Intellectual Disability Autosomal Recessive 65

Mendelian MONDO:0020850 Pathograph 16 Show in embeddings browser hereditary neurological disease syndromic intellectual disability Mendelian disorder of the epigenetic machinery

MRT65 is a rare autosomal recessive neurodevelopmental disorder caused by biallelic (homozygous or compound heterozygous) disruptive variants in KDM5B, the gene for a JmjC-domain histone demethylase that removes methyl groups from lysine 4 of histone H3. It was defined in 2018 by two papers published within a year of each other: a genome-wide recessive burden analysis of the Deciphering Developmental Disorders cohort, which named KDM5B and EIF3F as the two genes newly associated with recessive developmental disorders, and a pathway-based survey of the histone lysine methylases and demethylases, which described the resulting entity as a recognisable syndrome of developmental delay, facial dysmorphism and camptodactyly. Roughly ten individuals with biallelic KDM5B variants have been reported. Developmental delay or impaired intellectual development is present in all of them; facial dysmorphism, behavioural problems and macrocephaly are recurrent, and agenesis of the corpus callosum has been described in a subset. The interesting thing about this gene is that the recessive entity is only one end of a dose-response relationship, and the entry is scoped deliberately to that end. In the Deciphering Developmental Disorders cohort KDM5B was the only gene enriched for biallelic variants and de novo mutations at the same time. Heterozygous KDM5B loss-of-function alleles are found in unaffected relatives and in population controls, do not segregate cleanly within families, and at population scale associate with a measurable downward shift in adult cognitive function rather than with a discrete disease. One group put it as "a spectrum of recessiveness". So the reduced penetrance that is repeatedly documented in the KDM5B literature is a statement about the *heterozygous* state; it is not, on the sources available, a statement about the biallelic genotype that defines MRT65. See the inheritance block and the discussions for how far that distinction can currently be pushed. SCOPE NOTE. This entity is defined by biallelic KDM5B. It must not be conflated with (a) the disorders of the KDM5 paralogues, which are separate genes with separate disease associations - in particular KDM5C, which causes Claes-Jensen type X-linked intellectual disability and is curated separately here; (b) the proposed dominant, monoallelic KDM5B-related neurodevelopmental disorder, whose existence and boundaries are still argued over and which is the subject of a discussion below rather than of this entry; (c) the large somatic KDM5B cancer literature, in which the gene appears under its older names PLU-1 and JARID1B as an amplified oncogene in breast cancer and a driver of drug-tolerant persister states in melanoma - a different biological context entirely; or (d) RUSC2-related Alwadei syndrome (OMIM 617773), a distinct recessive intellectual disability syndrome that some tertiary aggregator pages conflate with this one.

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Mappings
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Inheritance
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Pathophys.
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Phenotypes
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Gaps
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Pathograph
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Genes
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Medical Actions
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Models
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References
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Deep Research
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Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
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Mappings

MONDO
MONDO:0019502 autosomal recessive non-syndromic intellectual disability DisMech
skos:broadMatch MONDO
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Two disruptive KDM5B alleles are required, in cis-trans configuration confirmed where phasing was possible; reported genotypes are homozygous nonsense, compound heterozygous nonsense or frameshift pairs, and one JmjC-domain missense allele in trans with a frameshift null. Penetrance is recorded as UNKNOWN, and that is a deliberate reading of what the sources will and will not support. Every reported individual carrying two disruptive KDM5B alleles has had developmental delay or impaired intellectual development, and no unaffected biallelic individual has been described. But all of those individuals were ascertained through an affected proband, in a literature of about ten cases, so the observation cannot distinguish complete penetrance from ascertainment. No study has estimated penetrance for the biallelic genotype, and none of the sources reviewed reports an unaffected homozygous or compound heterozygous relative. COMPLETE would overstate a case series; INCOMPLETE would import a finding that belongs to a different genotype. That different genotype is the heterozygous one, and there the reduced penetrance is documented and repeatedly restated: heterozygous KDM5B loss-of-function alleles turn up in unaffected relatives and in population controls, dominant loss-of-function variants do not segregate with disease within families, and the gnomAD observed-to-expected ratio for loss-of-function of about 0.57 is read by the same authors as partial penetrance of heterozygous loss of function. Keeping the two apart is the point: the KDM5B penetrance literature is about carriers, not about patients with MRT65. Expressivity is recorded as VARIABLE. Severity of the intellectual disability ranges from mild in the two biallelic individuals of the 2024 cohort to moderate-to-severe in the earlier literature, and structural brain malformation is present in some biallelic individuals and absent in others.
Autosomal recessive inheritance Penetrance: UNKNOWN Expressivity: VARIABLE
Show evidence (5 references)
PMID:39202393 SUPPORT Human Clinical
"Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65."
States the recessive, biallelic genotype that defines this entity.
PMID:39202393 SUPPORT Human Clinical
"In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives."
The documented unaffected carriers are heterozygous, not biallelic. This is the sentence behind the entry's decision to record reduced penetrance as a property of the heterozygous state and to leave biallelic penetrance unknown.
PMID:39202393 SUPPORT Human Clinical
"This is in line with a partial penetrance of heterozygous LoF KDM5B variants."
The authors' own reading of the gnomAD constraint data, stated for the heterozygous genotype specifically.
+ 2 more references
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Discussions and Knowledge Gaps

