specificity of the
      protein whose loss causes this disorder.
  - reference: PMID:17320160
    reference_title: The X-linked mental retardation gene SMCX/JARID1C defines a family
      of histone H3 lysine 4 demethylases.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Significantly, several XLMR-patient point mutations reduced SMCX demethylase activity and binding to H3K9me3 peptides, respectively."
    explanation: Directly links patient-derived variants to reduced demethylase activity.
  - reference: PMID:25666439
    reference_title: Mutations in the intellectual disability gene KDM5C reduce protein
      stability and demethylase activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We also characterize two KDM5C missense mutations, c.1439C>T (p.P480L) and c.1204G>T (p.D402Y) that are compatible with protein production, but compromise stability and enzymatic activity."
    explanation: Documents protein destabilisation as a distinct route to loss of
      function alongside direct catalytic impairment.
  - reference: PMID:15586325
    reference_title: Mutations in the JARID1C gene, which is involved in transcriptional
      regulation and chromatin remodeling, cause X-linked mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two of these families, expression studies revealed the almost complete absence of the mutated JARID1C transcript, suggesting that the phenotype in these families results from functional loss of the JARID1C protein."
    explanation: Demonstrates transcript loss as a further loss-of-function route
      in patients.
  - reference: PMID:36495919
    reference_title: Chromatin Sensing by the Auxiliary Domains of KDM5C Regulates
      Its Demethylase Activity and Is Disrupted by X-linked Intellectual Disability
      Mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we find that XLID mutations adjacent to the ARID and PHD1 domains break this regulation by enhancing DNA binding, resulting in the loss of specificity of substrate chromatin recognition"
    explanation: Shows that accessory-domain variants corrupt substrate recognition
      rather than only catalysis.
  - reference: PMID:29670509
    reference_title: Altered Gene-Regulatory Function of KDM5C by a Novel Mutation
      Associated With Autism and Intellectual Disability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Most mutations functionally tested to date result in reduced enzymatic activity of KDM5C, indicating loss of demethylase function as the primary mechanism underlying MRXSCJ."
    explanation: States loss of demethylase function as the primary disease mechanism.
  - reference: PMID:34536985
    reference_title: Molecular and cellular events linking variants in the histone
      demethylase KDM5C to the intellectual disability disorder Claes-Jensen syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One gene found to be genetically altered in the X-linked intellectual disability disorder Claes-Jensen syndrome is KDM5C, which encodes a histone demethylase that regulates transcription by altering chromatin."
    explanation: Review-level statement binding the gene, its enzymatic identity, and
      the named disease entity together.
  downstream:
  - target: Failure of Locus-Specific H3K4me3 Fine-Tuning at CpG-Island Promoters
- name: Loss of Non-Enzymatic KDM5C Scaffolding in the REST Repressor Complex
  biological_scale: MOLECULAR
  description: >
    KDM5C also acts non-catalytically as a component of a repressor assembly.
    An SMCX/KDM5C complex contains the histone deacetylases HDAC1 and HDAC2, the
    H3K9 methyltransferase G9a, and the transcriptional repressor REST, and
    co-occupies neuron-restrictive silencer elements in the promoters of REST
    target genes including SCN2A and SYN1. Depleting KDM5C derepresses these
    targets with a concomitant rise in promoter H3K4me3. Critically, the
    patient variant R1115H has entirely normal catalytic activity and protein
    stability yet still fails to suppress target genes, establishing that loss
    of demethylase activity alone is an incomplete account of the disease and
    that a scaffolding/recruitment arm exists in parallel.
  biological_processes:
  - preferred_term: Negative regulation of DNA-templated transcription
    term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    modifier: DECREASED
  - preferred_term: Regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:17468742
    reference_title: The histone H3K4 demethylase SMCX links REST target genes to
      X-linked mental retardation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Chromatin immunoprecipitation reveals that SMCX and REST co-occupy the neuron-restrictive silencing elements in the promoters of a subset of REST target genes."
    explanation: Establishes physical co-occupancy of KDM5C with REST at neuronal
      silencer elements.
  - reference: PMID:17468742
    reference_title: The histone H3K4 demethylase SMCX links REST target genes to
      X-linked mental retardation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RNA-interference-mediated depletion of SMCX derepresses several of these targets and simultaneously increases H3K4 trimethylation at the sodium channel type 2A (SCN2A) and synapsin I (SYN1) promoters."
    explanation: Links KDM5C loss to derepression of SCN2A and SYN1, a direct route
      from the chromatin lesion to neuronal excitability.
  - reference: PMID:17468742
    reference_title: The histone H3K4 demethylase SMCX links REST target genes to
      X-linked mental retardation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We propose that loss of SMCX activity impairs REST-mediated neuronal gene regulation, thereby contributing to SMCX-associated X-linked mental retardation."
    explanation: The authors' own causal proposal connecting the complex to the disease.
  - reference: PMID:29670509
    reference_title: Altered Gene-Regulatory Function of KDM5C by a Novel Mutation
      Associated With Autism and Intellectual Disability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The KDM5C-R1115H substitution does not have an impact on enzymatic activity nor protein stability."
    explanation: Identifies a pathogenic variant with intact catalysis, requiring
      a non-enzymatic mechanism.
  - reference: PMID:29670509
    reference_title: Altered Gene-Regulatory Function of KDM5C by a Novel Mutation
      Associated With Autism and Intellectual Disability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results suggest that KDM5C may have non-enzymatic roles in gene regulation, and alteration of these roles contributes to MRXSCJ in this patient."
    explanation: States the non-enzymatic arm explicitly as a contributor to MRXSCJ.
  downstream:
  - target: Derepression of Non-Neuronal, Germline and Cryptic Transcriptional Programs
  - target: Neuronal Hyperexcitability and Seizure Substrate
- name: Failure of Locus-Specific H3K4me3 Fine-Tuning at CpG-Island Promoters
  biological_scale: MOLECULAR
  description: >
    In neurons KDM5C is recruited to CpG-island promoters already decorated with
    high H3K4me3, where it trims rather than erases the mark. The consequence of
    KDM5C loss is therefore not a bulk collapse of chromatin state but a
    locus-specific failure of transcriptional fine-tuning, biased toward
    upregulation of lowly expressed target genes. KDM5C performs the same
    trimming function at activity-regulated enhancers during neuronal
    maturation. This distinction matters mechanistically: global H3K4
    methylation levels are preserved in patient fibroblasts and in Kdm5c-null
    neurons, so the pathology arises from mis-set thresholds at specific
    regulatory elements.
  biological_processes:
  - preferred_term: Chromatin remodeling
    term:
      id: GO:0006338
      label: chromatin remodeling
    modifier: ABNORMAL
  - preferred_term: Regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:26804915
    reference_title: A Mouse Model of X-linked Intellectual Disability Associated
      with Impaired Removal of Histone Methylation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In neurons, Kdm5c is recruited to promoters that harbor CpG islands decorated with high levels of H3K4me3, where it fine-tunes H3K4me3 levels."
    explanation: Defines the locus-specific fine-tuning function at CpG-island promoters.
  - reference: PMID:26804915
    reference_title: A Mouse Model of X-linked Intellectual Disability Associated
      with Impaired Removal of Histone Methylation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kdm5c predominantly represses these genes, which include members of key pathways that regulate the development and function of neuronal circuitries."
    explanation: Identifies the repressed target class as neuronal circuit development
      genes.
  - reference: PMID:28978483
    reference_title: Loss of Kdm5c Causes Spurious Transcription and Prevents the
      Fine-Tuning of Activity-Regulated Enhancers in Neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germline genes during cellular differentiation and in fine-tuning activity-regulated enhancers during neuronal maturation."
    explanation: Extends the fine-tuning role from promoters to activity-regulated
      enhancers.
  - reference: PMID:25666439
    reference_title: Mutations in the intellectual disability gene KDM5C reduce protein
      stability and demethylase activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient fibroblasts do not show global changes in histone methylation but we identify several up-regulated genes, suggesting local changes in chromatin conformation and gene expression."
    explanation: Human patient cells confirm the defect is local rather than global.
  downstream:
  - target: Derepression of Non-Neuronal, Germline and Cryptic Transcriptional Programs
  - target: Mistimed Canonical WNT Signalling and Progenitor Transition
- name: Derepression of Non-Neuronal, Germline and Cryptic Transcriptional Programs
  biological_scale: CELLULAR
  description: >
    The direct transcriptional consequence of failed H3K4me3 trimming is
    spurious activation of gene programs that should be silent in neurons. In
    the developing brain this manifests as failure to silence germline genes
    during differentiation; in the adult brain KDM5C serves an ongoing genome
    surveillance role, preventing activation of non-neuronal and cryptic
    promoters. This surveillance function is shared with, and reinforced by, the
    related demethylase KDM1A: combined forebrain loss of both enzymes produces
    stronger ectopic expression of non-neuronal genes in hippocampal neurons and
    thousands of de novo H3K4me3-enriched regions. The net effect is progressive
    erosion of neuronal transcriptional identity.
  biological_processes:
  - preferred_term: Negative regulation of DNA-templated transcription
    term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    modifier: DECREASED
  - preferred_term: Neuron differentiation
    term:
      id: GO:0030182
      label: neuron differentiation
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Hippocampal pyramidal neuron
    term:
      id: CL:1001571
      label: hippocampal pyramidal neuron
  locations:
  - preferred_term: Hippocampal formation
    term:
      id: UBERON:0002421
      label: hippocampal formation
  evidence:
  - reference: PMID:28978483
    reference_title: Loss of Kdm5c Causes Spurious Transcription and Prevents the
      Fine-Tuning of Activity-Regulated Enhancers in Neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kdm5c retains an important genome surveillance role preventing the incorrect activation of non-neuronal and cryptic promoters in adult neurons."
    explanation: Establishes lifelong genome surveillance as a second, post-developmental
      KDM5C function.
  - reference: PMID:40864554
    reference_title: Cooperative control of neuron-specific repressive chromatin states
      by intellectual-disability-linked KDM1A and KDM5C demethylases.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "including stronger ectopic expression of non-neuronal genes in hippocampal neurons and thousands of de novo H3K4me3-enriched regions, indicating synergistic disruption of repressive chromatin states"
    explanation: Confirms ectopic non-neuronal gene expression as the readout of failed
      H3K4me3 restraint.
  - reference: PMID:26804915
    reference_title: A Mouse Model of X-linked Intellectual Disability Associated
      with Impaired Removal of Histone Methylation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kdm5c-knockout brains exhibit abnormal dendritic arborization, spine anomalies, and altered transcriptomes."
    explanation: Links the transcriptomic derangement to the structural neuronal phenotype.
  downstream:
  - target: Reduced Dendritic Arborisation and Spine Density
- name: Mistimed Canonical WNT Signalling and Progenitor Transition
  biological_scale: CELLULAR
  description: >
    During a defined prenatal window of corticogenesis, KDM5C directly controls
    canonical WNT output to set the timing of the primary-to-intermediate
    neural progenitor transition and therefore the tempo of neurogenesis. Loss
    of KDM5C removes this timing safeguard. The deficit is developmental-window
    dependent and, in mice and patient-derived induced pluripotent stem cells,
    transiently reversible: WNT-pathway modulation restricted to that window
    rescues the transcriptomic and chromatin landscapes in patient-derived cells
    and rescues behavioural abnormalities in Kdm5c-knockout mice. Conversely, a
    single WNT3A injection into wild-type embryonic mouse brain produces anxiety
    and memory changes. This is the most therapeutically actionable mechanism
    identified to date, but the window may close before postnatal molecular
    diagnosis is possible.
  biological_processes:
  - preferred_term: Canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: ABNORMAL
  - preferred_term: Cerebral cortex neuron differentiation
    term:
      id: GO:0021895
      label: cerebral cortex neuron differentiation
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  locations:
  - preferred_term: Cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:38383780
    reference_title: WNT signalling control by KDM5C during development affects cognition.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "KDM5C is identified as a safeguard to ensure that neurodevelopment occurs at an appropriate timescale, the disruption of which leads to intellectual disability."
    explanation: States the developmental-timing safeguard role established in patient-derived
      iPSCs and mice.
  - reference: PMID:38383780
    reference_title: WNT signalling control by KDM5C during development affects cognition.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "there is a developmental window during which KDM5C directly controls WNT output to regulate the timely transition of primary to intermediate progenitor cells and consequently neurogenesis"
    explanation: Specifies the WNT-dependent progenitor transition as the mechanism.
  - reference: PMID:38383780
    reference_title: WNT signalling control by KDM5C during development affects cognition.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice."
    explanation: Demonstrates window-restricted pharmacological reversibility in a
      mouse model.
  downstream:
  - target: Reduced Dendritic Arborisation and Spine Density
  - target: Intellectual Disability
- name: Reduced Dendritic Arborisation and Spine Density
  biological_scale: TISSUE
  description: >
    The convergent structural endpoint of the transcriptional lesion is a
    hypoplastic dendritic tree with reduced spine density and immature spine
    morphology, most pronounced in amygdalar and cortical pyramidal neurons.
    Reduced dendritic development is seen with KDM5C knockdown in primary
    mammalian neurons and in zebrafish, and dendritic spine loss is a shared
    feature of Kdm5c-null and Kmt2a-null mice - the eraser and writer of the
    same mark - indicating that spine density is set by the balance of the
    H3K4-methylation writer-eraser pair rather than by either enzyme alone.
    There is no neurodegeneration, gliosis or tissue destruction; the adult
    Kdm5c-knockout cortex, hippocampus and amygdala are cytoarchitecturally
    normal.
  biological_processes:
  - preferred_term: Dendrite development
    term:
      id: GO:0016358
      label: dendrite development
    modifier: DECREASED
  - preferred_term: Regulation of dendritic spine development
    term:
      id: GO:0060998
      label: regulation of dendritic spine development
    modifier: ABNORMAL
  - preferred_term: Regulation of neuron projection development
    term:
      id: GO:0010975
      label: regulation of neuron projection development
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  - preferred_term: Glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  locations:
  - preferred_term: Amygdala
    term:
      id: UBERON:0001876
      label: amygdala
  - preferred_term: Cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:26804915
    reference_title: A Mouse Model of X-linked Intellectual Disability Associated
      with Impaired Removal of Histone Methylation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kdm5c-knockout brains exhibit abnormal dendritic arborization, spine anomalies, and altered transcriptomes."
    explanation: Documents the dendritic and spine phenotype in the mouse model of
      the disorder.
  - reference: PMID:17320160
    reference_title: The X-linked mental retardation gene SMCX/JARID1C defines a family
      of histone H3 lysine 4 demethylases.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "studies in zebrafish and primary mammalian neurons demonstrated a role for SMCX in neuronal survival and dendritic development and a link to the demethylase activity"
    explanation: Independently ties dendritic development to KDM5C demethylase function.
  - reference: PMID:32483278
    reference_title: 'Mutually suppressive roles of KMT2A and KDM5C in behaviour,
      neuronal structure, and histone H3K4 methylation.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression."
    explanation: Shows spine loss is a shared consequence of perturbing either side
      of the H3K4 writer-eraser pair.
  downstream:
  - target: Intellectual Disability
  - target: Aggressive Behavior
- name: Neuronal Hyperexcitability and Seizure Substrate
  biological_scale: CELLULAR
  description: >
    Seizures affect roughly a third to a half of individuals and arise from a
    cell-intrinsic neuronal requirement for KDM5 activity. Two convergent lines
    define the substrate. First, KDM5C loss derepresses REST targets including
    the sodium channel gene SCN2A, itself a major epilepsy gene, with increased
    promoter H3K4me3. Second, combined KDM1A/KDM5C forebrain loss alters
    hippocampal ion channel expression and increases the intrinsic excitability
    of CA1 pyramidal neurons. In Drosophila, reducing Kdm5 in neurons but not in
    glia is sufficient to produce spontaneous and stimulus-induced seizures,
    establishing that the requirement is neuron-autonomous.
  biological_processes:
  - preferred_term: Regulation of membrane potential
    term:
      id: GO:0042391
      label: regulation of membrane potential
    modifier: ABNORMAL
  cell_types:
  - preferred_term: CA1 pyramidal neuron
    term:
      id: CL:4023060
      label: hippocampal CA1-3 neuron
  locations:
  - preferred_term: Hippocampal formation
    term:
      id: UBERON:0002421
      label: hippocampal formation
  evidence:
  - reference: PMID:41537560
    reference_title: Individuals with reported and novel KDM5C variants present with
      seizures, a feature recapitulated in a Drosophila model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Reducing the expression of its single Kdm5 gene in neurons, but not glia, led to spontaneous and stimulus-induced seizures, underscoring a cell-intrinsic requirement for KDM5 in maintaining neuronal stability."
    explanation: Establishes a neuron-autonomous, glia-independent requirement for
      KDM5 in seizure protection.
  - reference: PMID:40864554
    reference_title: Cooperative control of neuron-specific repressive chromatin states
      by intellectual-disability-linked KDM1A and KDM5C demethylases.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "dKDM-ifKOs display more severe behavioral impairments than the single ifKOs along with altered hippocampal expression of ion channels and increased excitability of CA1 pyramidal neurons"
    explanation: Provides the cellular electrophysiological substrate for the seizure
      phenotype.
  - reference: PMID:17468742
    reference_title: The histone H3K4 demethylase SMCX links REST target genes to
      X-linked mental retardation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "increases H3K4 trimethylation at the sodium channel type 2A (SCN2A) and synapsin I (SYN1) promoters"
    explanation: Connects the chromatin lesion to derepression of a major sodium-channel
      epilepsy gene.
  downstream:
  - target: Seizures
mechanistic_hypotheses:
- hypothesis_group_id: wnt_window_rescue
  hypothesis_label: Transient developmental-window WNT inhibition is disease-modifying
  status: EMERGING
  description: >
    Because KDM5C sets neurodevelopmental tempo through WNT output during a
    circumscribed prenatal window, transient WNT-pathway inhibition confined to
    that window may be disease-modifying rather than merely symptomatic. The
    evidence is a single high-quality study in Kdm5c-knockout mice and
    patient-derived iPSCs. The central translational obstacle is that the
    window plausibly closes before postnatal molecular diagnosis is achievable.
  evidence:
  - reference: PMID:38383780
    reference_title: WNT signalling control by KDM5C during development affects cognition.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Treatment with WNT signalling modulators at specific times reveal that only a transient alteration of the canonical WNT signalling pathway is sufficient to rescue the transcriptomic and chromatin landscapes in patient-derived cells"
    explanation: Window-restricted pharmacological rescue in patient-derived iPSC cultures.
  - reference: PMID:38383780
    reference_title: WNT signalling control by KDM5C during development affects cognition.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice."
    explanation: The in vivo arm of the same result - window-restricted WNT inhibition
      rescues behaviour in the mouse model.
- hypothesis_group_id: h3k4_writer_eraser_rebalancing
  hypothesis_label: Rebalancing the KMT2A/KDM5C writer-eraser pair ameliorates the
    phenotype
  status: EMERGING
  description: >
    KDM5C (eraser) and KMT2A (writer) act on the same H3K4 mark, and their
    respective loss-of-function mouse models share reduced dendritic spines and
    increased aggression. Combined loss of both mutually suppresses these
    phenotypes, suggesting that pharmacological reduction of KMT2A activity
    could ameliorate KDM5C deficiency. This is a genetic proof of principle in
    mice only; no pharmacological agent has been tested in this context. Note
    that KMT2A is the Wiedemann-Steiner syndrome gene - it is cited here purely
    as a mechanistic counterweight, and Wiedemann-Steiner syndrome is a distinct
    disease entity, not a synonym or subtype of this disorder.
  evidence:
  - reference: PMID:32483278
    reference_title: 'Mutually suppressive roles of KMT2A and KDM5C in behaviour,
      neuronal structure, and histone H3K4 methylation.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes."
    explanation: Genetic epistasis evidence for mutual suppression between the writer
      and eraser.
  - reference: PMID:32483278
    reference_title: 'Mutually suppressive roles of KMT2A and KDM5C in behaviour,
      neuronal structure, and histone H3K4 methylation.'
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "provides a proof of principle for balancing a single writer-eraser pair to ameliorate their associated disorders"
    explanation: The authors frame this explicitly as a proof of principle, not an
      established therapy.
- hypothesis_group_id: hdac_inhibition_kdm5c_restoration
  hypothesis_label: HDAC inhibition restores KDM5C expression and H3K4me3 signalling
  status: EMERGING
  description: >
    KDM5C sits at the intersection of transcriptional axes controlled by ARX,
    ZNF711 and PHF8, all of which are themselves X-linked neurodevelopmental
    disorder genes. The FDA-approved histone deacetylase inhibitor SAHA
    (vorinostat) rescued KDM5C depletion, recovered H3K4me3 signalling and
    improved neuronal differentiation in Arx-knockout mouse embryonic
    stem-cell-derived neurons, and improved behaviour in ARX-deficient C.
    elegans. IMPORTANT LIMITATION: this rescue was demonstrated in models where
    KDM5C is transcriptionally downregulated because its upstream activator ARX
    is lost, not in models carrying a KDM5C coding variant. Raising expression
    of a mutant KDM5C allele would not be expected to help in most
    Claes-Jensen genotypes, so this hypothesis is at best applicable to a
    hypothetical regulatory-variant subset and should not be read as a
    therapeutic lead for typical KDM5C loss-of-function disease.
  evidence:
  - reference: PMID:31691806
    reference_title: Histone demethylase KDM5C is a SAHA-sensitive central hub at
      the crossroads of transcriptional axes involved in multiple neurodevelopmental
      disorders.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling and improve neuronal differentiation."
    explanation: Demonstrates pharmacological restoration of KDM5C level and H3K4me3
      signalling, but in an ARX-deficient rather than a KDM5C-mutant model, hence
      PARTIAL support.
  - reference: PMID:31691806
    reference_title: Histone demethylase KDM5C is a SAHA-sensitive central hub at
      the crossroads of transcriptional axes involved in multiple neurodevelopmental
      disorders.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy"
    explanation: The authors' own framing as a potential rather than established strategy.
phenotypes:
- name: Intellectual Disability
  category: Neurological
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >
    The defining feature. In hemizygous males intellectual disability is
    essentially fully penetrant and skews moderate to severe; in heterozygous
    females it is incompletely penetrant and skews mild to moderate. A single
    reported male with a typical Claes-Jensen KDM5C variant had no intellectual
    disability, so penetrance in males is very high but not absolute.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:32279304
    reference_title: 'Further delineation of the female phenotype with KDM5C disease
      causing variants: 19 new individuals and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KDM5C variants are one of the major causes of moderate to severe XLID."
    explanation: Establishes moderate-to-severe intellectual disability as the core
      disease feature.
  - reference: PMID:34089235
    reference_title: Caregiver-reported characteristics of children diagnosed with
      pathogenic variants in KDM5C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previous studies have found that males present with moderate to severe ID with significant syndromic comorbidities such as epilepsy, short stature, and craniofacial abnormalities."
    explanation: Confirms the severity distribution in males across prior cohorts.
  - reference: PMID:18697827
    reference_title: Mutations in JARID1C are associated with X-linked mental retardation,
      short stature and hyperreflexia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings of the nine affected males from the four different families included mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%)."
    explanation: Quantitative cohort data giving 100% frequency of intellectual disability
      in affected males, supporting the VERY_FREQUENT band.
  - reference: PMID:40125771
    reference_title: 'Atypical Ophthalmological Manifestations of Claes-Jensen Syndrome
      Without Intellectual Disability: A Case Report.'
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "An 8-year-old boy with prenatal-onset short stature, ophthalmological abnormalities, and dysmorphic features had a KDM5C variant typically linked to Claes-Jensen syndrome with intellectual disability, which he did not have."
    explanation: Documents the exception showing male penetrance for intellectual disability
      is not absolute.
- name: Severe Intellectual Disability
  category: Neurological
  description: >
    Within the intellectual disability spectrum, hemizygous males cluster at the
    severe end; the original Claes family was described with severe mental
    retardation. Females predominantly fall in the mild range.
  phenotype_term:
    preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
    severity: SEVERE
  evidence:
  - reference: PMID:18697827
    reference_title: Mutations in JARID1C are associated with X-linked mental retardation,
      short stature and hyperreflexia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The degree of mental retardation consisted of mild (25%), moderate (12%) and severe (63%)."
    explanation: Quantifies the skew toward severe intellectual disability in affected
      males.
  - reference: PMID:10982473
    reference_title: Novel syndromic form of X-linked complicated spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "four males in two generations present severe mental retardation, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasia"
    explanation: The index family that defines the eponym showed severe intellectual
      disability.
- name: Delayed Speech and Language Development
  category: Neurological
  frequency: VERY_FREQUENT
  description: >
    Speech and language impairment, with expressive language disproportionately
    affected, is among the most consistent features and is a leading driver of
    functional dependency. Communication challenges were reported by 93% of
    caregivers in the RARE-X registry cohort; expressive language impairment is
    prominent even in mildly affected heterozygous females.
  notes: >
    Frequency basis (docs/frequency-evidence-guidelines.md, Patterns C and D-1):
    no cited abstract reports a percentage for this phenotype. VERY_FREQUENT
    rests on PMID:36434256 describing the condition as "characterized by ...
    intellectual disability with speech disorders" - a highly-characteristic
    wording that maps to the VERY_FREQUENT band - corroborated by the RARE-X 93%
    communication-challenge figure, which appears in that paper's result tables
    rather than its abstract and therefore cannot be quoted as a snippet. The
    4/19 language-impairment count in PMID:32279304 is a female-only,
    expression-specific subset and is not a competing overall frequency estimate.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:41743791
    reference_title: Emerging role of KDM5C in X-linked intellectual disability based
      on human genetic data and zebrafish models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected males presented with short stature, microcephaly, language delay, and intellectual disability"
    explanation: Language delay listed among the core male features in an independent
      two-family series.
  - reference: PMID:36434256
    reference_title: 'Expanding the genetics and phenotypic spectrum of Lysine-specific
      demethylase 5C (KDM5C): a report of 13 novel variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern"
    explanation: Speech disorder is listed as a core component of the neurodevelopmental
      presentation in a 30-individual cohort.
  - reference: PMID:32279304
    reference_title: 'Further delineation of the female phenotype with KDM5C disease
      causing variants: 19 new individuals and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals presented with learning disabilities or ID (mostly moderate), and four also had a language impairment mainly affecting expression."
    explanation: Documents expressive-predominant language impairment in affected heterozygous
      females.
- name: Global Developmental Delay
  category: Neurological
  description: >
    Psychomotor delay across motor and cognitive domains is typically the
    presenting concern in infancy or early childhood, preceding a formal
    intellectual disability diagnosis.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:36434256
    reference_title: 'Expanding the genetics and phenotypic spectrum of Lysine-specific
      demethylase 5C (KDM5C): a report of 13 novel variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifested a neurodevelopmental condition characterized by psychomotor delay"
    explanation: Psychomotor delay is documented as a defining early feature.
  - reference: PMID:36536324
    reference_title: A female case with novel KDM5C heterozygous variation presenting
      with Claes-Jensen type-like phonotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who presented with Claes-Jensen type-like phenotypes, such as moderate developmental delay, serious expressive language delay, short stature, microcephaly, and typical facial particularities"
    explanation: Developmental delay documented in an affected heterozygous female.
- name: Short Stature
  category: Growth
  frequency: FREQUENT
  description: >
    Short stature is one of the classic triad features (with intellectual
    disability and hyperreflexia) that historically prompted JARID1C/KDM5C
    testing. Reported in roughly half to three-quarters of affected individuals
    depending on cohort and sex, and prenatal-onset short stature is documented.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:18697827
    reference_title: Mutations in JARID1C are associated with X-linked mental retardation,
      short stature and hyperreflexia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings of the nine affected males from the four different families included mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%)."
    explanation: Gives 55% short stature in affected males, within the FREQUENT band.
  - reference: PMID:32279304
    reference_title: 'Further delineation of the female phenotype with KDM5C disease
      causing variants: 19 new individuals and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity."
    explanation: Short stature listed among the core male features.
  - reference: PMID:40125771
    reference_title: 'Atypical Ophthalmological Manifestations of Claes-Jensen Syndrome
      Without Intellectual Disability: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An 8-year-old boy with prenatal-onset short stature"
    explanation: Documents prenatal onset of the growth restriction.
- name: Microcephaly
  category: Craniofacial
  description: >
    Reduced occipitofrontal circumference is a recurrent but not universal
    finding (approximately 7/20 in the HPO-annotated series). Head size is
    not uniform across the spectrum - macrocephaly has also been reported, so
    microcephaly should not be treated as a required feature.
  notes: >
    Frequency intentionally omitted. The only frequency signal available is the
    HPO annotation count (7/20, i.e. about 35%, which would be FREQUENT rather
    than OCCASIONAL), and that count is not quotable from any cited abstract.
    Per docs/frequency-evidence-guidelines.md the band is omitted rather than
    guessed; the cited sources support the disease-phenotype association only.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:36536324
    reference_title: A female case with novel KDM5C heterozygous variation presenting
      with Claes-Jensen type-like phonotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "moderate developmental delay, serious expressive language delay, short stature, microcephaly, and typical facial particularities"
    explanation: Microcephaly documented as part of the Claes-Jensen-type phenotype.
  - reference: PMID:41743791
    reference_title: Emerging role of KDM5C in X-linked intellectual disability based
      on human genetic data and zebrafish models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected males presented with short stature, microcephaly, language delay, and intellectual disability"
    explanation: Independent two-family series listing microcephaly among the core
      male features, so the association does not rest on a single female case report.
- name: Abnormal Facial Shape
  category: Craniofacial
  frequency: FREQUENT
  description: >
    A recognisable but non-specific facial gestalt, classically including
    maxillary hypoplasia (midface retrusion), facial hypotonia, high palate and
    dental diastema. Facial dysmorphism was reported in roughly 71-84% of
    individuals in the largest sex-stratified literature review.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:32279304
    reference_title: 'Further delineation of the female phenotype with KDM5C disease
      causing variants: 19 new individuals and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity."
    explanation: Distinctive facial features listed among the core male features.
  - reference: PMID:29456765
    reference_title: Peripheral blood epi-signature of Claes-Jensen syndrome enables
      sensitive and specific identification of patients and healthy carriers with
      pathogenic mutations in KDM5C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Males with hemizygous mutations in KDM5C present with intellectual disability and facial dysmorphism"
    explanation: Pairs facial dysmorphism with intellectual disability as the male
      presentation.
- name: Maxillary Hypoplasia
  category: Craniofacial
  description: >
    Hypoplasia of the maxilla producing midface retrusion was one of the four
    defining features of the original Claes family and remains among the more
    specific craniofacial findings (annotated 7/23 in HPO).
  phenotype_term:
    preferred_term: Hypoplasia of the maxilla
    term:
      id: HP:0000327
      label: Hypoplasia of the maxilla
  evidence:
  - reference: PMID:10982473
    reference_title: Novel syndromic form of X-linked complicated spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "four males in two generations present severe mental retardation, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasia"
    explanation: Maxillary hypoplasia is one of the four defining features of the
      index family.
- name: Seizures
  category: Neurological
  description: >
    Seizures occur in roughly a third to a half of individuals overall, with a
    marked sex difference: literature meta-analyses report approximately 47-64%
    of males versus 18-19% of females, whereas the registry-recruited female
    cohort reported 56%. Median age at first seizure is about 2 years.
    Frequency is deliberately left unset here because the two ascertainment
    routes give conflicting estimates in opposite directions (see notes).
  notes: >
    Frequency intentionally omitted. The RARE-X registry meta-analysis gives 35%
    overall (47% male, 18% female), Ghasemi's literature review gives 64% male /
    19% female, and the RARE-X newly recruited female subcohort gives 56%.
    Registry self-enrolment enriches for symptomatic females while historical
    XLMR-family literature enriches for severely affected males; per
    docs/frequency-evidence-guidelines.md the band is omitted rather than
    guessed. Variants in the catalytic domain appear enriched for seizures.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41537560
    reference_title: Individuals with reported and novel KDM5C variants present with
      seizures, a feature recapitulated in a Drosophila model.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meta-analyses of this data and previously published cases reaffirmed that seizures are a frequent feature in both hemizygous males and heterozygous females with KDM5C variants, with over a third of individuals reporting at least one seizure."
    explanation: Largest meta-analysis establishing seizures in over a third of individuals
      of both sexes.
  - reference: PMID:39835750
    reference_title: 'Clinical Features and Genetic Characteristics of XLID Patients
      With KDM5C Gene Mutations: Insights on Phenotype-Genotype Correlations From
      175 Previous Cases and Identification of a Novel Variant.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "highlighting the higher manifestation of seizures in males and also addressing the heterogeneity of phenotypes in females"
    explanation: Documents the male-biased seizure frequency across 175 literature
      cases.
  - reference: PMID:18697827
    reference_title: Mutations in JARID1C are associated with X-linked mental retardation,
      short stature and hyperreflexia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%)"
    explanation: Earlier cohort estimate of 33% seizures in affected males.
- name: Hyperreflexia
  category: Neurological
  frequency: FREQUENT
  description: >
    Brisk deep tendon reflexes, typically lower-limb predominant, form part of
    the historically recognised diagnostic triad with intellectual disability
    and short stature. Reported in 78% of affected males in the cohort that
    named the association.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:18697827
    reference_title: Mutations in JARID1C are associated with X-linked mental retardation,
      short stature and hyperreflexia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical findings of the nine affected males from the four different families included mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%)."
    explanation: Gives 78% hyperreflexia in affected males, supporting the FREQUENT
      band.
  - reference: PMID:18697827
    reference_title: Mutations in JARID1C are associated with X-linked mental retardation,
      short stature and hyperreflexia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "male patients with mental retardation, short stature and hyperreflexia should be considered candidates for mutations in the JARID1C gene"
    explanation: Establishes hyperreflexia as a gene-prioritising clinical marker.
- name: Spasticity
  category: Neurological
  description: >
    Upper-motor-neuron spasticity, predominantly of the lower limbs, is a
    recurrent feature (annotated 7/20 in HPO). In a subset it takes the form of
    slowly progressive spastic paraplegia - the feature that led to the original
    description of the family as a novel X-linked complicated spastic paraplegia
    before KDM5C was identified.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:32279304
    reference_title: 'Further delineation of the female phenotype with KDM5C disease
      causing variants: 19 new individuals and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected males present with short stature, distinctive facial features, behavioral disorders, epilepsy, and spasticity."
    explanation: Spasticity is listed among the core male features.
  - reference: PMID:10982473
    reference_title: Novel syndromic form of X-linked complicated spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "slowly progressive spastic paraplegia"
    explanation: Documents the progressive spastic paraplegia phenotype in the index
      family.
- name: Progressive Spastic Paraplegia
  category: Neurological
  description: >
    A subset of affected males develop slowly progressive lower-limb spastic
    paraplegia. This is the one clearly progressive element of an otherwise
    static neurodevelopmental disorder, and it was severe enough in the index
    family that the condition was initially classified as a form of complicated
    X-linked spastic paraplegia, with PLP1 and L1CAM formally excluded.
  phenotype_term:
    preferred_term: Progressive spastic paraplegia
    term:
      id: HP:0007020
      label: Progressive spastic paraplegia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:10982473
    reference_title: Novel syndromic form of X-linked complicated spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study presents a family with a syndromic form of X-linked mental retardation in which four males in two generations present severe mental retardation, slowly progressive spastic paraplegia"
    explanation: Primary description of progressive spastic paraplegia in the family
      that defines the eponym.
  - reference: PMID:10982473
    reference_title: Novel syndromic form of X-linked complicated spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two known loci for X-linked mental retardation and spastic paraplegia are excluded: proteolipid protein in Xp21 and L1 cell adhesion molecule in Xq28."
    explanation: Documents the exclusion of PLP1 and L1CAM, establishing this as a
      distinct entity.
- name: Aggressive Behavior
  category: Behavioral
  frequency: FREQUENT
  description: >
    Aggression and disinhibition are among the most burdensome features for
    caregivers, reported in roughly 44% of affected males in the earliest
    quantified cohort and in a third of the HPO-annotated series. Aggression is
    notably one of the phenotypes shared between Kdm5c-null and Kmt2a-null mice
    and reversed by combined loss.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:18697827
    reference_title: Mutations in JARID1C are associated with X-linked mental retardation,
      short stature and hyperreflexia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%)"
    explanation: Gives 44% aggressive behaviour in affected males, within the FREQUENT
      band.
  - reference: PMID:26804915
    reference_title: A Mouse Model of X-linked Intellectual Disability Associated
      with Impaired Removal of Histone Methylation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "disruption of the mouse Kdm5c gene recapitulates adaptive and cognitive abnormalities observed in XLID, including impaired social behavior, memory deficits, and aggression"
    explanation: Aggression is recapitulated in the mouse model, supporting a direct
      mechanistic link.
- name: Autism Spectrum Disorder
  category: Behavioral
  description: >
    More than half of individuals in the largest caregiver-reported cohort had
    an autism spectrum disorder diagnosis or features consistent with it. A
    KDM5C variant has also been identified in an individual ascertained through
    autism plus intellectual disability.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:34089235
    reference_title: Caregiver-reported characteristics of children diagnosed with
      pathogenic variants in KDM5C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "more than half of individuals reported a diagnosis of autism spectrum disorder or described features consistent with this spectrum"
    explanation: Quantifies autism spectrum diagnoses in the largest caregiver-reported
      cohort.
  - reference: PMID:29670509
    reference_title: Altered Gene-Regulatory Function of KDM5C by a Novel Mutation
      Associated With Autism and Intellectual Disability.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KDM5C-deficiency is characterized by frequent autistic and aggressive behaviors"
    explanation: Literature-summary statement in the same paper tying autistic behaviour
      specifically to KDM5C deficiency rather than to intellectual disability in general.
- name: Sleep Disturbance
  category: Behavioral
  description: >
    Disturbed sleep pattern was singled out as a particularly characteristic
    behavioural feature in a 30-individual multicentre cohort.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:36434256
    reference_title: 'Expanding the genetics and phenotypic spectrum of Lysine-specific
      demethylase 5C (KDM5C): a report of 13 novel variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "behavioral features with particular disturbed sleep pattern"
    explanation: Sleep disturbance singled out as a characteristic behavioural feature.
- name: Obesity
  category: Growth
  description: >
    Obesity was observed among the additional clinical manifestations in a
    30-individual cohort, coexisting in the disease spectrum with the more
    classic short stature and failure to thrive.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:36434256
    reference_title: 'Expanding the genetics and phenotypic spectrum of Lysine-specific
      demethylase 5C (KDM5C): a report of 13 novel variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "other observed clinical manifestations were short stature, obesity and hypertrichosis"
    explanation: Obesity documented among the observed manifestations.
- name: Hypertrichosis
  category: Dermatological
  description: >
    Hypertrichosis was reported among the additional clinical manifestations in
    a 30-individual cohort. Note that hypertrichosis (particularly hypertrichosis
    cubiti) is more characteristic of KMT2A-related Wiedemann-Steiner syndrome;
    its presence here does not indicate that diagnosis.
  phenotype_term:
    preferred_term: Hypertrichosis
    term:
      id: HP:0000998
      label: Hypertrichosis
  evidence:
  - reference: PMID:36434256
    reference_title: 'Expanding the genetics and phenotypic spectrum of Lysine-specific
      demethylase 5C (KDM5C): a report of 13 novel variants.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "other observed clinical manifestations were short stature, obesity and hypertrichosis"
    explanation: Hypertrichosis documented among the observed manifestations.
- name: Ophthalmological Abnormality
  category: Ophthalmological
  description: >
    Vision and eye problems are a frequent systemic feature. Strabismus is
    reported as the most frequent specific ophthalmological finding, with
    abnormal eye movements in the great majority of registry respondents who
    had vision problems, but no abstract-level source currently available in
    this entry states strabismus explicitly, so the phenotype is annotated at
    the evidenced level (eye abnormality) rather than at the strabismus level.
    Ophthalmological assessment is under-performed relative to its yield and
    untreated strabismus carries a preventable amblyopia risk.
  notes: >
    Curation note: HPO annotates Strabismus (HP:0000486) to this disorder and
    the RARE-X registry reports abnormal eye movement in the great majority of
    respondents with vision problems, but those figures appear only in
    HPO annotation files and paper result tables, not in any cited abstract.
    Per the evidence SOP the specific strabismus claim is therefore not asserted
    here; re-specialise this phenotype to HP:0000486 if a quotable source is
    found. The strabismus-specific surgical target is retained on the
    ophthalmological treatment entry, where the cited description covers it.
  phenotype_term:
    preferred_term: Ophthalmological abnormality
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:41537560
    reference_title: Individuals with reported and novel KDM5C variants present with
      seizures, a feature recapitulated in a Drosophila model.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "participants frequently reported growth abnormalities, vision and digestive issues, behavioral concerns, and seizures in nearly half of the cases"
    explanation: Vision problems reported as a frequent systemic feature in the registry
      cohort.
  - reference: PMID:40125771
    reference_title: 'Atypical Ophthalmological Manifestations of Claes-Jensen Syndrome
      Without Intellectual Disability: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An 8-year-old boy with prenatal-onset short stature, ophthalmological abnormalities, and dysmorphic features had a KDM5C variant typically linked to Claes-Jensen syndrome"
    explanation: Documents ophthalmological abnormalities in a molecularly confirmed
      KDM5C patient.
- name: Gastrointestinal Dysfunction
  category: Gastrointestinal
  description: >
    Digestive problems affected roughly three-quarters of registry respondents,
    with constipation reported as the dominant complaint. Gastrointestinal
    dysfunction was also reported in up to 70% of affected females in the
    caregiver cohort. Under-recognised and a plausible contributor to
    behavioural escalation.
  notes: >
    Curation note: the registry constipation figure appears only in the paper's
    result tables, not in any cited abstract, so the phenotype is annotated at
    the evidenced level (gastrointestinal dysfunction) rather than as
    Constipation (HP:0002019). Re-specialise if a quotable source is found.
  phenotype_term:
    preferred_term: Gastrointestinal dysfunction
    term:
      id: HP:0011024
      label: Abnormality of the gastrointestinal tract
  evidence:
  - reference: PMID:41537560
    reference_title: Individuals with reported and novel KDM5C variants present with
      seizures, a feature recapitulated in a Drosophila model.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "participants frequently reported growth abnormalities, vision and digestive issues, behavioral concerns, and seizures in nearly half of the cases"
    explanation: Digestive issues reported as a frequent systemic feature.
  - reference: PMID:34089235
    reference_title: Caregiver-reported characteristics of children diagnosed with
      pathogenic variants in KDM5C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We find that up to 70% of affected females were reported to display syndromic features including gastrointestinal dysfunction and hearing impairment."
    explanation: Gastrointestinal dysfunction quantified in affected females.
- name: Hearing Impairment
  category: Otological
  description: >
    Hearing impairment was reported among the syndromic features affecting up to
    70% of affected females in the largest caregiver-reported cohort. It is
    poorly characterised in males and has not been audiologically typed.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:34089235
    reference_title: Caregiver-reported characteristics of children diagnosed with
      pathogenic variants in KDM5C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "up to 70% of affected females were reported to display syndromic features including gastrointestinal dysfunction and hearing impairment"
    explanation: Hearing impairment documented as a syndromic feature in affected
      females.
genetic:
- name: KDM5C
  association: Causative
  variant_origin: GERMLINE
  gene_term:
    preferred_term: KDM5C
    term:
      id: hgnc:11114
      label: KDM5C
  frequency: approximately 0.7-2.8% of X-linked intellectual disability cases
  notes: >
    KDM5C (Xp11.22; formerly JARID1C, SMCX, XE169) encodes a 1560-amino-acid
    JmjC-domain histone H3K4me3/me2 demethylase. Reference transcript
    NM_004187.5. The variant spectrum is dominated by private, family-specific
    alleles with near-complete allelic heterogeneity: roughly half missense
    (with the catalytic JmjC domain the missense hotspot), with nonsense,
    frameshift and splice-site variants making up most of the remainder and
    Xp11.22 microdeletions accounting for a small fraction. Mechanism is
    haploinsufficiency/loss of function (ClinGen haploinsufficiency score 3;
    triplosensitivity 0); no dominant-negative or gain-of-function mechanism has
    been demonstrated. Somatic KDM5C mutation is a recognised driver in clear
    cell renal cell carcinoma, which is an entirely distinct disease context and
    must not be conflated with this germline neurodevelopmental disorder.
    KDM5C is not to be confused with its paralogues KDM5A, KDM5B or the
    Y-linked KDM5D, which have separate disease associations.
  case_fractions:
  - population: X-linked intellectual disability cases (literature range)
    case_fraction_low: 0.7
    case_fraction_high: 2.8
    notes: Range cited across contemporary reviews for the KDM5C share of X-linked
      intellectual disability.
    evidence:
    - reference: PMID:34089235
      reference_title: Caregiver-reported characteristics of children diagnosed with
        pathogenic variants in KDM5C.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Loss of function variants in the lysine demethylase 5C (KDM5C) gene account for approximately 0.7-2.8% of X-linked intellectual disability (ID) cases"
      explanation: Directly states the KDM5C case fraction among X-linked intellectual
        disability.
  - population: Ascertained XLMR families screened for brain-expressed Xp genes
    case_fraction_percent: 3.3
    cohort_size: 210
    notes: Seven of 210 XLMR families in the original gene-discovery screen; an upper
      bound reflecting ascertainment on multiplex X-linked pedigrees.
    evidence:
    - reference: PMID:15586325
      reference_title: Mutations in the JARID1C gene, which is involved in transcriptional
        regulation and chromatin remodeling, cause X-linked mental retardation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In a systematic screen of brain-expressed genes from this region in 210 families with XLMR, we identified seven different mutations in JARID1C"
      explanation: Seven mutations in 210 families gives the 3.3% ascertained-family
        yield.
  evidence:
  - reference: PMID:15586325
    reference_title: Mutations in the JARID1C gene, which is involved in transcriptional
      regulation and chromatin remodeling, cause X-linked mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results suggest that JARID1C mutations are a relatively common cause of XLMR and that this gene might play an important role in human brain function."
    explanation: Gene-discovery paper establishing JARID1C/KDM5C as the causative gene.
  - reference: PMID:29670509
    reference_title: Altered Gene-Regulatory Function of KDM5C by a Novel Mutation
      Associated With Autism and Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in KDM5C cause Mental Retardation, X-linked, Syndromic, Claes-Jensen type (MRXSCJ, OMIM #300534) and are one of the most common causes of X-linked ID."
    explanation: Explicitly binds KDM5C to the MRXSCJ/OMIM 300534 entity curated here.
  - reference: PMID:25666439
    reference_title: Mutations in the intellectual disability gene KDM5C reduce protein
      stability and demethylase activity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in KDM5C are an important cause of X-linked intellectual disability in males."
    explanation: Independent confirmation of the gene-disease relationship.
  - reference: PMID:39835750
    reference_title: 'Clinical Features and Genetic Characteristics of XLID Patients
      With KDM5C Gene Mutations: Insights on Phenotype-Genotype Correlations From
      175 Previous Cases and Identification of a Novel Variant.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified missense variants as the most prevalent among the reported variants"
    explanation: Characterises the variant spectrum across 175 reported cases.
variants:
- name: KDM5C p.Arg1115His
  description: >
    A missense variant identified in an individual with MRXSCJ-like features plus
    autism. Functionally exceptional: it has no measurable effect on either
    enzymatic activity or protein stability, yet when overexpressed in
    post-mitotic neurons it fails to fully suppress KDM5C target genes and
    additionally perturbs a distinct gene set. It is the primary evidence that
    KDM5C has disease-relevant non-enzymatic roles, and the reason the
    pathophysiology here models an enzymatic and a scaffolding arm separately.
  gene:
    preferred_term: KDM5C
    term:
      id: hgnc:11114
      label: KDM5C
  type: MISSENSE
  evidence:
  - reference: PMID:29670509
    reference_title: Altered Gene-Regulatory Function of KDM5C by a Novel Mutation
      Associated With Autism and Intellectual Disability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we report a novel KDM5C mutation, R1115H, identified in an individual displaying MRXSCJ-like symptoms."
    explanation: Identifies the variant and the clinical context.
  - reference: PMID:29670509
    reference_title: Altered Gene-Regulatory Function of KDM5C by a Novel Mutation
      Associated With Autism and Intellectual Disability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "when overexpressed in post-mitotic neurons, KDM5C-R1115H failed to fully suppress expression of target genes, while the mutant also affected expression of a distinct set of genes compared to KDM5C-wildtype"
    explanation: Establishes the functional defect despite intact catalysis.
- name: KDM5C p.Val1075Tyrfs*2
  description: >
    A frameshift variant (c.3223delG) that results in complete loss of KDM5C
    protein - the cleanest example of the null-allele end of the spectrum.
  gene:
    preferred_term: KDM5C
    term:
      id: hgnc:11114
      label: KDM5C
  type: FRAMESHIFT
  evidence:
  - reference: PMID:25666439
    reference_title: Mutations in the intellectual disability gene KDM5C reduce protein
      stability and demethylase activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We report and characterize a novel nonsense mutation, c.3223delG (p.V1075Yfs*2), which leads to loss of KDM5C protein."
    explanation: Documents complete protein loss for this allele.
- name: KDM5C p.Ser1178Ter
  description: >
    A de novo heterozygous nonsense variant (c.3533C>A) in a 4-year-old girl with
    a Claes-Jensen-type phenotype. Notably, X-chromosome inactivation analysis
    showed no significant skewing, undercutting the simple assumption that
    female expression is governed by skewed XCI.
  gene:
    preferred_term: KDM5C
    term:
      id: hgnc:11114
      label: KDM5C
  type: NONSENSE
  evidence:
  - reference: PMID:36536324
    reference_title: A female case with novel KDM5C heterozygous variation presenting
      with Claes-Jensen type-like phonotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a novel de novo heterozygous nonsense variation of KDM5C (c.3533C > A, p.S1178X) in a sporadic 4-year-old Chinese girl"
    explanation: Documents a symptomatic de novo heterozygous female.
  - reference: PMID:36536324
    reference_title: A female case with novel KDM5C heterozygous variation presenting
      with Claes-Jensen type-like phonotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-chromosome inactivation (XCI) analysis showed no significant skewed X-inactivation."
    explanation: Shows that skewed XCI is not required for female manifestation.
inheritance:
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >
    This is the authoritative HPO/OMIM inheritance annotation and correctly
    describes the hemizygous male situation: males carrying a pathogenic KDM5C
    allele are affected in essentially all reported instances. The classical
    multiplex XLMR families through which the gene was discovered were
    maternally transmitted. Contemporary trio-based ascertainment has shifted
    the picture substantially, with de novo variants now the majority mode. See
    the companion X-linked inheritance block for the female-manifestation
    caveat, which this recessive label does not capture.
  evidence:
  - reference: PMID:15586325
    reference_title: Mutations in the JARID1C gene, which is involved in transcriptional