5
Is there a distinct dominant, monoallelic KDM5B neurodevelopmental disorder, or is MRT65 the only KDM5B disease and heterozygous loss of function merely a quantitative shift in cognitive function?
CONTROVERSY OPEN kdm5b_dominant_disorder_existence
Attached to
genetic#KDM5B inheritance#Autosomal recessive inheritance disease#Intellectual Disability Autosomal Recessive 65
The literature has argued both sides and has not settled. On one side, a 2018 functional study of splice variants concluded flatly that KDM5B haploinsufficiency is not a mechanism in intellectual disability and that the KDM5B loss-of-function disorder is recessive; the same paper notes that de novo loss-of-function and missense KDM5B variants have been found in unaffected individuals as well as in patients. On the other, a 2024 genotype-phenotype study of 21 individuals - nineteen of them monoallelic - describes a monoallelic phenotype in detail and argues for the pathogenicity of certain dominant missense variants. Its own framing is that there is "a spectrum of recessiveness" in KDM5B disease. The population data are what make this hard rather than merely under-reported. Heterozygous KDM5B protein-truncating variants are common enough in the general adult population to be studied at biobank scale, where they associate with a measurable downward shift in cognitive function - a quantitative effect, not a disease. That is compatible either with a dominant disorder of very reduced penetrance or with no dominant disorder at all and a dose-response relationship whose lower end is subclinical. What this entry does about it: it scopes itself to the biallelic genotype, which is what MONDO:0020850 and OMIM 618109 name and what every source agrees is disease-causing. It does not curate a dominant KDM5B entity, and it does not import monoallelic phenotype frequencies into the biallelic phenotype list. If a dominant entity is eventually accepted with its own MONDO term, it should be a separate entry, not a subtype here.
Show evidence (4 references)
PMID:30217758 SUPPORT Human Clinical
"Our data reinforces the recent observation that the KDM5B haploinsufficiency is not a mechanism involved in intellectual disability and that KDM5B disorder associated with LOF variants is a recessive disorder."
The recessive-only position, stated explicitly.
PMID:30217758 SUPPORT Human Clinical
"Interestingly, de novo loss-of-function and missense variants in KDM5B were identified in patients with intellectual disability (ID) and autism spectrum disorder (ASD) but also in unaffected individuals."
The observation that drives the recessive-only position: the same de novo alleles appear in affected and unaffected people.
PMID:39202393 REFUTE Human Clinical
"In our opinion, there is a spectrum of recessiveness in KDM5B-related diseases"
Graded REFUTE against the strict recessive-only position quoted above: this cohort argues that monoallelic KDM5B variants can be pathogenic and that the recessive-versus-dominant question is not binary. It does not refute the biallelic disease claim, which this paper affirms elsewhere in the entry.
+ 1 more reference
What is the penetrance of the biallelic KDM5B loss-of-function genotype? No study has estimated it, and the reduced penetrance that the KDM5B literature repeatedly documents belongs to the heterozygous state.
KNOWLEDGE GAP OPEN kdm5b_biallelic_penetrance_unmeasured
Attached to
inheritance#Autosomal recessive inheritance genetic#KDM5B
Every published individual with two disruptive KDM5B alleles has been affected. That is a real observation and it is why the entry does not record incomplete penetrance. But all of them were ascertained through an affected proband in a literature of about ten cases, so it cannot separate complete penetrance from the ascertainment that produced the case series, and no source reviewed here reports an unaffected homozygous or compound heterozygous relative. Penetrance is therefore recorded as UNKNOWN rather than COMPLETE. The reason the question is live rather than pedantic is the gene's behaviour one dose up. Heterozygous loss-of-function alleles are tolerated well enough to sit in population reference data at an observed-to-expected ratio near 0.57, which the 2024 cohort reads as partial penetrance, and they do not segregate with disease in families. A gene whose heterozygous null state is that permissive is exactly the kind of gene where an unaffected biallelic individual would be worth actively looking for. Resolving it needs population-scale data rather than more case reports: a genotype-first search of a large biobank or a consanguineous-population cohort for biallelic KDM5B loss-of-function individuals, with phenotyping that does not presuppose they were referred for developmental delay.
Proposed experiments
Genotype-first ascertainment of biallelic KDM5B loss-of-function carriers
kdm5b_genotype_first_biallelic_ascertainment
Search large unselected exome or genome cohorts, weighted toward populations with high autozygosity, for individuals homozygous or compound heterozygous for KDM5B protein-truncating alleles, then phenotype them through linked health records and direct cognitive assessment rather than through the referral route that produced the existing case series.
Decision criterion
Whether any ascertained biallelic individual lacks developmental delay or intellectual disability on direct assessment.
Would support
inheritance#Autosomal recessive inheritance
Supporting outcome
  • Every biallelic individual found by genotype-first ascertainment has developmental delay or intellectual disability, which would move penetrance from UNKNOWN toward COMPLETE.
Refuting outcome
  • Unaffected or minimally affected biallelic individuals are found, which would establish incomplete penetrance for the biallelic genotype and change both the recurrence-risk counselling and the diagnostic weight of a biallelic finding.
Show evidence (2 references)
PMID:39202393 SUPPORT Human Clinical
"This is in line with a partial penetrance of heterozygous LoF KDM5B variants."
The documented partial penetrance, stated for the heterozygous genotype. This is the claim that must not be transferred to the biallelic genotype.
PMID:39202393 SUPPORT Human Clinical
"Moderate-to-severe DD and impaired intellectual development were common to all."
All reported biallelic individuals were affected, which is the observation the gap is about: it is consistent with complete penetrance and equally consistent with ascertainment.
Mice without KDM5B demethylase activity show autism-like behaviour, yet the reported biallelic human individuals do not have autistic behaviours. Is the NMDAR2D mechanism traced in the mouse relevant to MRT65 at all, or is it a model of the monoallelic human phenotype?
HUMAN MODEL MISMATCH OPEN kdm5b_mouse_autism_vs_human_biallelic
Attached to
pathophysiology#Increased Grin2d and NMDA Receptor Subunit 2D Expression animal_models#Kdm5b demethylase-deficient mouse (neocortical H3K4me3 study) phenotypes#Behavioral Abnormalities
This is a mismatch of the specific kind the HUMAN_MODEL_MISMATCH label exists for: the model evidence is strong and the human evidence is not absent, they simply point different ways. The mouse chain is unusually complete for a chromatinopathy - raised H3K4me3 at the Grin2d promoter, raised transcript, raised NMDAR2D protein in synaptosomes, socio-communication deficits, and rescue of the vocalisation deficit by memantine. But the endpoint it lands on is the feature the biallelic human individuals do not have. The 2024 cohort states that both of its biallelic individuals had behavioural problems without autistic behaviours, and notes the same monoallelic-versus-biallelic split for autistic behaviour that it had previously reported for another epigenetic regulator. Two readings survive. Either the mouse models the monoallelic end of the human dose-response, in which case its mechanism is about the contested dominant disorder and not about MRT65; or autistic behaviour in biallelic humans is simply undercounted at a denominator of two plus a small pooled literature. Nothing in the sources distinguishes them, and the entry does not pick: the Grin2d node is retained with mechanism_confidence HYPOTHETICAL, and autistic behaviour is not curated as a phenotype of this entity.
Show evidence (2 references)
PMID:42160407 SUPPORT Model Organism
"These mice exhibited autism-like behaviors and increased brain size."
The model phenotype, in mice without KDM5B demethylase activity.
PMID:39202393 REFUTE Human Clinical
"Both individuals with bi-allelic variants displayed behavioral problems such as mood swings and aggressivity, but they did not display autistic behaviors."
Graded REFUTE against the proposition that the mouse autism-like phenotype corresponds to a feature of the biallelic human disorder. It is the human observation that creates the mismatch.
Does NMDA receptor antagonism have any therapeutic potential in KDM5B-related neurodevelopmental disorder, given that memantine rescued a vocalisation deficit in demethylase-deficient mice?
EMERGING HYPOTHESIS OPEN kdm5b_nmdar_antagonism_as_target
Attached to
pathophysiology#Increased Grin2d and NMDA Receptor Subunit 2D Expression treatments#Supportive and Symptom-Directed Management
This is recorded as a hypothesis and nothing more. A single mouse study reports that memantine rescued ultrasonic vocalisation deficits in mice lacking KDM5B demethylase activity, downstream of raised Grin2d expression. That is a mechanistically motivated result, and it names a drug that is already licensed for other indications, which is why it is worth recording at all. Against it: the rescued endpoint is a mouse vocalisation deficit whose human counterpart is a socio-communication phenotype that the reported biallelic individuals do not have; no human has been treated; and no trial exists. The entry does not list memantine as a treatment, and this discussion should not be read as suggesting it be used.
Show evidence (1 reference)
PMID:42160407 SUPPORT Model Organism
"Treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalizations."
The rescue result. Mouse only, and the endpoint is a vocalisation measure.
Is the cognitive impairment in MRT65 fixed at the end of development, or does part of it reflect an ongoing adult requirement for KDM5B that might in principle remain modifiable?
OPEN QUESTION OPEN kdm5b_developmental_versus_ongoing_requirement
Attached to
pathophysiology#Impaired Activity-Dependent Gene Expression and Synaptic Plasticity animal_models#Adult hippocampal Kdm5b knockdown mouse
Knocking Kdm5b down in the adult mouse hippocampus alone - after development is complete - produces long-term memory and long-term potentiation deficits. That is a genuinely interesting result for a disorder that is otherwise described as a static developmental disability, because it separates the developmental requirement for the gene from a continuing one. Whether any part of the human phenotype has the same character is unknown: no longitudinal cognitive data exist for biallelic individuals, and the oldest reported individual is described only cross-sectionally. The question is recorded because it bears directly on whether a postnatal intervention window could exist at all, not because any intervention is available.
Show evidence (1 reference)
PMID:38575342 SUPPORT Model Organism
"Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits."
Adult-restricted knockdown is sufficient for the deficits, which is what raises the question of an ongoing rather than purely developmental requirement.
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Pathophysiology

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Biallelic KDM5B Loss of Function
Mechanism confidence: Established
The initiating lesion. Two disruptive KDM5B alleles - nonsense, frameshift, canonical splice-site, or a catalytic-domain missense in trans with a null - leave the cell without functional KDM5B. A single such allele does not produce this disorder, which is the whole content of calling the entity recessive.
KDM5B (lysine demethylase 5B) hgnc:18039 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDM5B (lysine demethylase 5B), annotated with KDM5B (hgnc:18039). hgnc:18039 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context KDM5B (lysine demethylase 5B) hgnc:18039 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns KDM5B (lysine demethylase 5B), annotated with KDM5B (hgnc:18039). hgnc:18039 is a gene from the HUGO Gene Nomenclature Committee. allele_type: nonsense, frameshift, canonical splice-site, or catalytic-domain missense in trans with a null allele variant_origin: GERMLINE allelic_hit_role: BIALLELIC_INACTIVATION zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Zygosity is recorded as HOMOZYGOUS because that is the single value the slot takes and homozygous nonsense alleles are the reported archetype; compound heterozygous genotypes are equally common in the case literature and are described in the genetic section.
Downstream
Loss of KDM5B H3K4 Demethylase Activity
Show evidence (2 references)
PMID:30409806 SUPPORT Human Clinical
"We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models."
The founding gene-disease association, from a genome-wide recessive burden analysis of 6,040 Deciphering Developmental Disorders families. Graded HUMAN_CLINICAL because the association itself is a human cohort finding; the same sentence also reports mouse and cellular validation, but a single quote carries a single grade.
PMID:29276005 SUPPORT Human Clinical
"Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly."
Names both reported biallelic configurations and the syndrome they produce.
Loss of KDM5B H3K4 Demethylase Activity
Mechanism confidence: Established
KDM5B is an Fe(II)/2-oxoglutarate-dependent JmjC-domain demethylase whose substrate is methylated lysine 4 of histone H3. Without it, the cell loses the enzyme that erases that mark. Note the direction of travel here: unlike most chromatinopathies, where a writer is lost and a permissive mark falls, the lesion in MRT65 removes an eraser, so the permissive mark accumulates.
histone H3K4me3/me2/me1 demethylase activity GO:0034647 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves histone H3K4me3/me2/me1 demethylase activity, annotated with histone H3K4me/H3K4me2/H3K4me3 demethylase activity (GO:0034647), qualified as loss of function. GO:0034647 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION histone H3K4 demethylase activity GO:0032453 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone H3K4 demethylase activity (GO:0032453). GO:0032453 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Elevated H3K4 Trimethylation at Developmental Gene Promoters
Show evidence (1 reference)
PMID:35905858 SUPPORT Other
"KDM5B is responsible for the demethylation of lysine 4 on the amino tail of histone 3 and plays a vital role in normal development and regulating cell differentiation."
States the enzyme's substrate specificity. Graded OTHER because this is a narrative review that reports no primary data of its own; the underlying biochemistry is in the papers it cites.
Elevated H3K4 Trimethylation at Developmental Gene Promoters
Mechanism confidence: Provisional
H3K4me3 is a promoter-proximal permissive mark. With the eraser gone it accumulates at the promoters of developmentally regulated and activity-dependent genes, shifting the permissive-repressive balance toward permissive - the same imbalance the chromatinopathy module describes, reached from the opposite direction. Recorded as PROVISIONAL for human disease: the accumulation is directly measured in mouse neocortex and has not been shown in tissue from an individual with MRT65.
chromatin organization GO:0006325 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated chromatin organization (GO:0006325). GO:0006325 is a biological process from the Gene Ontology. ↕ DYSREGULATED
chromatin GO:0000785 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves chromatin (GO:0000785). GO:0000785 is a cellular component from the Gene Ontology.
Animal models
Kdm5b demethylase-deficient mouse (neocortical H3K4me3 study) Mus musculus recapitulates H3K4me3 and neurodevelopmental gene expression are both raised in the developing mutant neocortex, which is the predicted consequence of losing the eraser.
Downstream
Dysregulated Neurodevelopmental Transcriptional Program
Show evidence (1 reference)
PMID:42160407 SUPPORT Model Organism
"H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex."
Direct measurement of the mark in the developing neocortex of mice lacking KDM5B demethylase activity.
Dysregulated Neurodevelopmental Transcriptional Program
Mechanism confidence: Provisional
The transcriptional consequence, and it is bidirectional rather than a simple upward shift. Neurodevelopmental genes are expressed at higher levels in the developing mutant neocortex, while activity-dependent immediate-early genes sit lower at baseline and then overshoot on stimulation. What the mark change costs the neuron is regulated, appropriately timed transcription, not transcription as such.
regulation of DNA-templated transcription GO:0006355 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves regulation of DNA-templated transcription (GO:0006355), qualified as loss of function. GO:0006355 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION nervous system development GO:0007399 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased nervous system development (GO:0007399). GO:0007399 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Increased Grin2d and NMDA Receptor Subunit 2D Expression
Impaired Activity-Dependent Gene Expression and Synaptic Plasticity
Altered Cortical Neurodevelopment and Brain Overgrowth
Show evidence (1 reference)
PMID:38575342 SUPPORT Model Organism
"The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice."
The bidirectional dysregulation, in demethylase-inactive mice.
Increased Grin2d and NMDA Receptor Subunit 2D Expression
Mechanism confidence: Hypothetical
One specific downstream target has been traced end to end in the mouse: raised H3K4me3 at the Grin2d promoter, raised Grin2d expression, and more NMDAR2D protein in synaptosomes from early postnatal neocortex. Recorded as HYPOTHETICAL for MRT65 because it is entirely a mouse result and because the behavioural readout it was traced to - socio-communication deficit - is the feature that biallelic human individuals conspicuously do not have. It is kept in the graph because it is the only mechanistically complete chromatin-to-synapse link anyone has for this gene, and because it names a druggable node.
Animal models
Kdm5b demethylase-deficient mouse (neocortical H3K4me3 study) Mus musculus recapitulates Raised H3K4me3 at the Grin2d promoter, raised Grin2d expression, and more NMDAR2D protein in synaptosomes from early postnatal neocortex.
Downstream
Impaired Activity-Dependent Gene Expression and Synaptic Plasticity
Show evidence (1 reference)
PMID:42160407 SUPPORT Model Organism
"Increased H3K4me3 levels at the promoter and associated expression of the Grin2d gene were associated with increased levels of N-methyl-d-aspartate receptor subunit 2D (NMDAR2D) protein in synaptosomes isolated from the early postnatal Kdm5b-deficient neocortex."
The full mark-to-transcript-to-protein chain, measured in Kdm5b-deficient mouse neocortex.
Impaired Activity-Dependent Gene Expression and Synaptic Plasticity
Mechanism confidence: Provisional
Where the chromatin defect becomes a neuronal one. Demethylase-inactive mice lose hippocampal long-term potentiation and long-term memory while short-term memory is spared, and knocking KDM5B down in the adult hippocampus alone reproduces that, which places part of the requirement for the enzyme after development rather than during it.
hippocampal neuron CL:0002608 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hippocampal neuron (CL:0002608). CL:0002608 is a cell type from the Cell Ontology. neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
regulation of synaptic plasticity GO:0048167 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of synaptic plasticity (GO:0048167). GO:0048167 is a biological process from the Gene Ontology. ↓ DECREASED long-term synaptic potentiation GO:0060291 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased long-term synaptic potentiation (GO:0060291). GO:0060291 is a biological process from the Gene Ontology. ↓ DECREASED learning or memory GO:0007611 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased learning or memory (GO:0007611). GO:0007611 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Kdm5b demethylase-inactive (delta-ARID) mouse Mus musculus recapitulates Hyperactivity and hippocampus-dependent long-term memory deficits, with immediate-early gene expression low at baseline and overshooting on a learning stimulus.