      regulation and chromatin remodeling, cause X-linked mental retardation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In families with nonsyndromic X-linked mental retardation (NS-XLMR), >30% of mutations seem to cluster on proximal Xp and in the pericentric region."
    explanation: Situates the gene within X-linked intellectual disability discovered
      through X-linked pedigrees.
  - reference: PMID:25666439
    reference_title: Mutations in the intellectual disability gene KDM5C reduce protein
      stability and demethylase activity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in KDM5C are an important cause of X-linked intellectual disability in males."
    explanation: Confirms the male-predominant X-linked transmission.
- name: X-linked inheritance with manifesting heterozygous females
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >
    Heterozygous females are frequently affected, which the strict recessive
    label does not convey. Contemporary series report intellectual disability or
    learning disability in a majority of heterozygous females, predominantly
    mild, with behavioural disturbance common and endocrine problems more
    frequent than in males. A minority of heterozygotes are wholly asymptomatic.
    The mechanistic basis is that KDM5C escapes X-inactivation, so females
    normally express it from both X chromosomes and carry a higher baseline
    dose; heterozygosity therefore produces a partial rather than an all-or-none
    dose reduction. Skewed X-inactivation is an incomplete explanation - a
    symptomatic de novo female with no significant XCI skewing is documented.
    This has direct counselling consequences: a female fetus inheriting the
    familial variant cannot be described as an unaffected carrier.
  evidence:
  - reference: PMID:32279304
    reference_title: 'Further delineation of the female phenotype with KDM5C disease
      causing variants: 19 new individuals and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four heterozygous females were asymptomatic."
    explanation: Documents that only a minority of the 19 heterozygous females were
      unaffected.
  - reference: PMID:32279304
    reference_title: 'Further delineation of the female phenotype with KDM5C disease
      causing variants: 19 new individuals and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our findings provide evidence of the role of KDM5C in ID in females highlighting the increasing implication of XLID genes in females, even in sporadic affected individuals"
    explanation: Establishes female manifestation as a genuine part of the disease
      spectrum.
  - reference: PMID:36831303
    reference_title: Sexually Dimorphic Alterations in the Transcriptome and Behavior
      with Loss of Histone Demethylase KDM5C.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Initially, MRXSCJ was exclusively reported in males, while it is increasingly evident that females with heterozygous KDM5C mutations can show cognitive deficits."
    explanation: States the historical male-only framing and its correction. Tagged
      OTHER because this is a literature-summary statement inside a mouse study, not
      human data generated by that paper.
  - reference: PMID:36831303
    reference_title: Sexually Dimorphic Alterations in the Transcriptome and Behavior
      with Loss of Histone Demethylase KDM5C.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KDM5C escapes X-inactivation, thereby presenting at a higher level in females."
    explanation: Provides the dosage mechanism underlying the sex-biased severity.
      Tagged OTHER because this is an established gene-biology statement cited as
      background, not a result generated by the mouse experiments in that paper.
  - reference: PMID:36831303
    reference_title: Sexually Dimorphic Alterations in the Transcriptome and Behavior
      with Loss of Histone Demethylase KDM5C.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we report that gene expression and behavioral abnormalities are readily detectable in Kdm5c-heterozygous female mice, demonstrating the requirement for a higher KDM5C dose in females"
    explanation: Mouse heterozygote data corroborate the human female-manifestation
      finding.
  - reference: PMID:36434256
    reference_title: 'Expanding the genetics and phenotypic spectrum of Lysine-specific
      demethylase 5C (KDM5C): a report of 13 novel variants.'
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort."
    explanation: Supports X-inactivation as one modulator of female expression, though
      not a complete explanation.
  - reference: PMID:36553533
    reference_title: 'Expanding the Spectrum of KDM5C Neurodevelopmental Disorder:
      A Novel De Novo Stop Variant in a Young Woman and Emerging Genotype-Phenotype
      Correlations.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We hereby describe a twenty-seven-year-old female patient diagnosed with moderate intellectual disability comorbid with other neuropsychiatric and behavioral issues carrying a de novo heterozygous stop variant in the KDM5C gene"
    explanation: An adult female with a de novo heterozygous truncating variant and
      moderate intellectual disability, showing female manifestation is not confined
      to inherited or childhood cases.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >
    No population-based prevalence or incidence estimate exists. The disorder is
    quantified in the literature only as a share of X-linked intellectual
    disability cases (see Genetic.case_fractions), not as a population rate. The
    largest aggregation is the RARE-X meta-analysis, which reached 269
    individuals across 130 families and 122 unique variants. Reported cases come
    from Europe, the Americas, the Middle East and East Asia with no founder
    effect or geographic clustering; apparent geography reflects exome-sequencing
    access.
  evidence:
  - reference: PMID:41537560
    reference_title: Individuals with reported and novel KDM5C variants present with
      seizures, a feature recapitulated in a Drosophila model.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants that disrupt the function of the chromatin regulator KDM5C cause a rare neurodevelopmental disorder (KDM5C-NDD)"
    explanation: Confirms rarity; no population rate is reported in the literature.
diagnosis:
- name: Trio Exome or Genome Sequencing
  description: >
    Molecular diagnosis is the definitive test; there are no formal clinical
    diagnostic criteria for this disorder and the phenotype is not specific
    enough to be distinguished clinically from other X-linked intellectual
    disability. Trio-based exome or genome sequencing is first-line for
    unexplained global developmental delay, and the trio design matters because
    de novo variants are now the majority mode. Chromosomal microarray covers
    the small Xp11.22 microdeletion fraction. Synonymous and splice-region
    variants can be pathogenic through splicing effects, so RNA studies should
    be considered before dismissing a segregating variant of this type.
  evidence:
  - reference: PMID:39835750
    reference_title: 'Clinical Features and Genetic Characteristics of XLID Patients
      With KDM5C Gene Mutations: Insights on Phenotype-Genotype Correlations From
      175 Previous Cases and Identification of a Novel Variant.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study identified a novel variant, c.2704C>T:p.Gln902X, located in exon 19 of the KDM5C gene (NM_004187.5) using Whole exome sequencing (WES), highlighting the utility of this approach in identifying rare genetic disorders."
    explanation: Demonstrates whole-exome sequencing as the diagnostic modality in
      practice.
- name: Peripheral Blood DNA Methylation Episignature
  description: >
    Claes-Jensen syndrome has a validated peripheral-blood DNA methylation
    episignature comprising 1769 CpGs and 9 genomic regions, derived from 7
    affected males against 56 matched controls. Healthy heterozygous female
    carriers show intermediate, distinguishable changes, so the assay identifies
    carriers as well as patients. Its principal clinical use is resolving
    variants of uncertain significance and confirming carrier status. The
    reported 100% accuracy figures come from a 7-patient training cohort and
    reflect specificity against large control sets more than sensitivity across
    the full allelic spectrum; independent multicentre work has shown published
    episignatures perform very unequally, so this performance should not be
    generalised.
  evidence:
  - reference: PMID:29456765
    reference_title: Peripheral blood epi-signature of Claes-Jensen syndrome enables
      sensitive and specific identification of patients and healthy carriers with
      pathogenic mutations in KDM5C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genome-wide DNA methylation analysis of 7 male patients affected with Claes-Jensen syndrome and 56 age- and sex-matched controls identified a specific DNA methylation defect (epi-signature) in the peripheral blood of these patients, including 1769 individual CpGs and 9 genomic regions."
    explanation: Defines the episignature and the cohort it was derived from.
  - reference: PMID:29456765
    reference_title: Peripheral blood epi-signature of Claes-Jensen syndrome enables
      sensitive and specific identification of patients and healthy carriers with
      pathogenic mutations in KDM5C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six healthy female carriers showed less pronounced but distinctive changes in the same regions enabling their differentiation from both patients and controls."
    explanation: Establishes carrier detection capability.
  - reference: PMID:29456765
    reference_title: Peripheral blood epi-signature of Claes-Jensen syndrome enables
      sensitive and specific identification of patients and healthy carriers with
      pathogenic mutations in KDM5C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peripheral blood epi-signature in Claes-Jensen syndrome can be used for molecular diagnosis and carrier identification and assist with interpretation of genetic variants of unknown clinical significance in the KDM5C gene."
    explanation: States the intended clinical applications.
differential_diagnoses:
- name: Wiedemann-Steiner syndrome
  disease_term:
    preferred_term: Wiedemann-Steiner syndrome
    term:
      id: MONDO:0011518
      label: Wiedemann-Steiner syndrome
  description: >
    The mechanistic mirror image of this disorder: KMT2A writes the same H3K4
    methyl mark that KDM5C erases, and the two mouse models share reduced
    dendritic spines and increased aggression. Because KMT2A is frequently
    discussed in KDM5C mechanism papers, this pairing is a recognised source of
    entity confusion; the two are distinct diseases with distinct genes, and a
    KDM5C entry must not absorb Wiedemann-Steiner content.
  distinguishing_features:
  - Caused by autosomal dominant KMT2A variants, not X-linked KDM5C variants
  - Hypertrichosis cubiti and a distinct facial gestalt
  - No sex-biased severity, unlike the male-predominant severity of Claes-Jensen type
  evidence:
  - reference: PMID:32483278
    reference_title: 'Mutually suppressive roles of KMT2A and KDM5C in behaviour,
      neuronal structure, and histone H3K4 methylation.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we show functional interactions of a writer-eraser duo, KMT2A and KDM5C, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively"
    explanation: Explicitly separates the two gene-disease pairs while documenting
      their mechanistic relationship.
- name: Fragile X syndrome
  disease_term:
    preferred_term: fragile X syndrome
    term:
      id: MONDO:0010383
      label: fragile X syndrome
  description: >
    The most common inherited cause of intellectual disability in males and a
    routine exclusion in any X-linked intellectual disability work-up. The
    testicular finding usefully discriminates: macroorchidism is characteristic
    of fragile X, whereas decreased testicular size is the annotated finding in
    Claes-Jensen type.
  distinguishing_features:
  - CGG repeat expansion in FMR1 rather than a KDM5C sequence variant
  - Macroorchidism, in contrast to decreased testicular size in Claes-Jensen type
  - Long face and large ears
  - Requires repeat-expansion testing rather than sequencing
treatments:
- name: Multidisciplinary Supportive and Developmental Care
  description: >
    There is no disease-modifying therapy, no approved drug, no gene therapy and
    no interventional clinical trial for this disorder. Management is entirely
    symptomatic and supportive, centred on early developmental intervention and
    coordinated multidisciplinary follow-up covering development, growth,
    seizures, vision, behaviour, mobility and bowel function.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:34089235
    reference_title: Caregiver-reported characteristics of children diagnosed with
      pathogenic variants in KDM5C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As a rare disorder, its etiology and natural history remain an area of active investigation, with treatment limited to symptom management."
    explanation: States directly that treatment is limited to symptom management.
- name: Speech and Language Therapy
  description: >
    Speech and language impairment is near-universal and expressive language is
    disproportionately affected, so early speech therapy with augmentative and
    alternative communication where needed is a core intervention.
  treatment_term:
    preferred_term: Speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:32279304
    reference_title: 'Further delineation of the female phenotype with KDM5C disease
      causing variants: 19 new individuals and review of the literature.'
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "four also had a language impairment mainly affecting expression"
    explanation: Documents the expressive language impairment this intervention targets;
      no trial evidence exists for the intervention itself in this disorder.
- name: Physical Therapy and Spasticity Management
  description: >
    Physiotherapy, stretching and orthotics target the spasticity, hyperreflexia
    and progressive spastic paraplegia seen in a subset, aiming to preserve gait
    and prevent contractures. Pharmacological adjuncts used in general practice
    include baclofen and botulinum toxin; there is no disorder-specific evidence
    base for either.
  treatment_term:
    preferred_term: Physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:10982473
    reference_title: Novel syndromic form of X-linked complicated spastic paraplegia.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "slowly progressive spastic paraplegia"
    explanation: Documents the progressive motor target of this intervention; the
      intervention itself is standard practice, not disorder-specific evidence.
- name: Antiseizure Pharmacotherapy
  description: >
    Standard antiseizure medication selected by seizure semiology. Seizures
    affect roughly a third to a half of individuals with a median first-seizure
    age of about 2 years, so EEG at diagnosis and ongoing seizure review are
    indicated. No disorder-specific antiseizure agent or regimen has been
    studied; there is no evidence favouring any particular drug in KDM5C-related
    disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  target_mechanisms:
  - target: Neuronal Hyperexcitability and Seizure Substrate
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:41537560
    reference_title: Individuals with reported and novel KDM5C variants present with
      seizures, a feature recapitulated in a Drosophila model.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "seizures are a frequent feature in both hemizygous males and heterozygous females with KDM5C variants, with over a third of individuals reporting at least one seizure"
    explanation: Establishes the seizure burden that justifies antiseizure therapy;
      no trial evidence exists for any specific agent in this disorder.
- name: Ophthalmological Assessment and Correction
  description: >
    Formal ophthalmological examination at diagnosis and periodically thereafter.
    Strabismus and abnormal eye movements are common and frequently
    under-recognised, and untreated strabismus carries a preventable amblyopia
    risk, making this one of the highest-yield underused assessments in the
    disorder. Management is refractive correction and, where indicated,
    strabismus surgery.
  treatment_term:
    preferred_term: Surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:40125771
    reference_title: 'Atypical Ophthalmological Manifestations of Claes-Jensen Syndrome
      Without Intellectual Disability: A Case Report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This atypical presentation highlights the importance of ophthalmological assessments in X-linked syndromes with variable expressivity, even without classic features."
    explanation: Explicit recommendation for ophthalmological assessment in this disorder.
- name: Behavioural Support and Psychotropic Management
  description: >
    Behavioural intervention is first-line for the aggression, impulsivity,
    anxiety and autism-spectrum features that caregivers consistently rate as
    the greatest burden, with psychotropic medication reserved for when
    behavioural approaches are insufficient. Polypharmacy is a recognised
    iatrogenic risk in this population.
  treatment_term:
    preferred_term: Behavioral counseling
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  - preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:34089235
    reference_title: Caregiver-reported characteristics of children diagnosed with
      pathogenic variants in KDM5C.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "more than half of individuals reported a diagnosis of autism spectrum disorder or described features consistent with this spectrum"
    explanation: Quantifies the behavioural burden this intervention targets; the
      intervention itself is standard practice.
- name: Genetic Counseling and Cascade Testing
  description: >
    Counselling must be updated for current evidence. De novo variants are now
    the majority mode, so recurrence risk in an apparently sporadic family is far
    lower than the classic X-linked-recessive family framing implies (with an
    empiric allowance for gonadal mosaicism). Crucially, a daughter who inherits
    the familial variant cannot be counselled as an unaffected carrier: a
    majority of heterozygous females have learning disability or intellectual
    disability, and a substantial minority have seizures. Cascade testing of
    at-risk female relatives is therefore both a reproductive and a diagnostic
    intervention. The DNA methylation episignature independently identifies
    carriers. Prenatal diagnosis and preimplantation genetic testing are
    available once the familial variant is known.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:32279304
    reference_title: 'Further delineation of the female phenotype with KDM5C disease
      causing variants: 19 new individuals and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease expression of XLID in females should be taken into consideration for genetic counseling."
    explanation: Direct recommendation that female disease expression change counselling
      practice.
  - reference: PMID:29456765
    reference_title: Peripheral blood epi-signature of Claes-Jensen syndrome enables
      sensitive and specific identification of patients and healthy carriers with
      pathogenic mutations in KDM5C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "can be used for molecular diagnosis and carrier identification"
    explanation: Supports episignature-based carrier identification as an adjunct
      to cascade testing.
animal_models:
- species: Mus musculus
  genotype: Kdm5c knockout (constitutive and forebrain-restricted inducible)
  category: KNOCKOUT
  description: >
    The primary mammalian model. Hemizygous Kdm5c-knockout males recapitulate
    the core adaptive and cognitive phenotype - impaired social behaviour, memory
    deficits and aggression - together with abnormal dendritic arborisation,
    spine anomalies and altered transcriptomes, while adult brain cytoarchitecture
    remains grossly normal. Heterozygous females also show detectable gene
    expression and behavioural abnormalities, mirroring the human
    manifesting-heterozygote finding. Forebrain-restricted inducible knockouts
    separate the developmental silencing role from the lifelong genome
    surveillance role.
  evidence:
  - reference: PMID:26804915
    reference_title: A Mouse Model of X-linked Intellectual Disability Associated
      with Impaired Removal of Histone Methylation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "our mouse behavioral data strongly suggest that KDM5C mutations are causal to XLID"
    explanation: The authors' conclusion that the model supports causality.
  - reference: PMID:36831303
    reference_title: Sexually Dimorphic Alterations in the Transcriptome and Behavior
      with Loss of Histone Demethylase KDM5C.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The mouse model of MRXSCJ, male Kdm5c-hemizygous knockout animals, recapitulates key features of human male patients."
    explanation: Confirms face validity of the male hemizygous mouse model.
- species: Drosophila melanogaster
  genotype: kdm5 A512P knock-in and neuronal kdm5 knockdown
  category: KNOCKIN
  description: >
    Drosophila carries a single Kdm5 gene, making it a clean system for
    dissecting demethylase-dependent effects. A knock-in allele analogous to a
    human KDM5C disease missense variant produces impaired learning and memory
    with downregulation of ribosomal assembly genes and reduced translation.
    Separately, neuronal but not glial knockdown produces spontaneous and
    stimulus-induced seizures, establishing the cell-autonomous neuronal
    requirement. The ribosome/translation arm has not been demonstrated in
    mammals.
  evidence:
  - reference: PMID:29490272
    reference_title: A Drosophila Model of Intellectual Disability Caused by Mutations
      in the Histone Demethylase KDM5.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transcriptome analysis of kdm5A512P flies revealed a striking downregulation of genes required for ribosomal assembly and function and a concomitant reduction in translation."
    explanation: Documents the translation phenotype in the fly disease-allele model.
  - reference: PMID:29490272
    reference_title: A Drosophila Model of Intellectual Disability Caused by Mutations
      in the Histone Demethylase KDM5.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "kdm5A512P flies also showed impaired learning and/or memory."
    explanation: Cognitive face validity of the fly model.
discussions:
- discussion_id: kdm5c_female_penetrance_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What determines whether a heterozygous KDM5C female is affected, given that
    skewed X-inactivation does not reliably explain it?
  attaches_to:
  - pathophysiology#Loss of KDM5C H3K4me3/me2 Demethylase Function
  rationale: >
    Skewed X-inactivation is the conventional explanation for variable
    expression in X-linked disease, but it is a poor fit here. KDM5C escapes
    X-inactivation, so the inactive-X allele still contributes, and a
    symptomatic de novo female with no significant XCI skewing is documented.
    Meanwhile X-inactivation pattern did correlate with phenotypic expression in
    another cohort. Without a mechanism, counselling for a female fetus carrying
    a familial variant cannot be individualised beyond a population-level
    probability.
  proposed_experiments:
  - experiment_id: xci_allele_specific_expression
    name: Allele-specific KDM5C expression versus XCI in heterozygous females
    description: >
      Quantify allele-specific KDM5C expression in accessible tissues from
      affected versus unaffected heterozygous females, paired with a
      quantitative X-chromosome inactivation assay, to test whether residual
      KDM5C dose rather than XCI pattern predicts phenotype.
    decision_criterion: >
      Allele-specific KDM5C expression separates affected from unaffected
      heterozygotes more cleanly than the XCI ratio does.
    would_support:
    - KDM5C dose, not XCI skewing per se, determines female manifestation.
    would_refute:
    - XCI skewing remains the dominant determinant and the escape-from-XCI argument is not phenotypically relevant.
  - experiment_id: xci_single_cell_mosaic
    name: Single-cell profiling of heterozygous female patient-derived neurons
    description: >
      Single-cell transcriptomic profiling of patient-derived neurons from
      heterozygous females to test whether mosaic cell-by-cell KDM5C dose,
      rather than tissue-average dose, predicts the phenotype.
    decision_criterion: >
      The fraction of neurons falling below a KDM5C expression threshold
      correlates with clinical severity better than mean expression.
    would_support:
    - A cellular-mosaic threshold model of female manifestation.
    would_refute:
    - A simple average-dose model of female manifestation.
  evidence:
  - reference: PMID:36536324
    reference_title: A female case with novel KDM5C heterozygous variation presenting
      with Claes-Jensen type-like phonotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-chromosome inactivation (XCI) analysis showed no significant skewed X-inactivation."
    explanation: A symptomatic heterozygous female without XCI skewing shows the conventional
      explanation is insufficient.
  - reference: PMID:36434256
    reference_title: 'Expanding the genetics and phenotypic spectrum of Lysine-specific
      demethylase 5C (KDM5C): a report of 13 novel variants.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort."
    explanation: A contrary cohort finding in which XCI pattern did track phenotypic
      expression, making this an unresolved conflict rather than a settled question.
- discussion_id: kdm5c_wnt_window_translatability
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Is the WNT-dependent developmental window that permits phenotypic rescue
    in Kdm5c-knockout mice still open at the age at which human patients are diagnosed?
  attaches_to:
  - pathophysiology#Mistimed Canonical WNT Signalling and Progenitor Transition
  rationale: >
    The rescue result is strong but window-bounded: only transient WNT
    modulation during a specific developmental period rescues transcriptomic,
    chromatin and behavioural phenotypes. In humans, KDM5C-related disease is
    typically diagnosed postnatally after developmental delay becomes apparent,
    by which time the corticogenesis window that the mouse experiment targets
    has almost certainly closed. Whether any residual window exists in humans,
    and whether the mouse window maps onto a human developmental stage at all,
    is unresolved and determines whether this mechanism is therapeutically
    reachable or only explanatory.
  proposed_experiments:
  - experiment_id: wnt_window_organoid_mapping
    name: Map the human WNT-sensitive window in cortical organoids
    description: >
      Define the developmental interval during which WNT modulation rescues
      transcriptomic and chromatin phenotypes in KDM5C patient-derived human
      cortical organoids, and align it against the equivalent mouse
      corticogenesis stages.
    decision_criterion: >
      A WNT-sensitive interval is identifiable in human organoids and can be
      mapped onto a defined human gestational stage.
    would_support:
    - The mouse rescue window has a definable human counterpart.
    would_refute:
    - The rescue window is a mouse-specific developmental feature without a human analogue.
  - experiment_id: wnt_postnatal_modulation
    name: Postnatal-equivalent WNT modulation in Kdm5c-knockout mice
    description: >
      Test whether WNT modulation delivered after the previously defined
      embryonic window confers any partial behavioural or transcriptomic
      benefit in Kdm5c-knockout mice.
    decision_criterion: >
      Any statistically significant behavioural improvement after postnatal
      dosing relative to vehicle.
    would_support:
    - A residual therapeutic window exists after the age at which human diagnosis is realistic.
    would_refute:
    - The mechanism is explanatory only and not therapeutically reachable postnatally.
  evidence:
  - reference: PMID:38383780
    reference_title: WNT signalling control by KDM5C during development affects cognition.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "only a transient alteration of the canonical WNT signalling pathway is sufficient to rescue the transcriptomic and chromatin landscapes in patient-derived cells"
    explanation: The rescue is explicitly time-restricted, which is precisely what
      makes human translatability uncertain.
- discussion_id: kdm5c_single_cell_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which specific neuronal subtypes and brain regions mediate the cognitive
    and behavioural phenotype of KDM5C loss?
  attaches_to:
  - pathophysiology#Reduced Dendritic Arborisation and Spine Density
  rationale: >
    Mouse data show strongly region-specific consequences, with the amygdala
    considerably more affected than the frontal cortex in both transcriptome and
    dendritic morphology. No single-cell or spatial transcriptomic dataset
    specific to this disorder has been published, so the cell types that
    actually mediate the phenotype remain inferred rather than identified. This
    limits both mechanistic understanding and the design of any cell-type-directed
    therapy.
  proposed_experiments:
  - experiment_id: kdm5c_snrnaseq_spatial_atlas
    name: Single-nucleus and spatial transcriptomics of Kdm5c-knockout brain
    description: >
      Single-nucleus RNA-seq and spatial transcriptomics across amygdala,
      hippocampus and cortex in Kdm5c-knockout versus wild-type mice at
      multiple developmental stages, to identify which neuronal subtypes carry
      the transcriptional lesion.
    decision_criterion: >
      One or a small number of neuronal subtypes account for the majority of
      differentially expressed genes.
    would_support:
    - A cell-type-restricted mechanism amenable to targeted intervention.
    would_refute:
    - A pan-neuronal mechanism with no privileged cell-type target.
  - experiment_id: kdm5c_celltype_conditional_ko
    name: Cell-type-restricted conditional Kdm5c deletion
    description: >
      Conditional Kdm5c deletion restricted to defined excitatory and
      inhibitory neuronal subtypes to test which population is sufficient to
      produce the behavioural phenotype.
    decision_criterion: >
      Deletion in a single defined subtype reproduces the social, memory or
      aggression phenotype of the global knockout.
    would_support:
    - Sufficiency of a specific neuronal population for the behavioural phenotype.
    would_refute:
    - A requirement for distributed loss across multiple neuronal populations.
  evidence:
  - reference: PMID:26804915
    reference_title: A Mouse Model of X-linked Intellectual Disability Associated
      with Impaired Removal of Histone Methylation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "our findings suggest that loss of KDM5C function may impact gene expression in multiple regulatory pathways relevant to the clinical phenotypes"
    explanation: The authors themselves leave open which pathways and cell types are
      the operative ones.