Adult hippocampal Kdm5b knockdown mouse Mus musculus perturbs Acute adult knockdown produces spontaneous seizures, hyperactivity, and long-term memory and long-term potentiation deficits, so part of the requirement for KDM5B is postnatal and ongoing rather than developmental.
Downstream
Global Developmental Delay
Impaired Intellectual Development
Show evidence (2 references)
PMID:38575342 SUPPORT Model Organism
"These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms."
The authors' own summary of the mouse result and of how far they take it toward the human cognitive phenotype.
PMID:38575342 SUPPORT Model Organism
"Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits."
Adult-only knockdown reproduces the deficit, so the requirement for KDM5B is not exclusively developmental.
Altered Cortical Neurodevelopment and Brain Overgrowth
Mechanism confidence: Hypothetical
A second branch, and a much weaker one. Mice without KDM5B demethylase activity have larger brains, and macrocephaly is recorded in biallelic human individuals, so a growth arm to the phenotype is plausible. Whether the same process accounts for the structural malformations seen in a subset - agenesis of the corpus callosum in particular - is not established, and the route from chromatin dysregulation to the craniofacial and hand features of the syndrome has not been worked out at all for this gene. Recorded as HYPOTHETICAL for that reason.
cerebral cortex neuron differentiation GO:0021895 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cerebral cortex neuron differentiation (GO:0021895). GO:0021895 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Kdm5b demethylase-deficient mouse (neocortical H3K4me3 study) Mus musculus partially recapitulates Increased brain size, which is the mouse counterpart of the macrocephaly recorded in biallelic human individuals.
Downstream
Macrocephaly
Agenesis of the Corpus Callosum
Show evidence (1 reference)
PMID:42160407 SUPPORT Model Organism
"These mice exhibited autism-like behaviors and increased brain size."
The brain-size finding in mice without KDM5B demethylase activity. The autism-like behaviour reported in the same sentence is discussed under discussions rather than curated as a phenotype of this entity.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Intellectual Disability Autosomal Recessive 65 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Head and Neck 2
Facial Dysmorphism FREQUENT Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39202393 SUPPORT Human Clinical
"Both individuals with bi-allelic variants presented with facial dysmorphisms, including a broad forehead and full nasal tip."
Names the specific features in the biallelic individuals.
PMID:35905858 SUPPORT Other
"Recessive variants in the gene encoding histone modifying enzyme KDM5B are associated with a DD characterized by developmental delay, facial dysmorphism and camptodactyly."
Review-level statement of the recessive syndrome's defining triad. Graded OTHER because the review presents no primary data of its own.
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39202393 SUPPORT Human Clinical
"Both individuals with bi-allelic variants presented with macrocephaly."
Directly states the finding in the biallelic individuals.
Musculoskeletal 2
Camptodactyly HP:0012385 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Camptodactyly (HP:0012385). HP:0012385 is a phenotype from the Human Phenotype Ontology.
No frequency band is asserted. The founding description treats camptodactyly as characteristic, but no source reviewed here gives a count for it among biallelic individuals, and the 2024 cohort tabulates finger anomalies under a broader heading.
Show evidence (2 references)
PMID:29276005 SUPPORT Human Clinical
"Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly."
Camptodactyly is one of the three features in the founding description.
PMID:35905858 SUPPORT Other
"Recessive variants in the gene encoding histone modifying enzyme KDM5B are associated with a DD characterized by developmental delay, facial dysmorphism and camptodactyly."
Independent restatement, four years later, that camptodactyly belongs to the recessive phenotype specifically.
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34573379 SUPPORT Human Clinical
"She displayed severe developmental delay with poor speech (5 words) and hypotonia."
Same compound heterozygous individual. The paper records hypotonia twice more in this case, at day 4 and at three months. No frequency band is attached because the HPO annotation for the biallelic entity does not list it.
Nervous System 5
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39202393 SUPPORT Human Clinical
"Moderate-to-severe DD and impaired intellectual development were common to all."
Pooled across the reported biallelic individuals; supports the VERY_FREQUENT band as well as the association.
PMID:29276005 SUPPORT Human Clinical
"Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly."
Developmental delay is one of the three features in the founding description of the syndrome.
Impaired Intellectual Development VERY_FREQUENT Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39202393 SUPPORT Human Clinical
"Both individuals with bi-allelic variants presented with a mild ID, and one of them presented with a GDD."
The 2024 biallelic pair, at the mild end of the reported range.
PMID:34573379 SUPPORT Human Clinical
"KDM5B variants have been previously associated with moderate to severe developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and dysmorphism in a few individuals, but the pathogenetic mechanisms are not clear yet as patients with both monoallelic and biallelic..."
The moderate-to-severe end of the range. Note the same sentence records that the published KDM5B phenotype pools monoallelic and biallelic individuals, which is why this entry treats severity as unsettled.
Behavioral Abnormalities Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Behavioral abnormality, annotated with Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39202393 SUPPORT Human Clinical
"Both individuals with bi-allelic variants displayed behavioral problems such as mood swings and aggressivity, but they did not display autistic behaviors."
Supports behavioural abnormality in the biallelic individuals, and in the same sentence records the absence of autistic behaviour that keeps autistic behaviour out of this entry's phenotype list.
Agenesis of the Corpus Callosum OCCASIONAL Agenesis of corpus callosum HP:0001274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis of corpus callosum (HP:0001274). HP:0001274 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:34573379 SUPPORT Human Clinical
"We studied a family in which the first-born child, a girl, had developmental delay, facial dysmorphism, and agenesis of the corpus callosum (ACC)."
The index observation, in a child later shown to carry two KDM5B variants in trans.
PMID:34573379 SUPPORT Human Clinical
"Interestingly, one individual has previously been reported with ACC and severe ID in association with biallelic KDM5B variants."
An independent earlier biallelic case with the same finding, which is what turns a single family into a phenotype claim.
PMID:39202393 SUPPORT Human Clinical
"Structural brain malformations were noted for three of the seven individuals with dominant variants and one individual with bi-allelic variants."
Supports the OCCASIONAL band: structural brain malformation is present in a minority of imaged individuals, not in most of them.
Delayed Speech and Language Development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34573379 SUPPORT Human Clinical
"She displayed severe developmental delay with poor speech (5 words) and hypotonia."
Case 1 in this family carries compound heterozygous KDM5B variants, so the observation is biallelic-specific rather than drawn from the dominant cohort.
Growth 1
Overgrowth HP:0001548 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Overgrowth (HP:0001548). HP:0001548 is a phenotype from the Human Phenotype Ontology.
Sleep disorders and autistic behaviours also appear in this quoted list, but the same paper states that sleep issues were not noted in the biallelic individuals and that they displayed no autistic behaviours, so neither is curated as a phenotype of this entity.
Show evidence (1 reference)
PMID:39202393 SUPPORT Human Clinical
"The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth."
Places overgrowth among the commonest features of the KDM5B-related disorder. The list is drawn over the whole 21-individual cohort, of whom only two were biallelic, which is why no frequency band is asserted here.
🧬

Genetic Associations

1
KDM5B (Causative)
Gene: KDM5B (lysine demethylase 5B) hgnc:18039 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KDM5B (lysine demethylase 5B), annotated with KDM5B (hgnc:18039). hgnc:18039 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
PMID:30409806 SUPPORT Human Clinical
"We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models."
The founding gene-disease association, from a recessive burden analysis of 6,040 human families. The same sentence names EIF3F, whose disorder is curated separately here as MRT67.
PMID:29276005 SUPPORT Human Clinical
"Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly."
The contemporaneous independent description, which is what gives the biallelic genotype a recognisable clinical phenotype rather than only a statistical association.
PMID:39202393 SUPPORT Human Clinical
"In the deciphering developmental disorders (DDD) cohort, KDM5B was the only gene enriched for both biallelic variants and de novo mutations (DNMs), the latter including three missense and six loss-of-function (LoF) variants."
The dual enrichment that makes KDM5B's mode of inheritance genuinely contested rather than merely under-described.
+ 1 more reference
💊

Medical Actions

3
Supportive and Symptom-Directed Management
Category: Therapeutic Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Behavioral / lifestyle
There is no disease-modifying or gene-directed therapy for MRT65, and no MRT65-specific management guideline, GeneReviews chapter, or clinical trial was found. Management is what it is for any syndromic intellectual disability: multidisciplinary developmental support, and treatment of the individual anomalies a given child turns out to have.
Show evidence (1 reference)
PMID:35905858 SUPPORT Other
"There are very few treatment options available for DDs such that these are conditions with significant unmet clinical need."
A review of the KDM5B developmental-disorder literature stating the absence of treatment options for this class of condition. Graded OTHER because the review reports no primary data.
Developmental, Educational and Communication Therapy
Category: Therapeutic Action: speech and language therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech and language therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Platform: Behavioral / lifestyle
Early intervention, speech and language therapy, occupational therapy and physical therapy, directed at the developmental delay and the hand function that camptodactyly may limit. This is standard care for syndromic intellectual disability rather than anything established for MRT65.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Genetic Counseling
Category: Counseling / Informational Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Recurrence risk for the siblings of an affected child of two carrier parents is one in four on the standard recessive expectation, and prenatal or preimplantation testing is possible once the familial alleles are known - a sibling pair with corpus callosum agenesis was in fact ascertained partly prenatally. The counselling is harder than that arithmetic suggests, though, because carrier relatives of an affected child may themselves carry a heterozygous loss-of-function allele whose consequences are contested, and the 2024 cohort says plainly that variant interpretation in this gene is difficult in the light of reduced penetrance.
Show evidence (1 reference)
PMID:39202393 SUPPORT Human Clinical
"Genotypic interpretation remains difficult in the light of reduced penetrance."
The authors' own statement of what makes counselling for this gene difficult, and the reason this entry does not present a clean recessive counselling message.
🔬

Diagnosis

2
Exome or Genome Sequencing
Sequencing is how every reported case was found and is effectively the only diagnostic route. Camptodactyly with a recognisable facial gestalt and developmental delay may raise the question, but the phenotype is not distinctive enough to reach the gene without sequencing, and with about ten individuals published no clinician can be expected to recognise it.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Markers: Two disruptive KDM5B alleles in trans - nonsense, frameshift, canonical splice-site, or a JmjC-domain missense allele opposite a null. A single heterozygous loss-of-function allele does not establish this diagnosis, since such alleles occur in unaffected relatives and population controls.
Show evidence (2 references)
PMID:39202393 SUPPORT Human Clinical
"Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65."
Names the variant classes a sequencing report must show, and that they must be biallelic.
PMID:39202393 SUPPORT Human Clinical
"In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives."
Why phasing matters diagnostically: a single disruptive KDM5B allele is found in unaffected people, so a monoallelic finding does not make this diagnosis.
Brain Magnetic Resonance Imaging
Imaging is worth doing because agenesis of the corpus callosum has been found in biallelic individuals, including prenatally, and the authors of that report argued on that basis for putting KDM5B on diagnostic panels for corpus callosum agenesis. It is not a screening test for the diagnosis: structural malformation was present in only one of the biallelic individuals imaged in the 2024 cohort.
brain magnetic resonance imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:34573379 SUPPORT Human Clinical
"Together with the observations in this family, this suggests that agenesis of the corpus callosum may be part of the phenotypic spectrum associated with KDM5B variants and that the KDM5B gene should be included in gene panels to clarify the etiology of ACC both in the prenatal and postnatal setting."
The authors' recommendation, and the reason imaging findings feed back into the genetic differential rather than only into prognosis.
PMID:39202393 SUPPORT Human Clinical
"Structural brain malformations were noted for three of the seven individuals with dominant variants and one individual with bi-allelic variants."
Sets expectations: a normal scan does not argue against the diagnosis.
📊