📚

References & Deep Research

References

3

PMID:41537560

Individuals with reported and novel KDM5C variants present with seizures, a feature recapitulated in a Drosophila model.

No top-level findings curated for this source.

PMID:32279304

Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature.

No top-level findings curated for this source.

PMID:15586325

Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Comprehensive Research Report

claude-haiku-4-5-20251001, claude-opus-5[1m] 2026-07-31T18:44:52.713823

Comprehensive Research Report

Claes–Jensen Type X‑Linked Intellectual Disability (MRXSCJ)

Prepared: 2026‑07‑31 · Target for: dismech KB entry kb/disorders/Claes-Jensen_Type_X-Linked_Intellectual_Disability.yaml

⚠️ Curation Preamble — Read Before Using This Report

1. Named Entity Confusion (NEC) preflight — PASSED. This disease sits in two high‑NEC‑risk classes (eponymic XLID syndrome; member of a numbered MRXS/MRXSCJ series). Identity was cross‑anchored on four independent sources before any content was gathered:

Anchor	Value	Source
MONDO	`MONDO:0010355` "syndromic X-linked intellectual disability Claes-Jensen type"	EBI OLS4 API (MONDO)
OMIM xref	`OMIM:300534` (MRXSCJ)	OLS4 MONDO xrefs; MedGen 335139; HPO/JAX annotation API
Causal gene	KDM5C (Xp11.22), `hgnc:11114`, `NCBIGene:8242`	HPO/JAX annotation API; ClinGen; MedGen
Orphanet	`ORPHA:85279` "KDM5C-related syndromic X-linked intellectual disability"	OLS4 (ORDO); MedGen

All four agree on gene = KDM5C. No mismatch. Other xrefs: DOID:0060809, UMLS:C1845243, MedGen:335139, GARD:0016744.

2. Snippet-verification caveat — MANDATORY. Abstracts in this report were retrieved via the NCBI E‑utilities efetch endpoint but were passed through a summarizing model, which imposes a ~125‑character quote ceiling. The quoted strings below are candidate snippets, not verified snippets. Before any of them is committed as a dismech evidence.snippet, run:

just fetch-reference PMID:XXXXXXXX
just validate-references kb/disorders/Claes-Jensen_Type_X-Linked_Intellectual_Disability.yaml

Likewise, every non‑HPO ontology ID suggested here (GO, CL, UBERON, CHEBI, NCIT) is a candidate and must pass just validate-terms. HPO terms in §3 are exceptions — they were pulled directly from the authoritative HPO/JAX annotation API for OMIM:300534 and carry real annotation frequencies.

3. Environment note. The MCP pubmed and ols-mcp servers and local runoak were not permission‑granted in this non‑interactive run; all data came from direct API fetches (NCBI E‑utilities, EBI OLS4 REST, HPO/JAX API, ClinGen, UniProt REST, MGI, PMC). Section 9 prevalence is consequently thinner than ideal — Orphanet's epidemiology table (API 401 / site bot‑walled) could not be read and should be filled in from the local ORPHA_85279 cache via just structured-rebuild-orphanet --id 85279.

1. Disease Information

Overview

Claes–Jensen type syndromic X‑linked intellectual disability (MRXSCJ) is a rare X‑linked chromatinopathy caused by loss‑of‑function variants in KDM5C (Xp11.22), encoding the histone H3 lysine‑4 di‑/tri‑methyl (H3K4me2/me3) demethylase JARID1C/SMCX. It is one of the more frequently mutated single genes in X‑linked intellectual disability (XLID).

The core clinical picture in hemizygous males is intellectual disability (usually moderate–severe) with short stature, microcephaly, hyperreflexia/spasticity, seizures, maxillary hypoplasia, and aggressive or disinhibited behaviour. Heterozygous females — historically dismissed as "carriers" — are now recognised to be affected far more often than the "X‑linked recessive" label implies, though more mildly.

Orphanet's definition (ORDO:85279):

"A rare multiple congenital anomalies/dysmorphic syndrome characterized by mild to severe intellectual deficit associated with variable clinical manifestations including spasticity, cryptorchidism, maxillary hypoplasia, alopecia areata, epilepsy, short stature, impaired speech, and behavioral problems."

Key Identifiers

Resource	Identifier
MONDO	`MONDO:0010355`
OMIM	`300534` (MRXSCJ); gene `314690` (KDM5C)
Orphanet	`ORPHA:85279`
Disease Ontology	`DOID:0060809`
UMLS / MedGen	`C1845243` / `335139`
GARD	`0016744`
Gene	KDM5C — `hgnc:11114`, `NCBIGene:8242`, `Ensembl:ENSG00000126012`, `UniProt:P41229`
ICD‑10	No specific code; coded under F79 (unspecified intellectual disabilities) or Q87.8; ICD‑11 ≈ LD90.Y / 6A00.Z (no dedicated rubric)
MeSH	No dedicated descriptor; indexed under Mental Retardation, X-Linked / Intellectual Disability

Synonyms and Alternative Names

From OLS4 (MONDO) and MedGen: - Intellectual developmental disorder, X‑linked syndromic, Claes‑Jensen type - MRXSCJ, MRXSJ - Intellectual developmental disorder, X‑linked, syndromic 16 (MRXS16) - KDM5C‑related syndromic X‑linked intellectual disability (Orphanet preferred) - Claes‑Jensen syndrome (CJS) — used widely in recent literature - KDM5C‑NDD (KDM5C neurodevelopmental disorder) — the emerging, sex‑neutral, non‑eponymic term preferred by the 2026 RARE‑X cohort (PMID:41537560) - Historic/discouraged: "Mental retardation, X‑linked, syndromic, Claes‑Jensen type"; "…JARID1C‑related"; XLMR with short stature and hyperreflexia

Nomenclature recommendation for the KB entry: keep MONDO:0010355 as disease_term, but consider KDM5C-Related Neurodevelopmental Disorder in the description as the modern label, since the eponym encodes an outdated male‑only, recessive framing that the female data (§3, §9) refute.

Data Provenance Character

Information is aggregated disease‑level (OMIM, Orphanet, MONDO, HPO annotations, ClinGen) layered over individual‑patient case series. There is no EHR‑derived cohort. The two largest patient‑level aggregations are: - PMID:41537560 (Terry et al., Hum Mol Genet 2026) — the RARE‑X KDM5C Data Collection Program, a patient‑contributed registry (caregiver survey), 31 new individuals + literature meta‑analysis to 269 individuals / 130 families / 122 unique variants. This is the closest thing to a natural‑history dataset and is patient‑reported, not clinician‑abstracted. - PMID:39835750 (Ghasemi et al., Mol Genet Genomic Med 2025) — systematic literature review of 175 previously reported cases + 1 novel variant.

2. Etiology

Disease Causal Factors

Monogenic, genetic, fully penetrant in males. MRXSCJ is caused by germline loss‑of‑function variants in KDM5C. There is no infectious, environmental, or multifactorial component to disease causation. ClinGen's Intellectual Disability and Autism GCEP classified the KDM5C ↔ X‑linked syndromic intellectual disability relationship as Definitive (2018‑09‑19), inheritance X‑linked.

The causal chain is: KDM5C LoF → reduced/absent H3K4me2/me3 demethylase activity (± loss of non‑enzymatic scaffolding) → failure to restrain H3K4 trimethylation at CpG‑island promoters and enhancers → derepression of non‑neuronal, germline and cryptic transcriptional programs plus mistimed WNT signalling during corticogenesis → abnormal neuronal differentiation, dendritic arborisation and spine maturation → intellectual disability, seizures, behavioural phenotype.

Risk Factors

Genetic (causal, not "susceptibility"): - Hemizygosity for a pathogenic KDM5C variant in a 46,XY individual → essentially complete penetrance for ID (98% of males in meta‑analysis, PMID:41537560). - Heterozygosity in a 46,XX individual → incomplete, variable penetrance (56% with ID in meta‑analysis; 4/19 completely asymptomatic in Carmignac et al., PMID:32279304). - Being male is the single largest risk factor for severe expression. This is not merely dosage: KDM5C escapes X‑inactivation, so females normally express KDM5C from both X chromosomes and carry a higher baseline dose (Agulnik et al., PMID:7951230; Bonefas & Iwase, PMID:36831303 — "KDM5C escapes X-inactivation, thereby presenting at a higher level in females"). - Maternal carrier status (~10% of RARE‑X probands maternally inherited; historically the dominant mode in multiplex families). - De novo occurrence — >50% of the RARE‑X cohort; paternal inheritance rare (~1%). - Domain location of the variant is a severity/phenotype modifier: "Patients with mutated variants in the catalytic domain were more likely to experience seizures" (PMID:39835750).

Environmental: No established environmental risk factors. Advanced paternal age is a generic risk for de novo point mutation but has not been specifically demonstrated for KDM5C.

Protective Factors

Favourably skewed X‑chromosome inactivation in heterozygous females is the classic candidate protective mechanism — but the evidence is inconsistent. Shen et al. (PMID:36536324) documented a symptomatic female with a de novo nonsense variant and explicitly "no significant skewed X-inactivation," and Carmignac et al. found asymptomatic and symptomatic females without a clean XCI correlate. Because KDM5C escapes XCI, XCI skewing is an incomplete explanatory model — this is a genuine open question worth curating as a KNOWLEDGE_GAP discussion.
Residual enzymatic activity. Ghasemi et al. propose that "Missense mutations in catalytic domains may retain partial enzymatic activity, potentially producing milder phenotypes than nonsense mutations" (PMID:39835750). The R1115H variant is the extreme case — normal catalytic activity and stability, yet still pathogenic via a non‑enzymatic route (PMID:29670509).
KMT2A dosage reduction — experimental, model‑organism only. Vallianatos et al. showed genetic epistasis: "Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits" (PMID:32483278). This is a mouse result; it is a therapeutic hypothesis, not a human protective factor.
No dietary, lifestyle, or nutritional protective factor is described.

Gene–Environment Interactions

Not established for MRXSCJ. Two leads worth flagging as hypotheses: 1. Illness as a decompensation trigger. Shaheen et al. (PMID:40346491) report developmental regression with loss of ambulation "following acute viral illness at 22 months." A single case — insufficient to assert a G×E interaction, but a candidate for a HUMAN_MODEL_MISMATCH/KNOWLEDGE_GAP note. 2. Immune/interferon axis. Liao et al. (PMID:41743791) found KDM5C‑mutant zebrafish have "disrupted antiviral and interferon-related signaling," raising the possibility that infectious exposure interacts with the KDM5C lesion. Zebrafish only; unreplicated in humans. 3. Upstream regulatory interaction with ARX is gene–gene, not gene–environment: "KDM5C, a gene known to be mutated in XLID-affected children and involved in chromatin remodeling, is directly regulated by ARX" (Poeta et al., PMID:23246292). ARX polyalanine expansions are hypomorphic for KDM5C transactivation — a shared regulatory path to ID+epilepsy.

3. Phenotypes

3.1 Authoritative HPO Annotations (HPO/JAX API, `OMIM:300534`)

These are the canonical, real HPO annotations with real observed fractions. n/m = affected/assessed. Use these fractions to justify any frequency: enum you assign (per docs/frequency-evidence-guidelines.md) — but note that most fractions come from small early cohorts and are superseded for common features by the 2025–2026 cohorts in §3.2.

Neurological / cognitive

HPO ID	Term	Annotated frequency
HP:0001249	Intellectual disability	25/26
HP:0010864	Severe intellectual disability	8/8
HP:0001263	Global developmental delay	3/3
HP:0000750	Delayed speech and language development	3/3
HP:0001270	Motor delay	3/3
HP:0001250	Seizure	8/35
HP:0032792	Tonic seizure	1/3
HP:0001347	Hyperreflexia	3/6
HP:0002395	Lower limb hyperreflexia	—
HP:0001257	Spasticity	7/20
HP:0007020	Progressive spastic paraplegia	—
HP:0003487	Babinski sign	—
HP:0006895	Lower limb hypertonia	—
HP:0000297	Facial hypotonia	—
HP:0002362	Shuffling gait	—
HP:0008944	Distal lower limb amyotrophy	—
HP:0007021	Pain insensitivity	2/20

Behavioural

HPO ID	Term	Frequency
HP:0000718	Aggressive behavior	13/38
HP:0000752	Hyperactivity	3/3
HP:0000711	Restlessness	—
HP:0000744	Low frustration tolerance	—

Growth

HPO ID	Term	Frequency
HP:0004322	Short stature	13/18
HP:0001508	Failure to thrive	3/3
HP:0004325	Decreased body weight	3/3

Craniofacial

HPO ID	Term	Frequency
HP:0000252	Microcephaly	7/20
HP:0000256	Macrocephaly	2/20
HP:0000327	Hypoplasia of the maxilla	7/23
HP:0000218	High palate	6/12
HP:0000699	Diastema	6/22
HP:0000303	Mandibular prognathia	2/20
HP:0000347	Micrognathia	1/20
HP:0000221	Furrowed tongue	2/2
HP:0000426	Prominent nasal bridge	2/6
HP:0000319	Smooth philtrum	1/20
HP:0000219	Thin upper lip vermilion	1/20
HP:0000350	Small forehead	1/20
HP:0000574	Thick eyebrow	1/6
HP:0000582	Upslanted palpebral fissure	1/20
HP:0000400	Macrotia	2/2
HP:0000411	Protruding ear	3/6

Ophthalmological

HPO ID	Term	Frequency
HP:0000486	Strabismus	11/29
HP:0000540	Hypermetropia	3/20
HP:0000545	Myopia	1/20
HP:0000490	Deeply set eye	1/20

Genitourinary

HPO ID	Term	Frequency
HP:0008734	Decreased testicular size	3/29
HP:0000028	Cryptorchidism	2/20
HP:0000054	Micropenis	1/20

Skeletal / limb

HPO ID	Term	Frequency
HP:0001773	Short foot	3/3
HP:0001176	Large hands	2/2
HP:0002967	Cubitus valgus	2/2
HP:0000767	Pectus excavatum	2/2
HP:0001156	Brachydactyly	—
HP:0009882	Short distal phalanx of finger	—
HP:0001762	Talipes equinovarus	—
HP:0008124	Talipes calcaneovarus	—
HP:0001371	Flexion contracture	1/6

Other systems

HPO ID	Term	Frequency
HP:0002205	Recurrent respiratory infections	3/3
HP:0002788	Recurrent upper respiratory tract infections	3/3
HP:0002232	Patchy alopecia	1/20
HP:0001081	Cholelithiasis	2/20

Onset / inheritance annotations: HP:0011463 Childhood onset (3/3); HP:0001419 X‑linked recessive inheritance.

3.2 Modern Cohort Frequencies (supersede HPO fractions for common features)

Ghasemi et al. 2025 (PMID:39835750) — 175 literature cases, sex‑stratified:

Feature	Males (n≈101)	Females (n≈53)
Intellectual disability	96%	79%
Speech / language impairment	91%	70%
Behavioural problems	88%	60%
Facial dysmorphism	84%	71%
Short stature	75%	50%
Seizures / epilepsy	64%	19%

Terry et al. 2026 RARE‑X (PMID:41537560) — 31 new (19 M / 12 F) + meta‑analysis to 269 individuals (153 M / 112 F / 4 unspecified):

Meta‑analysis: - Intellectual disability: 82% overall — 98% of males, 56% of females - ID severity: males predominantly severe (70%); females predominantly mild (56%) - Seizures: 35% overall — 47% of males, 18% of females

"47% of males having (or had) seizures, and 18% females having (or had) seizures"

RARE‑X new cohort (caregiver‑reported, therefore higher ascertainment of "soft" features): - Brain/nervous system involvement 100%; communication challenges 93% - Seizures 48% (M 42%, F 56%); first seizure age 1–10 y, median 2 y - Growth issues 78%; short stature 75% of growth respondents - Behavioural concerns 78%; short attention span 88%, impulsivity 88%, anxiety 71%, ASD 65% - Vision/eye problems 74%; abnormal eye movement (strabismus/nystagmus) 91% - Digestive issues 74%; constipation 83%

⚠️ Discrepancy to record in the KB, not smooth over. Female seizure frequency is 18–19% in the two literature meta‑analyses but 56% in the RARE‑X new female cohort. Male seizure frequency is 47% (RARE‑X meta) vs 64% (Ghasemi). These are ascertainment artefacts running in opposite directions: registry self‑enrolment enriches for symptomatic females; historical XLMR‑family literature enriches for severely affected males. Curate the range with both citations, or omit frequency: per the frequency‑evidence SOP.

3.3 Phenotype Characteristics

Age of onset: Congenital/neonatal in the sense that the lesion is germline; clinically recognised in infancy to early childhood. HPO annotates HP:0011463 childhood onset. Developmental delay is typically noticed in the first 1–3 years (walking ~12 months but first words at ~3 years in the Liao proband, PMID:41743791). Seizure onset median 2 years (range 1–10 y). Prenatal‑onset short stature is documented (PMID:40125771).

Severity: Highly variable. Males skew severe (70% severe ID); females skew mild (56% mild). The full range spans severe ID with progressive spastic paraplegia (the original Claes family) to a documented case with no intellectual disability at all — Murati et al. describe "An 8-year-old boy with prenatal-onset short stature, ophthalmological abnormalities" carrying a "KDM5C variant typically linked to Claes-Jensen syndrome" but without ID (PMID:40125771).

Progression: The cognitive deficit is static/non‑degenerative — a neurodevelopmental, not neurodegenerative, disorder. However, several elements are progressive: - Spastic paraplegia: "severe mental retardation, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasia" (Claes et al. 2000, PMID:10982473) - Seizures: episodic, may emerge in mid‑childhood after an initially seizure‑free period - Behavioural difficulties: often intensify around adolescence - One report of regression post‑viral illness with loss of ambulation (PMID:40346491) — isolated, needs replication

Quality‑of‑life impact (per phenotype): | Domain | Impact | |---|---| | Intellectual disability + communication (93%) | Dominant driver of dependency; lifelong support needs; most affected males non‑ or minimally verbal in the severe range | | Seizures (35–48%) | Injury risk, medication burden, driving/independence restriction, caregiver vigilance | | Behaviour: aggression, impulsivity (88%), anxiety (71%) | Frequently the leading caregiver stressor; drives placement decisions and psychotropic prescribing | | Spasticity / gait | Mobility loss, contractures, orthopaedic surgery, wheelchair dependency in the paraplegic subset | | Short stature (50–78%) | Cosmetic/psychosocial; endocrine work‑up burden | | Vision (74%; abnormal eye movement 91%) | Amblyopia risk if untreated; a highly actionable, under‑recognised domain (PMID:40125771) | | GI/constipation (83%) | Chronic discomfort, feeding difficulty, contributes to behavioural escalation |

No disease‑specific QoL instrument (EQ‑5D/SF‑36/PROMIS) has been applied to this cohort. This is a genuine gap.

4. Genetic / Molecular Information

Causal Gene

KDM5C — lysine demethylase 5C. Aliases: JARID1C, SMCX, XE169, DXS1272E. - Locus: Xp11.22 · hgnc:11114 · NCBIGene:8242 · OMIM 314690 · Ensembl:ENSG00000126012 · UniProt:P41229 - Reference transcript: NM_004187.5 - Protein: 1,560 aa; EC 1.14.11.67

Protein architecture (UniProt P41229):

Domain	Residues	Role
JmjN	14–55	Structural; stabilises JmjC fold
ARID	79–169	DNA binding (AT‑rich interaction domain)
PHD‑type 1 zinc finger	326–372	Reads unmodified/H3K9me3 histone tails
JmjC (catalytic)	468–634	Fe(II)/2‑oxoglutarate–dependent demethylase active site
C5HC2 zinc finger	707–759	Required for catalysis (completes the split JmjC)
PHD‑type 2 zinc finger	1187–1248	Reads H3K4me3 — product/substrate recognition

Note the "PLU‑1"/Tower region is used in the clinical literature to describe the long linker between C5HC2 and PHD2 (PMID:41743791, PMID:39835750). Cofactor: Fe²⁺ (one ion per subunit, catalytic). Localisation: nucleus. Tissue specificity: ubiquitous, highest in brain and skeletal muscle — directly consistent with the neurological + growth/muscle phenotype.

Enzymatic specificity: demethylates H3K4me3 → me2 → me1, not to unmethylated product, and does not act on H3K9/K27/K36/K79 or H4K20.

"SMCX (JARID1C), which encodes a JmjC-domain protein, reversed H3K4me3 to di- and mono- but not unmethylated products" — Iwase et al., Cell 2007 (PMID:17320160)

Pathogenic Variants

Variant spectrum (RARE‑X meta‑analysis, 122 unique variants across 130 families; PMID:41537560):

Class	Proportion
Missense	~50%
Nonsense	23%
Frameshift	18%
Splice	5%
Other (microdeletion, intronic)	3%

Concordant with Ghasemi et al. (PMID:39835750; 80 unique variants): missense 41 (51%), nonsense 27 (34%), del/dup 6 (8%), splice 6 (8%).

Missense variant distribution by domain (PMID:41537560): JmjC 36%, interdomain 33%, ARID 11%, C5HC2 9%, PLU‑1/Tower 5%, PHD2 3%, JmjN 3%. The catalytic JmjC domain is the missense hotspot — and catalytic‑domain variants are enriched for seizures (PMID:39835750).

Landmark variants:

Variant (protein)	Type	Functional consequence	Source
p.Asp87Gly (D87G)	Missense, ARID	No effect on activity or localisation; minimal effect on ARID stability/DNA binding	UniProt; PMID:16541399; PMID:26580603
p.Ala77Thr (A77T)	Missense, ARID	Minimal effect on ARID stability/DNA binding	PMID:18697827; PMID:26580603
p.Ala388Pro	Missense	Impairs enzymatic activity; reduces H3K9me3 binding	UniProt
p.Asp402Tyr	Missense, JmjC	Decreased enzymatic activity	UniProt
p.Ser451Arg (S451R)	Missense	Conserved residue; segregates with ID	PMID:16538222
p.Pro480Leu	Missense, JmjC	Reduced enzymatic activity in patient fibroblasts	UniProt
p.Cys640Tyr	Missense	De novo	UniProt
p.Phe642Leu	Missense, JmjC	Impairs enzymatic activity	UniProt; PMID:16541399
p.Leu731Phe	Missense, C5HC2	Impairs enzymatic activity	UniProt
p.Arg750Trp / p.Tyr751Cys	Missense, C5HC2	Y751C impairs activity	UniProt; PMID:16541399
p.Arg332*	Nonsense	Truncating	PMID:16541399
p.Cys724* (c.2172C>A)	Nonsense	Truncating	PMID:24583395
p.Gln902* (c.2704C>T, ex19)	Nonsense, Tower/SPECL2	Likely pathogenic (ACMG); ClinVar SCV004034082	PMID:39835750
p.Arg929* (c.2785C>T)	Nonsense	Triggers NMD: mRNA down but protein paradoxically up, with altered subcellular localisation	PMID:39948613
p.Arg943* (c.2827C>T)	Nonsense	De novo; regression phenotype	PMID:40346491
p.Val1075Tyrfs*2 (c.3223delG)	Frameshift	Complete loss of KDM5C protein	PMID:25666439
p.Ser1178* (c.3533C>A)	Nonsense	De novo in a female; no skewed XCI	PMID:36536324
p.Glu1283* (c.3847G>T)	Nonsense	De novo in a 27‑y‑old female; moderate ID	PMID:36553533
p.Arg1115His (R1115H)	Missense	Normal activity and stability, yet pathogenic — non‑enzymatic mechanism	PMID:29670509
p.Met1_Glu165del	Translation‑initiation	N‑terminally truncated, unstable, no detectable activity	PMID:25666439
c.3019del	Frameshift, PLU‑1	Impairs transcription, expression, stability; zebrafish phenotype	PMID:41743791
c.782‑2A>T	Splice acceptor (ARID–PHD1 linker)	Aberrant splicing → PTC in exon 7 → ~375 aa truncated protein	PMID:41743791
c.633G>C (p.Arg211Arg)	Synonymous	Predicted to create an exonic splicing enhancer; co‑segregates — VUS	PMID:24583395

Variant classification and population frequency: - ClinVar: 528 KDM5C records classified Pathogenic or Likely Pathogenic (E‑utilities count, July 2026). - gnomAD constraint (via ClinGen): pLI = 1, LOEUF = 0.17 — extreme intolerance to loss of function, among the most constrained genes in the genome. Pathogenic variants are absent or vanishingly rare in gnomAD; there is no meaningful population allele frequency. - ClinGen Dosage Sensitivity (2023‑07‑27): Haploinsufficiency score 3 — Sufficient Evidence; Triplosensitivity 0 — No Evidence. Haploinsufficiency (not gain‑of‑function or triplosensitivity) is the established mechanism. - Origin: Germline only for MRXSCJ. (Somatic KDM5C mutation is a well‑known driver in clear cell renal cell carcinoma — PMID:39955388, PMID:37293154 — but that is a distinct, unrelated disease context and must not be conflated with MRXSCJ.)

Functional consequence class — LOSS OF FUNCTION, achieved by at least four distinct routes: 1. Transcript loss / NMD — "expression studies revealed the almost complete absence of the mutated JARID1C transcript" (PMID:15586325) 2. Protein destabilisation — missense variants that "compromise stability and enzymatic activity" (PMID:25666439) 3. Direct catalytic impairment — "Several XLMR-patient point mutations reduced SMCX demethylase activity" (PMID:17320160) 4. Non‑enzymatic / scaffolding loss — R1115H: "The KDM5C-R1115H substitution does not have an impact on enzymatic activity," yet fails to suppress targets → "KDM5C may have non-enzymatic roles in gene regulation" (PMID:29670509). Reinforced in Drosophila: "KDM5 operates in conjunction with local chromatin contexts to employ demethylase-dependent and independent mechanisms" (PMID:41340160).

Route 4 is mechanistically important for the KB: it means "loss of demethylase activity" alone is an incomplete pathophysiology node. Model the enzymatic and non‑enzymatic arms separately.

Modifier Genes

KMT2A — the opposing H3K4 methyltransferase (Wiedemann‑Steiner syndrome gene). Mouse double mutants show mutual suppression: "shared reduced dendritic spines and increased aggression" in single mutants, reversed in doubles (PMID:32483278). The strongest candidate genetic modifier and the leading therapeutic hypothesis.
KDM1A (LSD1) — cooperative, not opposing: double forebrain‑specific KO produces "stronger ectopic expression of non-neuronal genes in hippocampal neurons and thousands of de novo H3K4me3-enriched regions" and "more severe behavioral impairments than the single ifKOs" (PMID:40864554). A candidate severity modifier.
ARX — upstream regulator, not a modifier per se: ARX polyalanine expansions reduce KDM5C transactivation, and "Kdm5c mRNA diminution led to a severe decrease in the KDM5C content during in vitro neuronal differentiation" (PMID:23246292).
KDM5D (Y‑linked paralogue) — a theoretical male‑specific partial buffer, but KDM5D is expressed in a restricted manner and does not rescue; in fact its Y‑linkage is part of why males lack the female two‑copy advantage. KDM5C and KDM5D have demonstrably non‑equivalent consequences (PMID:39955388, ccRCC context).

Epigenetic Information

This disease is an epigenetic disorder, and it also produces a secondary, measurable epigenetic signature.

Primary epigenetic lesion: failure to remove H3K4me3/me2 at CpG‑island promoters. Iwase et al. found "94% of Kdm5c-bound promoters contain a CpG island, representing significant enrichment" (P < 1×10⁻²⁶), with the effect concentrated on lowly expressed genes: "Low-expressed Kdm5c-target genes showed most noticeable increase in expression (~7% increase, P = 1.4 × 10⁻⁸) and H3K4me3 (~12% increase, P < 2.2 × 10⁻¹⁶)". Crucially, "global levels of H3K4me1, me2 or me3 are comparable in WT and Kdm5c-KO neurons" — the defect is locus‑specific fine‑tuning, not a bulk chromatin collapse. This is the single most important mechanistic nuance to encode.

Secondary DNA‑methylation episignature: Schenkel et al. defined a peripheral‑blood epi‑signature comprising 1,769 individual CpGs and 9 genomic regions in 7 male patients vs 56 controls, with 6 healthy female carriers showing intermediate changes (PMID:29456765). See §10 for diagnostic performance. Separately, Grafodatskaya/Chénier‑era work reported multilocus loss of DNA methylation in KDM5C‑mutant individuals (PMID:23356856), and a monozygotic‑twin methylation study exists (PMID:31419599).

Downstream chromatin consequences: patient fibroblasts show "local changes in chromatin conformation and gene expression" (PMID:25666439).

Chromosomal Abnormalities

MRXSCJ is predominantly a sequence‑level disorder. However: - Microdeletions involving KDM5C are within the ~3% "other" variant class (PMID:41537560) and one pathogenic hemizygous deletion was found by NGS gene‑dosage analysis in an XLID cohort (PMID:25649377). - ClinGen HI score 3 means an Xp11.22 CNV encompassing KDM5C is interpretable as causative in a male. - Larger contiguous Xp11.22 deletions may also involve neighbouring XLID genes (e.g. IQSEC2, SMC1A region) — expect a blended phenotype; check CMA breakpoints. - No recurrent translocation, inversion, or aneuploidy association.

5. Environmental Information

Not applicable as a causal category. MRXSCJ is a fully monogenic germline disorder.

Environmental factors / toxins / radiation / occupational exposure: none implicated. No CTD‑curated chemical–disease association specific to MRXSCJ.
Lifestyle factors: none causal. Relevant only as downstream management targets (nutrition for failure‑to‑thrive; activity for spasticity; sleep hygiene).
Infectious agents: none causal. Two peripheral observations, both weak and non‑causal: (a) one case of regression after acute viral illness (PMID:40346491); (b) recurrent respiratory/URT infections are annotated phenotypes (HP:0002205, HP:0002788, both 3/3 in a small series) — likely secondary to hypotonia/aspiration rather than a primary immunodeficiency. The zebrafish interferon/TLR finding (PMID:41743791) is a transcriptomic dysregulation of antiviral pathways, not evidence of infectious causation.

6. Mechanism / Pathophysiology

6.1 The Causal Chain (upstream → downstream)

[MOLECULAR] KDM5C loss-of-function variant (LoF / destabilised / catalytically dead / scaffold-dead)
      │
      ├─► Reduced H3K4me3/me2 demethylase activity at CpG-island promoters + enhancers
      │        (locus-specific, NOT global — bulk H3K4me levels are normal)
      │
      └─► Loss of non-enzymatic scaffolding (REST/HDAC1-2/G9a complex; R1115H arm)
 │
[MOLECULAR/CELLULAR]  ▼
   Failure of transcriptional fine-tuning:
      • Derepression of REST target neuronal genes at NRSE elements (SCN2A, SYN1)
      • Spurious transcription: germline genes, non-neuronal genes, cryptic promoters
      • Failure to fine-tune activity-regulated enhancers
      • Mistimed canonical WNT signalling output
 │
[CELLULAR]       ▼
   • Premature/mistimed primary → intermediate progenitor transition; altered neurogenesis timing
   • Reduced ribosome biogenesis and translation (Drosophila arm)
   • Loss of neuronal identity maintenance (adult genome surveillance failure)
 │
[TISSUE]         ▼
   • Reduced dendritic arborisation (basolateral amygdala pyramidal neurons)
   • Reduced dendritic spine density (~45% of WT in BLA; 9% reduction in motor cortex)
   • Immature, thin (non-mushroom) spine morphology
   • Increased CA1 pyramidal neuron intrinsic excitability; altered ion channel expression
 │
[ORGANISM]       ▼
   Intellectual disability · seizures · aggression/anxiety/ASD · impaired social behaviour
   · memory deficits · short stature · spasticity

6.2 Molecular Pathways

(a) H3K4 methylation writer–eraser balance (the core axis). KDM5C is the eraser; KMT2A/MLL1 is the writer. The disorder is a stoichiometry disease of this pair. Suggested GO: GO:0032453 (histone H3K4 demethylase activity — verify label), GO:0034720/GO:0140939 (histone H3K4 demethylation — label changed in recent GO releases; must verify with OAK), GO:0006338 chromatin remodeling, GO:0005506 iron ion binding.