Prevalence

1
Worldwide, published biallelic KDM5B cases
Cases In Literature Ultra Rare
No population prevalence or incidence estimate exists for MRT65. The disorder is known from a case literature of roughly ten individuals with biallelic KDM5B variants: the founding descriptions in 2018, a compound heterozygous sibling pair in 2021, and two further individuals in the 2024 genotype-phenotype cohort. The 2024 paper is internally inconsistent about the running total - its discussion counts four previously described biallelic cases attributable to the two 2018 reports, while its literature-comparison table uses a denominator of eight - so "roughly ten" is the honest figure and a precise count is not asserted here. No numeric rate is recorded. A theoretical birth incidence near 1 in 1.3 million appears in one of the committed deep-research reports, but it is a calculation from an assumed carrier frequency and an assumed complete penetrance, not a measurement, and it is not curated as a prevalence value here.
Show evidence (1 reference)
PMID:39202393 SUPPORT Human Clinical
"Four cases of bi-allelic KDM5B variants with intellectual developmental disorder autosomal recessive-65 (MRT65) (OMIM: 618109) have been described in the literature"
The published case count attributed to the two founding reports, which is what places this disorder in the ultra-rare band and rules out any population-rate claim.
🐁

Animal Models

3
Kdm5b demethylase-inactive (delta-ARID) mouse
Mice homozygous for a Kdm5b allele that removes demethylase activity while leaving the rest of the protein. Viable into adulthood, which the constitutive null largely is not, so this is the model in which adult cognition can be studied at all.
Species
Mus musculus
Genotype
Kdm5b delta-ARID homozygous (demethylase-inactive)
Genes
KDM5B (lysine demethylase 5B) hgnc:18039 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns KDM5B (lysine demethylase 5B), annotated with KDM5B (hgnc:18039). hgnc:18039 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:38575342
Pathograph links
Impaired Activity-Dependent Gene Expression and Synaptic Plasticity recapitulates fidelity: moderate observes: organism Hyperactivity and hippocampus-dependent long-term memory deficits, with immediate-early gene expression low at baseline and overshooting on a learning stimulus.
Limitations: The allele is demethylase-inactive rather than protein-null, so it models the catalytic arm of the human lesion and not the loss of KDM5B's demethylase-independent functions, which the same group notes exist. The readouts are behavioural and electrophysiological in a whole animal, one scale above the cellular node they are cited for, so the plasticity claim is inferred from what the animal does rather than measured in the human neuron. And it is a mouse: no biallelic human individual has had hippocampal plasticity measured.
Readouts
Hippocampus-dependent long-term memory
Direction: DECREASED
Interpretation: Behavioural correlate of the plasticity node, with short-term memory spared.
Show evidence (1 reference)
PMID:38575342 SUPPORT Model Organism
"Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits."
Reports the memory and long-term potentiation deficits, here in the adult knockdown arm of the same study.
Immediate-early gene expression at baseline and after a learning stimulus
Direction: ALTERED
Interpretation: Bidirectional dysregulation - down at baseline, hyperactivated on stimulation - rather than a simple loss of induction.
Show evidence (1 reference)
PMID:38575342 SUPPORT Model Organism
"The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice."
The measurement itself, in the demethylase-inactive homozygotes.
Show evidence (1 reference)
PMID:38575342 SUPPORT Model Organism
"These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms."
Attests that this model is informative for the plasticity node, and states how far the authors extend it toward the human phenotype.
The authors also note that some KDM5-family functions in brain appear to be independent of demethylase activity, which is a reason to treat this allele as a partial model of the human null rather than an equivalent of it.
Show evidence (1 reference)
PMID:38575342 SUPPORT Model Organism
"The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity."
Grounds the caveat that a demethylase-inactive allele does not reproduce everything a null allele would remove.
Adult hippocampal Kdm5b knockdown mouse
Knockdown restricted to the adult hippocampus of an otherwise wild-type mouse. The point of the experiment is timing: it removes KDM5B after development is over.
Species
Mus musculus
Genotype
Wild-type mouse with shRNA-mediated Kdm5b knockdown in adult hippocampus
Genes
KDM5B (lysine demethylase 5B) hgnc:18039 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns KDM5B (lysine demethylase 5B), annotated with KDM5B (hgnc:18039). hgnc:18039 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:38575342
Pathograph links
Impaired Activity-Dependent Gene Expression and Synaptic Plasticity perturbs fidelity: moderate observes: organism Acute adult knockdown produces spontaneous seizures, hyperactivity, and long-term memory and long-term potentiation deficits, so part of the requirement for KDM5B is postnatal and ongoing rather than developmental.
Limitations: An acute, regionally restricted, partial knockdown in an adult animal is not the human lesion, which is constitutive, whole-body and complete from conception. It shows that adult KDM5B loss is sufficient for these deficits; it does not show that the human deficits are caused that way. The seizures it produces have no counterpart in the reported biallelic human individuals, in whom the 2024 cohort found no seizures. Readouts are whole-animal, one scale above the cellular node.
Show evidence (1 reference)
PMID:38575342 SUPPORT Model Organism
"Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits."
The perturbation result that licenses treating the plasticity node as an ongoing adult requirement.
Show evidence (1 reference)
PMID:38575342 SUPPORT Model Organism
"Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA."
Describes the model itself - what was knocked down, where, and in what background - which is what makes it a timing experiment rather than a second constitutive model.
Kdm5b demethylase-deficient mouse (neocortical H3K4me3 study)
Mice without KDM5B demethylase activity, studied at the level of the developing neocortex rather than adult behaviour. This is the model that supplies the chromatin arm of the mechanism.
Species
Mus musculus
Genotype
Kdm5b demethylase-deficient homozygous
Genes
KDM5B (lysine demethylase 5B) hgnc:18039 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns KDM5B (lysine demethylase 5B), annotated with KDM5B (hgnc:18039). hgnc:18039 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:42160407
Pathograph links
Elevated H3K4 Trimethylation at Developmental Gene Promoters recapitulates fidelity: moderate observes: molecular H3K4me3 and neurodevelopmental gene expression are both raised in the developing mutant neocortex, which is the predicted consequence of losing the eraser.
Limitations: Measured in mouse neocortex. The equivalent measurement has never been made in tissue from an individual with MRT65, so the human node rests on the enzyme's known specificity plus this mouse result.
Show evidence (1 reference)
PMID:42160407 SUPPORT Model Organism
"H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex."
The direct measurement behind this node.
Increased Grin2d and NMDA Receptor Subunit 2D Expression recapitulates fidelity: moderate observes: molecular Raised H3K4me3 at the Grin2d promoter, raised Grin2d expression, and more NMDAR2D protein in synaptosomes from early postnatal neocortex.
Limitations: Entirely a mouse finding, and the behavioural endpoint it was traced to - socio-communication deficit - is the one feature the reported biallelic human individuals do not have. Its relevance to MRT65 specifically is therefore unestablished, which is why the corresponding node is marked HYPOTHETICAL.
Show evidence (1 reference)
PMID:42160407 SUPPORT Model Organism
"Increased H3K4me3 levels at the promoter and associated expression of the Grin2d gene were associated with increased levels of N-methyl-d-aspartate receptor subunit 2D (NMDAR2D) protein in synaptosomes isolated from the early postnatal Kdm5b-deficient neocortex."
The mark-to-transcript-to-protein chain, measured directly.
Altered Cortical Neurodevelopment and Brain Overgrowth partially recapitulates fidelity: low observes: organism Increased brain size, which is the mouse counterpart of the macrocephaly recorded in biallelic human individuals.
Limitations: Brain size in a mouse and occipitofrontal circumference in a child are not the same measurement, and the human observation rests on two individuals. The model does not reproduce the structural malformations - corpus callosum agenesis in particular - or the craniofacial and hand features, so it covers only the growth part of this node. Whole-animal readout cited for a tissue-level node.
Show evidence (1 reference)
PMID:42160407 SUPPORT Model Organism
"These mice exhibited autism-like behaviors and increased brain size."
The brain-size observation. The autism-like behaviour in the same sentence is treated as a model-human mismatch, not as support for a phenotype of this entity.
Show evidence (1 reference)
PMID:42160407 SUPPORT Model Organism
"To study the role of KDM5B (lysine demethylase 5B)-mediated H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity."
States what the model is - loss of demethylase activity rather than loss of the protein - and that it was built to interrogate the H3K4me3 arm of the mechanism this entry cites it for.
{ }