(b) REST/NRSF neuronal gene silencing.

"SMCX and REST co-occupy the neuron-restrictive silencing elements" · "loss of SMCX activity impairs REST-mediated neuronal gene regulation" (Tahiliani et al., Nature 2007, PMID:17468742)

SMCX assembles with HDAC1/HDAC2, the H3K9 methyltransferase G9a (EHMT2), and REST at NRSE elements in promoters of SCN2A and SYN1. RNAi depletion derepresses these targets with increased H3K4me3. Note the direct line from this to the seizure phenotype: SCN2A is itself a major epilepsy gene. Candidate GO: GO:0016575 histone deacetylation, GO:0045892 negative regulation of DNA-templated transcription.

(c) Canonical WNT signalling — the 2024 Nature mechanism, and the most therapeutically actionable. Karwacki‑Neisius et al. (PMID:38383780) established that "KDM5C is identified as a safeguard to ensure that neurodevelopment occurs at an appropriate timescale," acting by modulating WNT output during a defined developmental window to time the primary→intermediate progenitor transition. Critically, the deficit is pharmacologically reversible within that window: transient WNT inhibition "rescue[s] the transcriptomic and chromatin landscapes in patient-derived cells," and "WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice." The window matters — "only a transient alteration" is required, "WNT functioning in a transient nature to affect long-lasting cognitive function." Candidate GO: GO:0060070 canonical Wnt signaling pathway; GO:0021895 cerebral cortex neuron differentiation.

(d) Ribosome biogenesis / translation (invertebrate arm). Zamurrad et al. (PMID:29490272) found in kdm5^A512P flies "a striking downregulation of genes required for ribosomal assembly and function" with reduced translation, and "kdm5^A512P flies also showed impaired learning and/or memory." They argue "the primary defect of the KDM5A512P mutation is a loss of histone demethylase activity." Not yet demonstrated in mammals — flag as MODEL_ORGANISM and a candidate HUMAN_MODEL_MISMATCH.

(e) Interferon / Toll‑like receptor innate‑immune signalling (emerging, zebrafish only). Liao et al. (PMID:41743791): both novel variants produced overwhelmingly upregulated DEGs (355/363 and 320/326 up) enriched for "antiviral and interferon-related signaling," with TLR3, NFKB1, IFNB1, IRF7, SAT1a, SAT1b all up. The TLR inhibitor CU‑CPT 4a partially rescued morphology and restored spontaneous swimming. Candidate GO: GO:0034138 toll-like receptor 3 signaling pathway, GO:0060337 type I interferon-mediated signaling pathway. Zebrafish only; unreplicated; do not present as established human mechanism.

(f) ARX → KDM5C transcriptional axis (upstream). ARX directly binds a conserved noncoding element to activate KDM5C; polyalanine‑expanded ARX is hypomorphic. This links two XLID+epilepsy genes into one path (PMID:23246292).

6.3 Cellular Processes

Neuronal differentiation and identity maintenance. Scandaglia et al.: "Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germline genes" and, in the adult, "preventing the incorrect activation of non-neuronal and cryptic promoters in adult neurons" (PMID:28978483). This is a two‑phase role — developmental silencing plus lifelong genome surveillance — and both phases should be separate pathophysiology nodes.
Enhancer fine‑tuning during activity‑dependent plasticity — "fine-tuning activity-regulated enhancers during neuronal maturation" (PMID:28978483).
Dendritogenesis and spine maturation. Candidate GO: GO:0016358 dendrite development, GO:0060998 regulation of dendritic spine development.
Neuronal excitability. Martín‑González et al. found "altered hippocampal expression of ion channels" and increased CA1 pyramidal excitability in KDM1A/KDM5C double KO (PMID:40864554) — a direct cellular substrate for seizures.
Cell‑autonomous neuronal requirement. The RARE‑X Drosophila work is decisive: "Reducing the expression of its single Kdm5 gene in neurons, but not glia, led to spontaneous and stimulus-induced seizures" (PMID:41537560). Glia are dispensable for the seizure phenotype.
Chromatin‑context dependence. "altered gene expression in both alleles correlates with preexisting chromatin signatures" (PMID:41340160) — KDM5C's effect is conditional on the local chromatin state, not uniform.

6.4 Protein Dysfunction

Four mechanistically distinct failure modes (detailed in §4): transcript loss/NMD, protein destabilisation, catalytic inactivation, and scaffold/recruitment failure with intact catalysis. A fifth, unusual mode: the R929X allele shows "The mRNA levels of the mutant gene were down-regulated, while the protein level" was up, with "Altering the subcellular localization of the protein" (PMID:39948613) — i.e. a truncated protein that escapes to the wrong compartment. No amyloid/aggregation mechanism. No dominant‑negative mechanism has been demonstrated; ClinGen's HI‑3 / TS‑0 assignment supports pure haploinsufficiency.

6.5 Metabolic Changes

No primary metabolic derangement; MRXSCJ is not an inborn error of metabolism. Biochemical work‑up in the original Belgian family was normal: "Biochemical investigations, neuroimaging and neuropathology were normal" (PMID:9377804). The only metabolic dimension is the enzyme's own cofactor dependence — Fe²⁺ and 2‑oxoglutarate (candidate CHEBI: CHEBI:29033 iron(2+), CHEBI:16810 2-oxoglutarate — verify). Endocrine abnormalities are more frequent in affected females ("Endocrine disorders were more frequent in females", PMID:32279304) but are unexplained and not mechanistically linked.

6.6 Immune System Involvement

No autoimmunity, no immunodeficiency established. Two threads: recurrent respiratory infections as an annotated phenotype (likely secondary), and the zebrafish interferon/TLR overactivation (§6.2e) — "suggesting aberrant immune activation" (PMID:41743791). Treat as an emerging hypothesis, MODEL_ORGANISM evidence only.

6.7 Tissue Damage Mechanisms

There is no tissue destruction. No oxidative stress, ischaemia, fibrosis, necrosis, or inflammation‑driven damage. Adult Kdm5c‑KO mice show "no gross abnormalities in the cytoarchitecture of the adult Kdm5c-KO cerebral cortex, hippocampus, or amygdala" (PMID:26804915). The pathology is structural‑microscopic and functional — dendritic/spine hypoplasia and transcriptional miswiring, not lesional. The one progressive element (spastic paraplegia) implies a corticospinal‑tract dysfunction of unclear substrate; human neuropathology was normal (PMID:9377804).

Curation implication: do not conform this entry to a degeneration/fibrosis/injury module. If a module fits at all, it is developmental/chromatin, and the relevant near‑neighbour is the chromatinopathy class rather than any existing dismech module. Consider proposing a chromatin_h3k4_writer_eraser_imbalance module — KDM5C/KMT2A/KDM1A/KMT2D form a genuinely conserved, recurrent writer–eraser axis across Claes‑Jensen, Wiedemann‑Steiner, Kabuki and KDM1A‑related NDD.

6.8 Epigenetic Changes

Covered in §4 (primary H3K4me3 dysregulation; secondary DNA‑methylation episignature; multilocus methylation loss).

6.9 Molecular Profiling

Transcriptomics: - Mouse (Iwase 2016, PMID:26804915): "larger number of up-regulated genes than down-regulated genes is consistent with the enzymatic activity of Kdm5c, which removes the active chromatin mark H3K4me2/3." Brain‑region‑specific effects — "Synaptic pathways such as 'Glutamate Neurotransmitter Release Cycle' and 'Nicotinic acetylcholine receptors' are down-regulated in the KO amygdala but not in the frontal cortex." A class of genes was "down-regulated in KO amygdala but unchanged in KO frontal cortex… highly relevant for neuronal differentiation, neuron-projection development, and synapses." - Mouse, sex‑stratified (Bonefas & Iwase 2023, PMID:36831303): "gene expression and behavioral abnormalities are readily detectable in Kdm5c-heterozygous female mice." - Zebrafish (PMID:41743791): 363 DEGs (355↑/8↓) for c.3019del; 326 DEGs (320↑/6↓) for c.782‑2A>T — strongly derepression‑biased, matching the eraser‑loss prediction. - Human patient‑derived cells (PMID:38383780): WNT‑inhibitor treatment rescued transcriptomic and chromatin landscapes. - Drosophila (PMID:29490272): ribosomal assembly gene downregulation.

Epigenomics: ChIP‑seq for KDM5C occupancy and H3K4me3 (PMID:26804915, PMID:28978483, PMID:40864554, PMID:41340160); genome‑wide DNA methylation array (PMID:29456765, PMID:23356856).

Proteomics / metabolomics / lipidomics: No dedicated studies. Genuine gap.

Single‑cell / spatial transcriptomics: No published single‑cell or spatial dataset specific to MRXSCJ. Given the strong brain‑region‑ and cell‑type‑specificity of the mouse phenotype (amygdala ≫ cortex), single‑cell profiling is the highest‑value missing experiment. Record as a KNOWLEDGE_GAP with a proposed_experiments entry.

Functional genomics screens: KDM5C appears in a genome‑wide screen for 2‑cell‑like state regulators (PMID:37488355) — developmental biology context, not MRXSCJ.

7. Anatomical Structures Affected

Organ Level

Primary: Brain (UBERON:0000955) — the overwhelmingly dominant target. Within it: - Cerebral cortex (UBERON:0000956) — frontal/motor cortex spine density reduction - Hippocampal formation (UBERON:0002421) — ectopic non‑neuronal gene expression, CA1 hyperexcitability - Amygdala, specifically the basolateral amygdala — the most severely affected structure in the mouse (dendritic length ↓, spine density ~45% of WT). Candidate UBERON for BLA: UBERON:0002873 — verify with OAK - Forebrain (UBERON:0001890) — the conditional‑KO target region - Corticospinal tract — implied by progressive spastic paraplegia; no direct imaging/pathology evidence

Secondary / other systems: | System | Involvement | UBERON candidate | |---|---|---| | Musculoskeletal / growth axis | Short stature, brachydactyly, cubitus valgus, pectus excavatum, contractures | UBERON:0002204 musculoskeletal system | | Craniofacial skeleton | Maxillary hypoplasia, micrognathia/prognathia, high palate | UBERON:0002397 maxilla | | Visual system | Strabismus, refractive error, abnormal eye movement (91%) | UBERON:0000970 eye | | Reproductive | Cryptorchidism, small testes, micropenis | UBERON:0000473 testis | | GI | Constipation (83%), cholelithiasis | UBERON:0001155 colon; UBERON:0002110 gallbladder | | Respiratory | Recurrent infections (likely secondary) | UBERON:0001004 respiratory system | | Integumentary | Patchy alopecia / alopecia areata | UBERON:0002097 skin of body | | Skeletal muscle | High KDM5C expression (UniProt); no described myopathy | UBERON:0001134 skeletal muscle tissue |

Tissue and Cell Level

Nervous tissue is the affected tissue type. Cell populations, with candidate CL terms (all require OAK verification):

Cell type	Evidence	CL candidate
Neuron (generic)	Cell‑autonomous requirement — neurons not glia (PMID:41537560)	`CL:0000540`
Pyramidal neuron (BLA, CA1)	Dendritic/spine defects; hyperexcitability (PMID:26804915, PMID:40864554)	`CL:0000598`
Glutamatergic neuron	Glutamate release-cycle genes downregulated (PMID:26804915)	`CL:0000679`
Hippocampal neuron	Ectopic non‑neuronal gene expression (PMID:40864554)	`CL:0002608`
Neural progenitor / intermediate progenitor	Mistimed primary→intermediate transition (PMID:38383780)	`CL:0011020` (neural progenitor) — verify
Glia / astrocyte	Explicitly NOT required for the seizure phenotype (PMID:41537560)	`CL:0000127` (negative finding)
Dermal fibroblast	Patient cells used for functional assay — an assay substrate, not a disease site (PMID:25666439)	`CL:0000057`
Chondrocyte	Impaired cartilage development in zebrafish (PMID:41743791) — model organism only	`CL:0000138`

Subcellular Level

Nucleus (GO:0005634) — KDM5C's exclusive localisation (UniProt). Mislocalisation is itself pathogenic for the R929X allele (PMID:39948613).
Chromatin / nucleosome (GO:0000785) — the substrate. Specifically CpG‑island promoters and activity‑regulated enhancers.
Dendritic spine (GO:0043197) — the principal affected structure.
Synapse (GO:0045202) — downstream. No mitochondrial, ER, lysosomal, or peroxisomal involvement.

Localization and Lateralization

Brain involvement is bilateral and symmetric. Microcephaly is generalised. Spastic paraplegia is bilateral and lower‑limb predominant (HP:0006895 lower limb hypertonia, HP:0002395 lower limb hyperreflexia) — a length‑dependent corticospinal pattern. Strabismus may be unilateral or alternating. Cryptorchidism may be unilateral or bilateral. Alopecia is patchy/focal (HP:0002232). One neuroimaging finding: "faint hyperintensities in posterior periventricular white matter suggesting dysmyelination" (PMID:40346491) — single case, bilateral posterior periventricular.

8. Temporal Development

Onset

Biological onset: prenatal — WNT‑dependent progenitor mistiming occurs during corticogenesis, in utero (PMID:38383780). Prenatal‑onset short stature is documented (PMID:40125771).
Clinical onset: infancy to early childhood. HPO annotates HP:0011463 childhood onset (3/3).
Onset pattern: insidious / chronic. Not acute. Presents as failure to attain milestones rather than loss of them.
Typical presentation sequence: hypotonia and feeding/growth concerns in infancy → gross‑motor delay (walking ~12 mo or later) → marked expressive language delay (first words often ~3 y) → behavioural difficulties in preschool/school years → seizures (median 2 y, range 1–10 y) → spasticity/gait deterioration in some, from mid‑childhood.

Progression

Stages — no formal staging system exists. A pragmatic natural‑history framing:

Stage	Age	Features
Infancy	0–2 y	Hypotonia, feeding difficulty, failure to thrive, growth deceleration, early seizures in some
Early childhood	2–6 y	Global developmental delay declared; severe expressive language delay; ID becomes measurable; strabismus; seizure onset peak
School age	6–12 y	Behavioural phase — aggression, impulsivity, hyperactivity, anxiety; ASD diagnosis; emerging hyperreflexia/spasticity
Adolescence/adult	>12 y	Static cognitive plateau; behavioural challenges often peak; progressive spastic paraplegia and contractures in the affected subset; adult dependency established

Progression rate: The cognitive deficit is static — it does not degenerate. The motor phenotype is slowly progressive in the spastic‑paraplegia subset: "slowly progressive spastic paraplegia" (PMID:10982473). Overall course pattern: chronic, lifelong, static‑with‑a‑slowly‑progressive‑motor‑component, punctuated by episodic seizures.

Duration: Lifelong. Not self‑limited.

Patterns

Remission: No spontaneous remission of ID. Seizures may be well controlled or remit with antiseizure medication in a subset — no quantitative data available. Behavioural difficulties may improve with intervention and maturation.

Critical periods — the most important temporal fact in this disease. The 2024 Nature work established a discrete, closable developmental window during which WNT modulation is corrective: use of "WNT signalling modulators at specific times reveal that only a transient alteration" is needed, with WNT inhibition in that window rescuing both molecular and behavioural phenotypes in Kdm5c‑KO mice. This defines a time‑limited therapeutic opportunity in embryonic/early‑postnatal corticogenesis — and, by implication, means that intervention after that window may not be corrective for the cognitive phenotype. Additional practical windows: early amblyopia detection (visual critical period), and early language/behavioural intervention.

9. Inheritance and Population

Epidemiology

Point prevalence: not established. No population‑based prevalence or incidence estimate exists for MRXSCJ. Orphanet's epidemiology class for ORPHA:85279 could not be retrieved in this run (API 401 / site bot protection) — retrieve it from the local structured cache (just structured-rebuild-orphanet --id 85279) before populating a Prevalence record. Given ORPHA:85279's designation as a rare multiple‑congenital‑anomaly syndrome, expect BELOW_1_IN_1000000 or NOT_YET_DOCUMENTED.

What is quantified is the gene's share of XLID — a case‑fraction, not a prevalence. Curate this with Genetic.case_fractions, not as a Prevalence record:

Estimate	Cohort	Source
0.7–2.8% of XLID	Cited range in current reviews	Hatch et al. 2021, as cited in PMID:41743791 and PMID:40346491 ("Mutations, either maternally transmitted or de novo, account for 0.7-2.8%")
~3.3% (7/210 families)	XLMR families, brain‑expressed gene screen	Jensen et al. 2005 (PMID:15586325) — "in 210 families with XLMR, we identified seven different mutations in JARID1C"
0.7%	143 Brazilian males with probable XLID	Gonçalves et al. 2014 (PMID:24583395) — "KDM5C pathogenic mutational frequency of 0.7% among males with probable XLID"
Present among 18 pathogenic variants across 13 XLID genes	150 male XLID patients, targeted NGS of 107 genes	Tzschach et al. 2015 (PMID:25649377) — familial 26% (13/50) vs sporadic 5% (5/100) overall diagnostic yield

The widely repeated "2.8–3.3%" figure is best read as the upper bound from ascertained multiplex XLMR families, and 0.7% as the yield in unselected/regional cohorts. Report the range with both citations; do not pick one.

For context: ID affects "up to 2% of the population world-wide" (PMID:29670509), and XLID is genetically heterogeneous — "a genetically heterogeneous condition involving more than 100 genes" (PMID:32279304).

Genetic Etiology Parameters

Inheritance pattern: X‑linked. HPO annotates HP:0001419 X‑linked recessive inheritance and OMIM titles it X‑linked recessive — but this label is empirically wrong for females and should be curated with a caveat. With 56% of heterozygous females affected (PMID:41537560), the disorder behaves as X‑linked with markedly sex‑biased severity / incomplete female penetrance, not clean recessive.

KB recommendation: carry HP:0001419 (matching the authoritative annotation) but add a second Inheritance block or a notes field stating the empirical female penetrance. Do not silently assert HP:0001417 (X-linked dominant) — that overcorrects.

Modes of transmission (RARE‑X cohort, PMID:41537560): - De novo: >50% - Maternally inherited: ~10% - Paternally inherited: ~1% (rare; an affected/mosaic father transmitting to daughters) - Remainder untested/unknown

This is a major shift from the historical picture. Early gene discovery was done in multiplex XLMR families, which by construction were maternally transmitted; contemporary trio exome ascertainment reveals that de novo occurrence is now the majority mode.

Penetrance: - Males: essentially complete for ID — 96% (PMID:39835750) to 98% (PMID:41537560). The 8‑year‑old boy without ID (PMID:40125771) is the documented exception and shows penetrance is not literally 100%. - Females: incomplete — 56–79% with ID/learning disability; Carmignac et al. found 4/19 heterozygous females completely asymptomatic (PMID:32279304).

Expressivity: highly variable, in both sexes. Range spans no‑ID to severe ID with progressive spastic paraplegia, within and across families. Carmignac: "All affected individuals presented with learning disabilities or ID (mostly moderate)."

Genetic anticipation: Not applicable. No repeat expansion mechanism.

Germline mosaicism: Not specifically documented for KDM5C, but must be assumed possible for recurrence‑risk counselling given the high de novo rate (standard practice: quote ~1% empiric recurrence risk after an apparently de novo variant, higher if maternal mosaicism is detected).

Founder effects: None reported. Variants are private/family‑specific; the spectrum is dominated by unique variants (122 unique variants across 130 families — near‑complete allelic heterogeneity).

Consanguinity: Not a factor — X‑linked, not autosomal recessive.

Carrier frequency: Not estimable at population level. Given pLI=1 / LOEUF=0.17 and the near‑absence of LoF variants in gnomAD, carrier frequency is very low and dominated by de novo events.

Population Demographics

Affected populations: No ethnic predilection. Cases reported from Belgium (index family), Australia, USA, Germany, Netherlands, Italy, France, Brazil, China, Thailand, Estonia, Palestine, and elsewhere. First Latin American screen: PMID:24583395. First Palestinian case: PMID:40346491.

Geographic distribution: Worldwide, no clustering. Reporting bias favours countries with established exome‑sequencing diagnostics — apparent geography reflects diagnostic access, not biology.

Geographic distribution of specific variants: None; no recurrent founder allele.

Sex ratio: Historical literature: strongly male‑predominant (the RARE‑X literature meta‑analysis is 153 M : 112 F ≈ 1.4:1, already far less skewed than the classic "X‑linked recessive" expectation). The RARE‑X new cohort is 61% M : 39% F ≈ 1.6:1. Females are systematically under‑ascertained; the true molecular sex ratio in an unbiased sequencing cohort is likely closer to 1:1, with severity — not occurrence — being the sex‑biased variable.

Age distribution: RARE‑X participants ranged 2–20 years (mean 10.6 y males, 12.4 y females). Adults are markedly under‑represented in the literature — most published individuals are children, which biases natural‑history and prognosis data toward the paediatric course. Oldest well‑described individuals include a 27‑year‑old woman (PMID:36553533) and a 48‑year‑old (PMID:40544030).

10. Diagnostics

Clinical Tests

Laboratory tests: No diagnostic biochemical abnormality. Routine metabolic work‑up is normal — "Biochemical investigations, neuroimaging and neuropathology were normal" (PMID:9377804). Standard ID work‑up (CK, thyroid function, plasma amino acids, urine organic acids, acylcarnitines) serves to exclude alternatives. Endocrine evaluation (IGF‑1, growth‑hormone axis, thyroid) is warranted for short stature and for the female endocrine excess (PMID:32279304). No LOINC‑coded disease‑specific analyte.

Biomarkers: The DNA‑methylation episignature is the only validated biomarker (below). No protein or metabolite biomarker.

Imaging: Brain MRI is usually normal or non‑specific — its role is exclusionary. Reported findings are limited to "faint hyperintensities in posterior periventricular white matter suggesting dysmyelination" in a single case (PMID:40346491). Microcephaly is a clinical/OFC measurement, not an imaging diagnosis. Bone age and skeletal survey may be indicated for short stature/brachydactyly.

Functional tests: Formal neuropsychological/developmental assessment (Bayley, WISC, Vineland) is essential for ID diagnosis and severity grading. Ophthalmological assessment — explicitly under‑used and high‑yield given 91% abnormal eye movement and the amblyopia risk; PMID:40125771 argues "importance of ophthalmological assessments in X-linked syndromes."

Electrophysiology: EEG is indicated in all patients — 35–48% have seizures, tonic seizures documented (HP:0032792). No pathognomonic EEG signature described. EMG/NCS is not routinely indicated (the motor phenotype is upper‑motor‑neuron), though distal lower‑limb amyotrophy (HP:0008944) may prompt it. ECG not indicated.

Biopsy / pathology: Not diagnostically indicated. Human neuropathology was unremarkable (PMID:9377804). Skin biopsy for fibroblast culture is a research tool for functional variant assays (PMID:25666439).

Genetic Testing

Recommended approach. MRXSCJ is clinically non‑specific enough that gene‑first testing is standard:

Trio exome sequencing (WES) or genome sequencing (WGS) — first‑line for unexplained global developmental delay/ID. Trio design is essential given >50% de novo.
Chromosomal microarray (CMA) — either first‑line alongside, or reflex; detects the Xp11.22 microdeletion subset (~3% of the variant spectrum) that sequencing may miss.
XLID gene panel — a valid alternative in a family with an X‑linked pedigree. Tzschach et al.'s 107‑gene XLID panel achieved ">10 reads for approximately 96% of coding bases at mean coverage of 124 reads" and yielded 26% in familial vs 5% in sporadic cases (PMID:25649377). KDM5C is on all commercial XLID and ID/epilepsy panels; GTR lists dedicated single‑gene tests (e.g. GTR 581685).
Single‑gene KDM5C sequencing — only for targeted familial‑variant testing / cascade screening once a variant is known.
DNA methylation episignature (EpiSign) — see below; use as a reflex for VUS resolution and carrier confirmation.

Modalities not indicated: karyotype (too low resolution; normal in these patients), FISH (no recurrent rearrangement), mtDNA testing (not mitochondrial), repeat‑expansion testing (no repeat mechanism) — except as differential‑diagnosis exclusions (e.g. FMR1 CGG for fragile X).

A specific pitfall: synonymous and deep‑intronic variants can be pathogenic via splicing — c.633G>C (p.Arg211Arg) was predicted to create "an Exonic Splicing Enhancer sequence" and co‑segregated (PMID:24583395); c.782‑2A>T is a canonical splice‑acceptor change producing a PTC (PMID:41743791). RNA studies should be considered before dismissing a segregating synonymous or splice‑region variant.

Omics‑Based Diagnostics

Epigenomics — the standout. Schenkel et al.'s Claes‑Jensen episignature (PMID:29456765) is clinically deployed within the EpiSign framework: - Derived from 7 male patients vs 56 matched controls; 1,769 CpGs, 9 genomic regions - 6 healthy female carriers showed intermediate, distinguishable changes - "Highly specific computational model using the most significant methylation changes demonstrated 100% accuracy" in the training cohort - "The 100% specificity of this unique epi-signature was further confirmed on additional 500 unaffected controls" plus 600 ID/DD patients including other episignature cohorts - Clinical use: "can be used for molecular diagnosis and carrier identification and assist with interpretation of genetic variants" of unknown significance

Real‑world confirmation: Koparir et al. (PMID:41957673) applied EpiSign to 400 NDD individuals — "Seventeen percent of individuals (67/400) harbored variants in chromatinopathy-associated genes," "26 individuals (43%) exhibited disorder-specific episignatures," with KDM5C among the confirmed genes; "Integration of EpiSign analysis facilitated variant reclassification." Methylation profiling has been used specifically "to the reclassification of a variant" (PMID:35781022).

⚠️ Important caveat — do not overstate episignature performance. Husson et al.'s independent multicentre evaluation (PMID:37872275) found published episignatures perform very unequally: "While ATRX, DNMT3A, KMT2D, and NSD1 signatures displayed a 100% sensitivity, CREBBP-RSTS reached <40%," concluding "Episignatures do not perform equally well. Some signatures are ready for confident use" and "It is imperative to characterise the actual validity perimeter and interpretation of each episignature." The KDM5C signature's original 100% figures come from a 7‑patient training cohort and reflect specificity against large control sets more than sensitivity across the full allelic spectrum. Curate the 100% claim as training‑cohort performance with this limitation stated.

RNA sequencing: Research tool; potential clinical value for splice‑variant resolution. Proteomics, metabolomics, liquid biopsy: no diagnostic role.

Clinical Criteria

No formal, standardised diagnostic criteria exist (no DSM/ICD/society criteria for MRXSCJ). Diagnosis is molecular: a pathogenic/likely pathogenic KDM5C variant in a compatible phenotype. Historical clinical suspicion criteria remain useful for gene prioritisation — Abidi et al. concluded "male patients with mental retardation, short stature and hyperreflexia should be considered candidates for mutations in the JARID1C gene" (PMID:18697827), and reported in their nine males "mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%)."

Differential diagnosis:

Condition	Distinguishing features
Wiedemann‑Steiner syndrome (KMT2A)	The mechanistic mirror‑image (writer vs eraser); hypertrichosis cubiti, distinct facies; AD
Kabuki syndrome (KMT2D/KDM6A)	Characteristic facies, persistent fetal fingertip pads, cardiac defects, immune deficiency
KDM1A‑related NDD	Cooperative partner gene; overlapping chromatin phenotype
ATR‑X syndrome (ATRX)	Alpha‑thalassaemia, HbH inclusions, genital anomalies, severe XLID
Other XLID genes (IQSEC2, MED12, SLC9A6, CUL4B, OPHN1, UPF3B, ZDHHC9, AP1S2, DLG3, SMC1A, UBE2A)	All co‑detected in the same panels (PMID:25649377); require sequencing to distinguish
Fragile X (FMR1)	Macroorchidism (vs small testes in MRXSCJ — a useful discriminator), long face, large ears; repeat expansion
Coffin‑Lowry (RPS6KA3)	Tapering fingers, characteristic facies, drop attacks
Hereditary spastic paraplegia (SPG1/L1CAM, SPG2/PLP1)	Both explicitly excluded in the original Claes family — "The two known loci for X-linked mental retardation and spastic paraplegia are excluded" (PMID:10982473)
Snyder‑Robinson (SMS)	XLID with osteoporosis, thin habitus, seizures
Renpenning syndrome (PQBP1)	XLID with microcephaly and short stature — close phenocopy

Because the phenotype is non‑specific, the differential is effectively "all XLID/ID" and is resolved by sequencing, not by clinical discrimination.

Screening

Newborn screening: Not included in any programme; no treatable metabolic marker. Not appropriate under current criteria.
Carrier screening (population): Not offered; not on expanded carrier screening panels.
Cascade / family screening: yes, and important. Once a familial variant is known, test at‑risk female relatives — both for reproductive counselling and because carrier females are frequently affected and may benefit from their own diagnosis. The episignature independently identifies healthy carriers (PMID:29456765).
Prenatal / preimplantation: Available for known familial variants (see §13).
Risk stratification: No validated model. Male sex and a catalytic‑domain variant are the two crude severity predictors currently available.

11. Outcome / Prognosis

Evidence quality warning: there is no published survival study, no mortality analysis, and no longitudinal natural‑history cohort with adult outcomes for MRXSCJ. The RARE‑X cohort — the largest prospective dataset — has a maximum age of 20 years. Everything in this section about survival is inference, and should be curated as such (or omitted) rather than asserted.

Survival and Mortality

Survival rate (5‑/10‑year/overall): no data.
Life expectancy: Not established. There is no evidence of shortened lifespan attributable to the disorder itself — it is not a degenerative or organ‑failure condition, and individuals into their 40s are described (PMID:40544030). Any excess mortality would be expected to arise from the generic ID‑population risks: seizure‑related events (including SUDEP, given 35–48% epilepsy), aspiration in the hypotonic/dysphagic subset, and immobility complications in the spastic‑paraplegia subset. None of these has been quantified for MRXSCJ.
Mortality rate / disease‑specific mortality: no data.

Morbidity and Function

Morbidity is substantial and lifelong, dominated by cognitive and behavioural burden: - 82% ID overall (98% males, 56% females); males predominantly severe (70%) - Communication challenges 93%; most severely affected males have minimal expressive language - Behavioural concerns 78% — impulsivity 88%, short attention span 88%, anxiety 71%, ASD 65% - Mobility: progressive spastic paraplegia in a subset → contractures, gait loss, wheelchair dependency - Most affected males require lifelong supported living; independent living is realistic only for mildly affected individuals, disproportionately female - ICF domains affected: learning and applying knowledge, communication, mobility (subset), self‑care, interpersonal interactions

Quality‑of‑life measures: No EQ‑5D, SF‑36, PROMIS, or disease‑specific QoL instrument has been administered. The RARE‑X caregiver survey is the closest proxy and captures symptom burden rather than validated QoL. This is a clear, actionable research gap.

Disease Course and Complications

Complication	Notes
Epilepsy, potentially refractory	35–48%; median onset 2 y
Progressive spastic paraplegia, contractures	Subset; slowly progressive
Aggression / behavioural crisis	The leading cause of care breakdown and psychotropic escalation
Amblyopia from untreated strabismus	Preventable with early ophthalmology
Chronic constipation	83% — under‑recognised, drives discomfort/behaviour
Failure to thrive, feeding difficulty	Infancy
Aspiration / recurrent respiratory infection	Secondary to hypotonia
Cryptorchidism → fertility/malignancy risk	Requires urological management
Cholelithiasis	Reported (2/20), unexplained
Osteoporosis/fracture	Expected with immobility; not specifically studied

Recovery potential: None for the established cognitive deficit under current therapy — this is a static, structural neurodevelopmental condition. The WNT data (PMID:38383780) are the first credible evidence that the phenotype is biologically reversible, but only within an early developmental window and only in mice/patient cells.

Prediction

Prognostic factors (all weak, none validated): 1. Sex — the strongest predictor. Male → severe (70% severe ID); female → mild (56% mild). 2. Variant domain — catalytic (JmjC/C5HC2) variants associate with seizures (PMID:39835750). 3. Variant class — the hypothesis that "Missense mutations in catalytic domains may retain partial enzymatic activity, potentially producing milder phenotypes than nonsense mutations" (PMID:39835750). Unproven, and complicated by R1115H (normal activity, still pathogenic) and by D87G (normal activity, disease‑associated). Do not curate as established. 4. Early seizure onset — plausibly predicts worse cognitive outcome, as in most DEEs; not demonstrated in MRXSCJ. 5. Residual expressive language at age 5 — a general ID prognostic anchor; not MRXSCJ‑specific.

Prognostic biomarkers: None. The episignature is diagnostic, not prognostic — no correlation between episignature strength and severity has been established.

12. Treatment

There is no disease‑modifying therapy, no approved drug, no gene therapy, and no interventional clinical trial for MRXSCJ. Management is entirely symptomatic, supportive, and multidisciplinary. Everything below labelled "experimental" is preclinical.

Pharmacotherapy (all symptomatic)

Indication	Agents	NCIT candidate
Seizures	Standard antiseizure medications; choice by seizure semiology (tonic seizures documented). No MRXSCJ‑specific ASM data or recommended agent.	`NCIT:C15986` Pharmacotherapy + therapeutic_agent per drug
ADHD / impulsivity (88%)	Stimulants, alpha‑2 agonists — standard ID/ADHD practice	`NCIT:C15986`
Aggression / irritability	Atypical antipsychotics (risperidone, aripiprazole) — standard ASD/ID practice	`NCIT:C15986`
Anxiety (71%)	SSRIs — standard practice	`NCIT:C15986`
Spasticity	Baclofen, botulinum toxin	`NCIT:C15986`
Constipation (83%)	Osmotic laxatives, bowel regimen	`NCIT:C15986`
Short stature	Growth hormone not indicated absent documented GH deficiency; no MRXSCJ evidence base	—

Pharmacogenomics: ClinGen reports 0 CPIC and 0 PharmGKB records for KDM5C. No gene‑specific PGx guidance. Standard CYP2D6/CYP2C19 considerations apply to the psychotropics used, unrelated to KDM5C.

Advanced Therapeutics

Gene therapy / gene replacement: none. Conceptually challenging — a 1,560‑aa protein whose dose must be balanced (both loss and excess are deleterious, cf. the KMT2A epistasis) and whose critical window may be prenatal.
Gene editing: none.
RNA‑based therapies (ASO/siRNA/mRNA): none. Note that a KDM5C upregulation strategy (e.g. targeting a repressive element or NMD‑escape approach) is theoretically attractive for haploinsufficiency but entirely unexplored.
Cell therapy, immunotherapy, targeted therapy: none.

Experimental / Preclinical Strategies

Three distinct, non‑overlapping preclinical leads — worth curating as mechanistic_hypotheses with status: EMERGING and explicit MODEL_ORGANISM evidence tagging:

Transient WNT inhibition during a developmental window (strongest lead). "WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice" and rescues "the transcriptomic and chromatin landscapes in patient-derived cells" (PMID:38383780, Nature 2024). Limitation: the window may close before postnatal diagnosis is possible — the central translational obstacle.
Rebalancing the H3K4 writer–eraser pair (KMT2A inhibition). "Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits," supporting "balancing a single writer-eraser pair to ameliorate their associated disorders" (PMID:32483278). A genetic, not pharmacological, proof of concept; MLL1/menin inhibitors exist in oncology and are a conceivable repurposing route.
Toll‑like receptor pathway inhibition (CU‑CPT 4a). In zebrafish, treatment at ½ LC50 "partially restored morphological defects, including head area, body length and eye size" and "spontaneous swimming activity was restored"; the authors propose "Targeting the regulation of TRL related receptors (such as TLR3) may become a potential strategy" (PMID:41743791). Weakest of the three — zebrafish only, single study, unreplicated, and the interferon signature has no human correlate yet.

ClinicalTrials.gov: no interventional trial registered for MRXSCJ/KDM5C‑NDD. The RARE‑X KDM5C Data Collection Program (PMID:41537560) is an observational patient‑registry, not a trial, and is the appropriate referral for families seeking research participation.

Surgical and Interventional

Orchidopexy for cryptorchidism (NCIT:C15329 / NCIT:C16186 candidates)
Strabismus surgery and refractive correction (NCIT:C15329)
Orthopaedic surgery for contractures, foot deformity (talipes equinovarus/calcaneovarus), scoliosis (NCIT:C16186 Orthopedic Surgical Procedure)
Cholecystectomy if symptomatic cholelithiasis
Gastrostomy in the failure‑to‑thrive/dysphagia subset
Epilepsy surgery: no reported role

Supportive and Rehabilitative — the mainstay

Intervention	NCIT candidate	`therapeutic_modality`
Early intervention / developmental therapy	`NCIT:C15315` Rehabilitation	`BEHAVIORAL`
Speech and language therapy (93% communication challenges; AAC often needed)	`NCIT:C159273`	`BEHAVIORAL`
Physical therapy (spasticity, gait)	`NCIT:C15302`	`BEHAVIORAL`
Occupational therapy	`NCIT:C121351`	`BEHAVIORAL`
Applied behaviour analysis / behavioural support	`NCIT:C181743`	`BEHAVIORAL`
Special education, IEP	—	`BEHAVIORAL`
Nutritional support for FTT	`NCIT:C15433` — note CLAUDE.md caveat: do NOT auto‑tag as BEHAVIORAL	assess per intervention
Supportive care, coordination	`NCIT:C15747`	—
Genetic counselling	`NCIT:C15240`	—

Treatment Outcomes

Response rates: No quantitative data for any intervention. Adverse events: none disease‑specific; standard profiles for the symptomatic agents used. Aggression and hyperactivity in this population frequently drive polypharmacy — a recognised iatrogenic risk in ID generally.

Treatment Strategy

No published clinical practice guideline or care pathway exists for MRXSCJ. Practical algorithm, synthesised from the phenotype frequencies:

At diagnosis: baseline developmental/neuropsychological assessment; EEG; formal ophthalmological exam (91% abnormal eye movement — highest‑yield under‑performed test); growth chart with OFC; feeding/GI assessment; genital exam (males); genetic counselling; offer episignature if variant is a VUS.
Ongoing surveillance: annual growth/OFC; annual vision; developmental re‑assessment; seizure review; behavioural review; spasticity/gait exam; bowel review.
Escalate: ASM for seizures; behavioural intervention before psychotropics; PT/orthopaedics for progressive spasticity.
Family: cascade testing of at‑risk females; recurrence‑risk counselling; connect to RARE‑X registry and patient advocacy.

Combination therapies / personalised medicine: No genotype‑guided treatment exists. The nearest thing to precision stratification is domain‑based seizure risk (catalytic‑domain variants → heightened seizure surveillance) — reasonable clinical prudence, but not a validated rule.

13. Prevention

Primary prevention of the disease itself is not possible — it is a germline monogenic condition, and >50% of cases arise de novo, meaning most cases are unpredictable and unpreventable. "Prevention" here means recurrence prevention within families plus prevention of secondary complications.

Prevention Levels

Primary (preventing occurrence): Limited to reproductive options in families with a known variant (below). No vaccination, no risk‑factor modification, no environmental avoidance is relevant.

Secondary (early detection and intervention): This is where real benefit lies. - Early molecular diagnosis via trio WES/WGS in unexplained global developmental delay — ends the diagnostic odyssey, enables targeted surveillance, and (given the WNT critical‑window data) may eventually enable window‑timed intervention. - Cascade testing of at‑risk female relatives — identifies affected/at‑risk females who are currently under‑diagnosed. - Episignature testing to resolve VUS and confirm carriers (PMID:29456765). - Early ophthalmology to prevent amblyopia — the clearest preventable morbidity. - Early EEG and seizure recognition. - Early speech/AAC intervention.

Tertiary (preventing complications in affected individuals): - Seizure control to reduce injury and SUDEP risk - Spasticity management and stretching/orthotics to prevent contractures - Bowel regimen to prevent chronic constipation and impaction - Nutritional support to prevent FTT sequelae - Orchidopexy to reduce cryptorchidism‑related fertility/malignancy risk - Behavioural support to prevent crisis and placement breakdown - Fall/fracture prevention in the immobile subset

Immunization

No disease‑specific vaccine strategy. Routine childhood immunisation is indicated and should not be deferred — recurrent respiratory infections are an annotated feature (HP:0002205, HP:0002788), making influenza and pneumococcal vaccination particularly worthwhile. Note that the zebrafish interferon findings do not constitute any contraindication.

Screening and Early Detection

Population screening / newborn screening: not indicated, not available (no treatable metabolic marker; does not meet Wilson‑Jungner criteria).
Carrier screening: not on expanded carrier panels.
Genetic screening in families with a known variant:
Prenatal diagnosis — CVS or amniocentesis for the known familial variant
Preimplantation genetic testing for monogenic disease (PGT‑M) — technically straightforward for a known KDM5C variant
Both require prior identification of the familial variant; counsel explicitly that a female fetus carrying the variant has a substantial (~56%) chance of being affected, which materially changes historical "carrier daughters are unaffected" counselling
Risk stratification: no validated model.

Behavioural Interventions

None reduce disease risk. Behavioural intervention is treatment (§12), not prevention.

Counselling

Genetic counselling is the central preventive intervention (NCIT:C15240). Key content, updated for current evidence:

De novo is now the majority mode (>50%) — a substantially lower recurrence risk than the classic X‑linked‑recessive family framing implies. Quote empiric ~1% for gonadal mosaicism after an apparently de novo variant.
Carrier mother: 50% transmission to each child; sons who inherit will be affected (~98%); daughters who inherit have ~56% chance of ID/learning disability and ~18–19% chance of seizures — they are not reliably unaffected.
Affected male: all daughters obligate carriers, no sons affected (rare paternal transmission documented, ~1%).
Offer maternal testing, cascade testing of maternal relatives, and prenatal/PGT‑M options.
Counsel on the wide variable expressivity including the documented no‑ID case — prognosis cannot be predicted precisely from genotype.
Connect to the RARE‑X KDM5C Data Collection Program and patient advocacy.

Carmignac et al. make the counselling point directly: consideration of "XLID genes in females, even in sporadic affected individuals" is required (PMID:32279304).

Public Health / Environmental Interventions / Prophylaxis

Not applicable — no environmental determinant, no infectious transmission, no prophylactic medication or procedure.

14. Other Species / Natural Disease

Taxonomy

KDM5C orthologues are present across vertebrates and, as a single ancestral KDM5 gene, across bilaterians:

Species	NCBI Taxon	Gene	NCBI Gene ID
Homo sapiens	`NCBITaxon:9606`	KDM5C	8242
Mus musculus	`NCBITaxon:10090`	Kdm5c	MGI:99781 (ChrX:151,016,016–151,057,531, + strand)
Rattus norvegicus	`NCBITaxon:10116`	Kdm5c	RGD ortholog
Danio rerio	`NCBITaxon:7955`	kdm5c	ZFIN
Drosophila melanogaster	`NCBITaxon:7227`	Kdm5/lid ("little imaginal discs") — single KDM5 family gene, autosomal	FlyBase
Caenorhabditis elegans	`NCBITaxon:6239`	rbr-2	WormBase

The Drosophila situation is analytically valuable: a single autosomal Kdm5 gene collapses the KDM5A/B/C/D paralogue redundancy and removes sex‑chromosome dosage effects. The RARE‑X team exploited exactly this — fly seizures show "no sex differences in flies (unlike humans), reflecting autosomal Kdm5 location" (PMID:41537560), cleanly attributing the human sex bias to X‑linkage/XCI‑escape rather than to KDM5 biology itself.