Source YAML

click to show 
name: Intellectual Disability Autosomal Recessive 65
creation_date: "2026-09-07T22:00:00Z"
category: Mendelian
synonyms:
- MRT65
- mental retardation, autosomal recessive 65
- intellectual developmental disorder, autosomal recessive 65
- KDM5B-related recessive neurodevelopmental disorder
disease_term:
  preferred_term: intellectual disability, autosomal recessive 65
  term:
    id: MONDO:0020850
    label: intellectual disability, autosomal recessive 65
description: >-
  MRT65 is a rare autosomal recessive neurodevelopmental disorder caused by
  biallelic (homozygous or compound heterozygous) disruptive variants in KDM5B,
  the gene for a JmjC-domain histone demethylase that removes methyl groups from
  lysine 4 of histone H3. It was defined in 2018 by two papers published within a
  year of each other: a genome-wide recessive burden analysis of the Deciphering
  Developmental Disorders cohort, which named KDM5B and EIF3F as the two genes
  newly associated with recessive developmental disorders, and a
  pathway-based survey of the histone lysine methylases and demethylases, which
  described the resulting entity as a recognisable syndrome of developmental
  delay, facial dysmorphism and camptodactyly. Roughly ten individuals with
  biallelic KDM5B variants have been reported. Developmental delay or impaired
  intellectual development is present in all of them; facial dysmorphism,
  behavioural problems and macrocephaly are recurrent, and agenesis of the
  corpus callosum has been described in a subset.


  The interesting thing about this gene is that the recessive entity is only one
  end of a dose-response relationship, and the entry is scoped deliberately to
  that end. In the Deciphering Developmental Disorders cohort KDM5B was the only
  gene enriched for biallelic variants and de novo mutations at the same time.
  Heterozygous KDM5B loss-of-function alleles are found in unaffected relatives
  and in population controls, do not segregate cleanly within families, and at
  population scale associate with a measurable downward shift in adult cognitive
  function rather than with a discrete disease. One group put it as "a spectrum
  of recessiveness". So the reduced penetrance that is repeatedly documented in
  the KDM5B literature is a statement about the *heterozygous* state; it is not,
  on the sources available, a statement about the biallelic genotype that
  defines MRT65. See the inheritance block and the discussions for how far that
  distinction can currently be pushed.


  SCOPE NOTE. This entity is defined by biallelic KDM5B. It must not be
  conflated with (a) the disorders of the KDM5 paralogues, which are separate
  genes with separate disease associations - in particular KDM5C, which causes
  Claes-Jensen type X-linked intellectual disability and is curated separately
  here; (b) the proposed dominant, monoallelic KDM5B-related neurodevelopmental
  disorder, whose existence and boundaries are still argued over and which is
  the subject of a discussion below rather than of this entry; (c) the large
  somatic KDM5B cancer literature, in which the gene appears under its older
  names PLU-1 and JARID1B as an amplified oncogene in breast cancer and a driver
  of drug-tolerant persister states in melanoma - a different biological context
  entirely; or (d) RUSC2-related Alwadei syndrome (OMIM 617773), a distinct
  recessive intellectual disability syndrome that some tertiary aggregator pages
  conflate with this one.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019502
      label: autosomal recessive non-syndromic intellectual disability
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    notes: >-
      MONDO places MRT65 under a non-syndromic grouping, but the founding
      description is explicitly of a recognisable syndrome with facial
      dysmorphism and camptodactyly, and later reports add macrocephaly and
      corpus callosum agenesis. The mapping is recorded as a broad match
      (a cross-reference) rather than an exact or narrow one so that it does
      not assert the non-syndromic characterisation.
parents:
- hereditary neurological disease
- syndromic intellectual disability
- Mendelian disorder of the epigenetic machinery
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: UNKNOWN
  expressivity: VARIABLE
  description: >-
    Two disruptive KDM5B alleles are required, in cis-trans configuration
    confirmed where phasing was possible; reported genotypes are homozygous
    nonsense, compound heterozygous nonsense or frameshift pairs, and one
    JmjC-domain missense allele in trans with a frameshift null.


    Penetrance is recorded as UNKNOWN, and that is a deliberate reading of what
    the sources will and will not support. Every reported individual carrying two
    disruptive KDM5B alleles has had developmental delay or impaired intellectual
    development, and no unaffected biallelic individual has been described. But
    all of those individuals were ascertained through an affected proband, in a
    literature of about ten cases, so the observation cannot distinguish complete
    penetrance from ascertainment. No study has estimated penetrance for the
    biallelic genotype, and none of the sources reviewed reports an unaffected
    homozygous or compound heterozygous relative. COMPLETE would overstate a
    case series; INCOMPLETE would import a finding that belongs to a different
    genotype.


    That different genotype is the heterozygous one, and there the reduced
    penetrance is documented and repeatedly restated: heterozygous KDM5B
    loss-of-function alleles turn up in unaffected relatives and in population
    controls, dominant loss-of-function variants do not segregate with disease
    within families, and the gnomAD observed-to-expected ratio for
    loss-of-function of about 0.57 is read by the same authors as partial
    penetrance of heterozygous loss of function. Keeping the two apart is the
    point: the KDM5B penetrance literature is about carriers, not about patients
    with MRT65.