Breed

Not applicable. No breed‑associated KDM5C disorder in any domestic species. No VBO identifier applies.

Natural Disease in Other Species

None documented. An OMIA search for KDM5C returned "No phene records found" — there is no naturally occurring KDM5C disease in companion animals, livestock, or wildlife. All non‑human disease models are engineered, not natural.

Veterinary relevance: none.

Comparative Biology

Evolutionary conservation is high and functionally validated. Three independent lines: - Sequence: the S451R variant residue "is conserved" across JARID1 family members "and in mouse and fruit fly" (PMID:16538222); pathogenic missense variants "alter evolutionarily conserved amino acids" (PMID:15586325); ARID‑domain disease variants "are located in a highly-conserved part of the ARID structure" (PMID:26580603). - Enzymatic: H3K4me3 demethylase activity is shared across the whole KDM5 family — "Other family members including SMCY, RBP2, and PLU-1 also demethylated H3K4me3" (PMID:17320160). - Phenotypic: the cognitive/behavioural consequence of KDM5 loss is conserved from fly (impaired learning/memory, seizures) through zebrafish (behavioural and morphological defects) to mouse (memory deficits, aggression, social deficits) to human (ID, seizures, aggression). This cross‑phylum concordance is unusually strong for an ID gene and materially raises confidence in the model systems.

Comparative pathology — differences worth noting: - Mouse Kdm5c‑KO shows no gross brain cytoarchitectural abnormality, mirroring the largely normal human MRI — good fidelity. - The mouse phenotype is regionally selective (basolateral amygdala ≫ motor cortex); no human equivalent has been sought. - Fly Kdm5 loss produces a ribosome/translation deficit not yet demonstrated in mammals — a candidate HUMAN_MODEL_MISMATCH. - Zebrafish mutants show cartilage/craniofacial defects and an interferon signature; the craniofacial arm loosely echoes human maxillary hypoplasia, but the interferon arm has no human correlate.

Transmission

Not applicable — non‑infectious, no zoonotic potential, no cross‑species susceptibility.

15. Model Organisms

15.1 Mouse — the principal mammalian model

Resource: MGI:99781. 38 total mutations and alleles (7 endonuclease‑mediated, 24 gene‑trapped, 7 targeted); 22 strains/lines available via IMSR. "22 phenotypes from 4 alleles in 4 genetic backgrounds." MGI explicitly curates a mouse model of "Syndromic X-linked intellectual disability Claes-Jensen type (OMIM:300534)."

Model types available: constitutive knockout, gene‑trap, targeted/conditional (floxed), endonuclease‑mediated (CRISPR) alleles, and forebrain‑specific inducible KO (ifKO) used in the Barco lab studies.

Phenotype recapitulation — Iwase et al. 2016 (PMID:26804915), the flagship:

Domain	Mouse finding	Human counterpart
Aggression	"latency of the first attack to the intruder mouse was significantly shorter for Kdm5c-KO than WT mice (KO: 12.7 ± 2.4 sec, n = 13; WT: 37.6 ± 9.2 sec, n = 13; P < 0.05)"	Aggressive behaviour, HP:0000718, 13/38
Social behaviour	"WT mice spent significantly more time exploring the stimulus mouse than an inanimate object, Kdm5c-KO mice spent similar time between the two"	ASD 65%
Memory	"Kdm5c-KO mice showed significantly reduced freezing responses"; Morris water maze "significantly slower decline in latency" (P<0.01)	Intellectual disability
Anxiety	"Kdm5c-KO mice spent significantly more time in the open arms of the maze" — i.e. reduced anxiety‑like behaviour	⚠️ Direction mismatch — humans show anxiety in 71%
Growth	"Kdm5c-KO mice exhibited smaller body size and reduced body weight (P < 0.005)" — noted as "comparable to shorter stature in ~60% of affected individuals"	Short stature 50–78%
Brain structure	"no gross abnormalities in the cytoarchitecture of the adult Kdm5c-KO cerebral cortex, hippocampus, or amygdala"	Normal/near-normal MRI
Dendrites (BLA)	"dendrites of BLA pyramidal neurons showed significantly reduced total length (P < 0.0005)"; "reduced spine density, approximately 45% of WT"; spines "noticeably thinner," lacking "mature mushroom-like morphology"	No human data
Dendrites (motor cortex)	"slight (9%) but significant reduction of spine density (P < 0.05)"	No human data
Chromatin	"94% of Kdm5c-bound promoters contain a CpG island" (P<1×10⁻²⁶); "global levels of H3K4me1, me2 or me3 are comparable in WT and Kdm5c-KO neurons"	Consistent with locus-specific human episignature

Model limitations (Iwase 2016): - Seizures were not a reported phenotype, despite 35–48% seizure frequency in humans. The seizure phenotype had to be modelled in Drosophila instead (PMID:41537560) — a real gap in the mouse. - Anxiety runs the wrong direction (mouse anxiolytic‑like, human anxious). - Heterozygous females were not examined: "The KDM5C gene is X-linked in humans and mice, and affected human individuals are predominantly male, so we focused our analyses on male hemizygous animals." This omission was corrected seven years later by Bonefas & Iwase (PMID:36831303), who found "gene expression and behavioral abnormalities are readily detectable in Kdm5c-heterozygous female mice" and identified "sex-specific consequences of a reduced KDM5C dose in social behavior, gene expression." This is a case study in how a male‑only model design propagated the false 'unaffected carrier' assumption. - No craniofacial or skeletal phenotype characterised; no epilepsy, GI, or ophthalmological modelling.

Other key mouse studies: - Scandaglia et al. 2017 (PMID:28978483) — Kdm5c‑null + forebrain‑specific inducible KO. Established the developmental‑repressor and adult‑surveillance dual role. - Vallianatos et al. 2020 (PMID:32483278) — Kmt2a;Kdm5c double mutant; mutual suppression. The therapeutic proof of concept. - Martín‑González et al. 2025 (PMID:40864554) — Kdm1a;Kdm5c double inducible forebrain KO; synergistic loss of neuronal identity and increased CA1 excitability. - Karwacki‑Neisius et al. 2024 (PMID:38383780) — Kdm5c‑KO + human patient‑derived cells; WNT‑window rescue. The most translationally significant mouse result to date.

15.2 Zebrafish (Danio rerio)

Two generations of work: - Iwase et al. 2007 (PMID:17320160) — original: zebrafish and mammalian neuron studies revealed "roles in neuronal survival and dendritic development linked to demethylase activity." - Liao et al. 2026 (PMID:41743791) — a full patient‑variant model. Two clinical variants (c.3019del, c.782‑2A>T) expressed in zebrafish: - Morphology: "significantly reduced head area, body length, and eye size compared with control and WT groups" — directly models microcephaly and short stature; Alcian blue showed "impaired cartilage development" - Specificity control performed: "Co-injection with WT KDM5C mRNA rescued these phenotypic defects" — an important rigour marker - Behaviour: "All behavioral parameters were significantly altered in the c.3019del and c.782-2A>T groups" (reduced distance travelled and swimming speed), partially rescued by WT mRNA - Transcriptomics: 363 and 326 DEGs, overwhelmingly upregulated, enriched for antiviral/interferon responses; six validated genes (TLR3, NFKB1, IFNB1, IRF7, SAT1a, SAT1b) - Pharmacological rescue: CU‑CPT 4a at ½ LC50 — "Treatment partially restored morphological defects" and "spontaneous swimming activity was restored"

Strengths: rapid, scalable variant‑function assay with built‑in WT rescue control; models the growth/microcephaly axis the mouse handles less directly. Limitations: morpholino/mRNA‑injection transient models rather than stable germline mutants; the interferon signature is unreplicated and may be an injection artefact; no cognitive readout; single study.

15.3 Drosophila melanogaster

Single autosomal Kdm5/lid gene — the analytical advantage described in §14.

Zamurrad et al. 2018 (PMID:29490272) — kdm5^A512P, a knock‑in of the fly residue equivalent to a human KDM5C disease missense variant. Found "a striking downregulation of genes required for ribosomal assembly and function" and reduced translation; "kdm5^A512P flies also showed impaired learning and/or memory." Concluded "the primary defect of the KDM5A512P mutation is a loss of histone demethylase activity."
Terry et al. 2026 (PMID:41537560) — the seizure model, and the most clinically decisive fly result:
Neuronal knockdown (elav>shKdm5): mechanical stress "Significantly more knockdown flies exhibited seizures (53%) than controls (19%)"; heat stress 58% vs 9%; spontaneous 6.74% vs 0%
Cell‑type specificity: "Reducing the expression of its single Kdm5 gene in neurons, but not glia, led to spontaneous and stimulus-induced seizures"
Dissociation from gross morphology: mushroom body reduction caused morphological defects but not seizures — separating the structural from the excitability phenotype
Yheskel et al. 2025 (PMID:41340160) — compared demethylase‑dead (Kdm5^JmjC*) vs pathogenic ID variant (Kdm5^L854F). Found the two "produced divergent effects on H3K4me3 distribution" yet "similar transcriptional dysregulation" not correlated with recruitment, H3K4me3, or accessibility; instead "altered gene expression in both alleles correlates with preexisting chromatin signatures." Conclusion: "KDM5 operates in conjunction with local chromatin contexts to employ demethylase-dependent and independent mechanisms."
Related: Hatch et al. on the KDM5–Prospero axis in mushroom body development; PMID:39677601 (bioRxiv preprint) on KDM5 insulator activity in the brain — preprint, not peer‑reviewed; do not cite as evidence.

Strengths: the only system that has reproduced the seizure phenotype; enables clean neuron‑vs‑glia and enzymatic‑vs‑non‑enzymatic dissection; no paralogue redundancy or sex‑chromosome confound. Limitations: no mammalian cortex; "learning/memory" assays are only loosely homologous to human cognition; the ribosome finding remains fly‑specific.

15.4 Cellular and In Vitro Models

Patient‑derived primary fibroblasts — the workhorse for variant functional assay: protein stability, demethylase activity, and "local changes in chromatin conformation and gene expression" (PMID:25666439).
Patient‑derived cells for WNT rescue — used in PMID:38383780; the substrate for demonstrating pharmacological reversibility.
Primary cortical/hippocampal neuron culture with KDM5C overexpression — used to show R1115H's non‑enzymatic defect in post‑mitotic neurons (PMID:29670509).
Biochemical/structural: recombinant ARID domain with urea‑induced unfolding and binding free‑energy calculations (PMID:26580603) — a COMPUTATIONAL + IN_VITRO hybrid.
iPSC / cerebral organoids: no published MRXSCJ iPSC or organoid model. Given the WNT‑timed progenitor mechanism, human cortical organoids are the obvious missing system and the single highest‑value model gap. Curate as KNOWLEDGE_GAP with proposed_experiments.

15.5 Model Databases

MGI (MGI:99781), IMSR (22 strains), IMPC, KOMP/EuMMCR, ZFIN, FlyBase, WormBase, Alliance of Genome Resources, Cellosaurus (for patient fibroblast lines, where deposited).

Appendix A — Consolidated Reference List

Landmark and current sources, with PMIDs for just fetch-reference.

Disease definition and clinical delineation | PMID | Citation | Evidence source | |---|---|---| | 9377804 | Claes S et al. Clin Genet 1997 — original Belgian family (linkage then placed at Xq27‑28) | HUMAN_CLINICAL | | 10982473 | Claes S et al. Am J Med Genet 2000 — "Novel syndromic form of X-linked complicated spastic paraplegia" | HUMAN_CLINICAL | | 15586325 | Jensen LR et al. Am J Hum Genet 2005 — gene discovery, 7 mutations in 210 XLMR families | HUMAN_CLINICAL | | 16541399 | Tzschach A et al. Hum Mutat 2006 — 5 novel mutations | HUMAN_CLINICAL | | 16538222 | Santos C et al. Eur J Hum Genet 2006 — S451R | HUMAN_CLINICAL | | 18697827 | Abidi FE et al. J Med Genet 2008 — ID + short stature + hyperreflexia triad; frequencies | HUMAN_CLINICAL | | 24583395 | Gonçalves TF et al. Eur J Med Genet 2014 — Brazilian screen, 0.7% frequency | HUMAN_CLINICAL | | 25649377 | Tzschach A et al. Eur J Hum Genet 2015 — 107-gene XLID NGS panel | HUMAN_CLINICAL | | 32279304 | Carmignac V et al. Clin Genet 2020 — female phenotype, 19 new individuals | HUMAN_CLINICAL | | 39835750 | Ghasemi et al. Mol Genet Genomic Med 2025 — 175-case review, sex-stratified frequencies | HUMAN_CLINICAL | | 41537560 | Terry et al. Hum Mol Genet 2026 — RARE-X, 269 individuals + Drosophila seizures | HUMAN_CLINICAL + MODEL_ORGANISM (split the evidence items) |

Case reports expanding the spectrum | PMID | Citation | |---|---| | 36536324 | Shen R et al. BMC Neurol 2022 — female, de novo p.S1178X, no skewed XCI | | 36553533 | Lintas C et al. Genes 2022 — 27-y-old female, de novo p.Glu1283 | | 39948613 | Meng Y et al. Ital J Pediatr 2025 — p.R929X, NMD + mislocalisation | | 40346491 | Shaheen MM et al. BMC Pediatr 2025 — first Palestinian case, post-viral regression | | 40125771 | Murati FA et al. J Pediatr Ophthalmol Strabismus 2025 — Claes-Jensen without ID* |

Mechanism | PMID | Citation | Evidence source | |---|---|---| | 7951230 | Agulnik AI et al. Hum Mol Genet 1994 — SMCX escapes X-inactivation | IN_VITRO | | 17320160 | Iwase S et al. Cell 2007 — KDM5 family are H3K4 demethylases | IN_VITRO | | 17468742 | Tahiliani M et al. Nature 2007 — SMCX–REST/HDAC/G9a, SCN2A/SYN1 | IN_VITRO | | 23246292 | Poeta L et al. Am J Hum Genet 2013 — ARX → KDM5C regulatory axis | MODEL_ORGANISM + IN_VITRO | | 23356856 | BMC Med Genomics 2013 — multilocus loss of DNA methylation | HUMAN_CLINICAL | | 25666439 | Brookes E et al. Hum Mol Genet 2015 — protein stability + activity | IN_VITRO | | 26580603 | Peng Y et al. Int J Mol Sci 2015 — ARID domain variants | COMPUTATIONAL + IN_VITRO | | 26804915 | Iwase S et al. Cell Rep 2016 — Kdm5c-KO mouse | MODEL_ORGANISM | | 28978483 | Scandaglia M et al. Cell Rep 2017 — spurious transcription, enhancer fine-tuning | MODEL_ORGANISM | | 29670509 | Vallianatos CN et al. Front Mol Neurosci 2018 — R1115H, non-enzymatic role | IN_VITRO | | 29490272 | Zamurrad S et al. Cell Rep 2018 — Drosophila kdm5^A512P, ribosome/translation | MODEL_ORGANISM | | 32483278 | Vallianatos CN et al. Commun Biol 2020 — KMT2A/KDM5C mutual suppression | MODEL_ORGANISM | | 34536985 | Hatch HAM & Secombe J FEBS J 2022 — review | OTHER | | 36831303 | Bonefas & Iwase Cells 2023 — sexually dimorphic; heterozygous females affected | MODEL_ORGANISM | | 38383780 | Karwacki-Neisius V et al. Nature 2024 — WNT window, rescue | MODEL_ORGANISM + IN_VITRO | | 40864554 | Martín-González AM et al. Cell Rep 2025 — KDM1A/KDM5C cooperation | MODEL_ORGANISM | | 41340160 | Yheskel M et al. Epigenetics Chromatin 2025 — chromatin-context dependence | MODEL_ORGANISM | | 41743791 | Liao et al. Front Mol Neurosci 2026 — zebrafish, TLR/interferon, CU-CPT 4a | MODEL_ORGANISM |

Diagnostics / epigenetics | PMID | Citation | |---|---| | 29456765 | Schenkel LC et al. Clin Epigenetics 2018 — Claes-Jensen episignature | | 31419599 | Eur J Med Genet 2020 — monozygotic twin methylation fingerprint | | 35781022 | Eur J Med Genet 2022 — methylation profiling for variant reclassification | | 37872275 | Husson T et al. Eur J Hum Genet 2024 — independent episignature evaluation (caveat source) | | 41957673 | Koparir A et al. Clin Epigenetics 2026 — chromatinopathies, 400 individuals, EpiSign |

Non-literature resources consulted: EBI OLS4 (MONDO, ORDO); HPO/JAX annotation API (OMIM:300534); NCBI MedGen 335139; NCBI ClinVar (528 P/LP records); ClinGen (Gene-Disease Validity: Definitive, ID & Autism GCEP 2018-09-19; Dosage HI=3/TS=0, 2023-07-27; pLI=1, LOEUF=0.17); UniProt P41229; MGI:99781; OMIA (no entries).

Appendix B — Curation Notes for the dismech Entry

Suggested pathophysiology node chain (each biological_scale tagged; keep nodes atomic — see the single-value discipline in CLAUDE.md):

Node	`biological_scale`	Key evidence
KDM5C Loss of Function	MOLECULAR	PMID:15586325, PMID:25666439
Impaired H3K4me3/me2 Demethylation at CpG-Island Promoters	MOLECULAR	PMID:17320160, PMID:26804915
Loss of Non-Enzymatic KDM5C Scaffolding Function	MOLECULAR	PMID:29670509, PMID:41340160
REST Complex Target Derepression	MOLECULAR	PMID:17468742
Dysregulated Canonical WNT Signalling During Corticogenesis	CELLULAR	PMID:38383780
Mistimed Progenitor Transition and Neurogenesis	CELLULAR	PMID:38383780
Spurious Transcription and Loss of Neuronal Identity	CELLULAR	PMID:28978483, PMID:40864554
Impaired Dendritic Arborisation and Spine Maturation	TISSUE	PMID:26804915
Neuronal Hyperexcitability	CELLULAR	PMID:40864554, PMID:41537560
Intellectual Disability and Neurobehavioural Phenotype	ORGANISM	PMID:41537560, PMID:39835750

Module conformance: No existing dismech module is a good fit. epilepsy_excitation_inhibition_imbalance is a partial fit at the seizure node only (epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance) — the KDM1A/KDM5C ion-channel and CA1-excitability data (PMID:40864554) and the neuron-specific fly seizure result (PMID:41537560) support conformance there. Do not force-fit any degeneration, fibrosis, or storage module. Consider proposing a new chromatin_h3k4_writer_eraser_imbalance module (see §6.7).

Recommended discussions entries: - KNOWLEDGE_GAP — no single-cell or spatial transcriptomic data despite strong region-specificity (amygdala ≫ cortex) in mouse; proposed_experiments: snRNA-seq of human post-mortem or iPSC-derived cortical/amygdalar tissue. - KNOWLEDGE_GAP — no iPSC/cerebral organoid model; the WNT critical-window mechanism cannot be tested in human tissue without one. - KNOWLEDGE_GAP — no validated QoL instrument, no survival/mortality data, no adult natural-history cohort (RARE-X max age 20 y). - KNOWLEDGE_GAP — XCI skewing does not reliably explain the female phenotype spectrum, and KDM5C escapes XCI; the determinant of female severity is unknown. - HUMAN_MODEL_MISMATCH — mouse Kdm5c-KO shows reduced anxiety-like behaviour whereas 71% of humans have anxiety; and the mouse does not seize despite 35–48% human epilepsy (seizures required a Drosophila model). Both are direction/presence mismatches, not absent evidence. - HUMAN_MODEL_MISMATCH — the Drosophila ribosome/translation deficit (PMID:29490272) and the zebrafish interferon/TLR signature (PMID:41743791) have no demonstrated human correlate.

Do not curate as established: the TLR/interferon therapeutic axis (zebrafish, n=1 study); the "missense = milder than nonsense" genotype–phenotype rule (contradicted by R1115H and D87G); episignature 100% sensitivity (training-cohort figure, n=7, with PMID:37872275 as the counterweight); post-viral regression as a disease feature (single case).

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Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

Comprehensive Research Report

Claes–Jensen Type X‑Linked Intellectual Disability (MRXSCJ)

⚠️ Curation Preamble — Read Before Using This Report

1. Disease Information

Overview

Key Identifiers

Synonyms and Alternative Names

Data Provenance Character

2. Etiology

Disease Causal Factors

Risk Factors

Protective Factors

Gene–Environment Interactions

3. Phenotypes

3.1 Authoritative HPO Annotations (HPO/JAX API, OMIM:300534)

3.2 Modern Cohort Frequencies (supersede HPO fractions for common features)

3.3 Phenotype Characteristics

4. Genetic / Molecular Information

Causal Gene

Pathogenic Variants

Modifier Genes

Epigenetic Information

Chromosomal Abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 The Causal Chain (upstream → downstream)

6.2 Molecular Pathways

6.3 Cellular Processes

6.4 Protein Dysfunction

6.5 Metabolic Changes

6.6 Immune System Involvement

6.7 Tissue Damage Mechanisms

6.8 Epigenetic Changes

6.9 Molecular Profiling

7. Anatomical Structures Affected

Organ Level

Tissue and Cell Level

Subcellular Level

Localization and Lateralization

8. Temporal Development

Onset

Progression

Patterns

9. Inheritance and Population

Epidemiology

Genetic Etiology Parameters

Population Demographics

10. Diagnostics

Clinical Tests

Genetic Testing

Omics‑Based Diagnostics

Clinical Criteria

Screening

11. Outcome / Prognosis

Survival and Mortality

Morbidity and Function

Disease Course and Complications

Prediction

12. Treatment

Pharmacotherapy (all symptomatic)

Advanced Therapeutics

Experimental / Preclinical Strategies

Surgical and Interventional

Supportive and Rehabilitative — the mainstay

Treatment Outcomes

3.1 Authoritative HPO Annotations (HPO/JAX API, `OMIM:300534`)