    Expressivity is recorded as VARIABLE. Severity of the intellectual disability
    ranges from mild in the two biallelic individuals of the 2024 cohort to
    moderate-to-severe in the earlier literature, and structural brain
    malformation is present in some biallelic individuals and absent in others.
  evidence:
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65."
    explanation: >-
      States the recessive, biallelic genotype that defines this entity.
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives."
    explanation: >-
      The documented unaffected carriers are heterozygous, not biallelic. This is
      the sentence behind the entry's decision to record reduced penetrance as a
      property of the heterozygous state and to leave biallelic penetrance
      unknown.
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is in line with a partial penetrance of heterozygous LoF KDM5B variants."
    explanation: >-
      The authors' own reading of the gnomAD constraint data, stated for the
      heterozygous genotype specifically.
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moderate-to-severe DD and impaired intellectual development were common to all."
    explanation: >-
      Every biallelic individual in the pooled literature was affected, which is
      what makes COMPLETE tempting and what ascertainment through affected
      probands makes unsafe.
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both individuals with bi-allelic variants presented with a mild ID, and one of them presented with a GDD."
    explanation: >-
      The 2024 biallelic individuals sit at the mild end, against
      moderate-to-severe in the earlier literature. This severity range is the
      basis for expressivity VARIABLE.
references:
- reference: PMID:29276005
  title: Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
- reference: PMID:30409806
  title: Quantifying the contribution of recessive coding variation to developmental disorders.
- reference: PMID:30217758
  title: "Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences."
- reference: PMID:34573379
  title: Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants.
- reference: PMID:35905858
  title: Pathogenic KDM5B variants in the context of developmental disorders.
- reference: PMID:37231097
  title: The impact of rare protein coding genetic variation on adult cognitive function.
- reference: PMID:38575342
  title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
- reference: PMID:39202393
  title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
- reference: PMID:42160407
  title: Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
pathophysiology:
- name: Biallelic KDM5B Loss of Function
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The initiating lesion. Two disruptive KDM5B alleles - nonsense, frameshift,
    canonical splice-site, or a catalytic-domain missense in trans with a null -
    leave the cell without functional KDM5B. A single such allele does not
    produce this disorder, which is the whole content of calling the entity
    recessive.
  genes:
  - preferred_term: KDM5B (lysine demethylase 5B)
    term:
      id: hgnc:18039
      label: KDM5B
  genetic_context:
    gene:
      preferred_term: KDM5B (lysine demethylase 5B)
      term:
        id: hgnc:18039
        label: KDM5B
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    allelic_hit_role: BIALLELIC_INACTIVATION
    functional_impact_category: LOSS_OF_FUNCTION
    allele_type: nonsense, frameshift, canonical splice-site, or catalytic-domain
      missense in trans with a null allele
    notes: >-
      Zygosity is recorded as HOMOZYGOUS because that is the single value the
      slot takes and homozygous nonsense alleles are the reported archetype;
      compound heterozygous genotypes are equally common in the case literature
      and are described in the genetic section.
  downstream:
  - target: Loss of KDM5B H3K4 Demethylase Activity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30409806
    reference_title: Quantifying the contribution of recessive coding variation to developmental disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models."
    explanation: >-
      The founding gene-disease association, from a genome-wide recessive burden
      analysis of 6,040 Deciphering Developmental Disorders families. Graded
      HUMAN_CLINICAL because the association itself is a human cohort finding;
      the same sentence also reports mouse and cellular validation, but a single
      quote carries a single grade.
  - reference: PMID:29276005
    reference_title: Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly."
    explanation: >-
      Names both reported biallelic configurations and the syndrome they produce.
- name: Loss of KDM5B H3K4 Demethylase Activity
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    KDM5B is an Fe(II)/2-oxoglutarate-dependent JmjC-domain demethylase whose
    substrate is methylated lysine 4 of histone H3. Without it, the cell loses
    the enzyme that erases that mark. Note the direction of travel here: unlike
    most chromatinopathies, where a writer is lost and a permissive mark falls,
    the lesion in MRT65 removes an eraser, so the permissive mark accumulates.
  molecular_functions:
  - preferred_term: histone H3K4me3/me2/me1 demethylase activity
    term:
      id: GO:0034647
      label: histone H3K4me/H3K4me2/H3K4me3 demethylase activity
    modifier: LOSS_OF_FUNCTION
  - preferred_term: histone H3K4 demethylase activity
    term:
      id: GO:0032453
      label: histone H3K4 demethylase activity
    modifier: DECREASED
  downstream:
  - target: Elevated H3K4 Trimethylation at Developmental Gene Promoters
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42160407
      reference_title: Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex."
      explanation: >-
        Establishes the edge rather than either node: removing KDM5B demethylase
        activity is what raises H3K4me3 in developing neocortex. Demonstrated in
        mice without KDM5B demethylase activity, not in human tissue.
  evidence:
  - reference: PMID:35905858
    reference_title: Pathogenic KDM5B variants in the context of developmental disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KDM5B is responsible for the demethylation of lysine 4 on the amino tail of histone 3 and plays a vital role in normal development and regulating cell differentiation."
    explanation: >-
      States the enzyme's substrate specificity. Graded OTHER because this is a
      narrative review that reports no primary data of its own; the underlying
      biochemistry is in the papers it cites.
- name: Elevated H3K4 Trimethylation at Developmental Gene Promoters
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Permissive-Repressive Chromatin State Imbalance"
  description: >-
    H3K4me3 is a promoter-proximal permissive mark. With the eraser gone it
    accumulates at the promoters of developmentally regulated and
    activity-dependent genes, shifting the permissive-repressive balance toward
    permissive - the same imbalance the chromatinopathy module describes, reached
    from the opposite direction. Recorded as PROVISIONAL for human disease: the
    accumulation is directly measured in mouse neocortex and has not been shown
    in tissue from an individual with MRT65.
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: DYSREGULATED
  cellular_components:
  - preferred_term: chromatin
    term:
      id: GO:0000785
      label: chromatin
  downstream:
  - target: Dysregulated Neurodevelopmental Transcriptional Program
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42160407
      reference_title: Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These findings suggest that increased H3K4me3 levels and associated Grin2d gene up-regulation disrupt brain development and function, leading to socio-communication deficits and identify a potential therapeutic target for neurodevelopmental disorders associated with KDM5B deficiency."
      explanation: >-
        The authors' causal reading of their own data: raised H3K4me3 drives the
        transcriptional change, which drives the phenotype. Mouse.
  evidence:
  - reference: PMID:42160407
    reference_title: Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex."
    explanation: >-
      Direct measurement of the mark in the developing neocortex of mice lacking
      KDM5B demethylase activity.
- name: Dysregulated Neurodevelopmental Transcriptional Program
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Dysregulated Neurodevelopmental Transcriptional Program"
  description: >-
    The transcriptional consequence, and it is bidirectional rather than a simple
    upward shift. Neurodevelopmental genes are expressed at higher levels in the
    developing mutant neocortex, while activity-dependent immediate-early genes
    sit lower at baseline and then overshoot on stimulation. What the mark
    change costs the neuron is regulated, appropriately timed transcription, not
    transcription as such.
  biological_processes:
  - preferred_term: regulation of DNA-templated transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: LOSS_OF_FUNCTION
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: DECREASED
  downstream:
  - target: Increased Grin2d and NMDA Receptor Subunit 2D Expression
    causal_link_type: DIRECT
  - target: Impaired Activity-Dependent Gene Expression and Synaptic Plasticity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38575342
      reference_title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus"
      explanation: >-
        Supports the edge rather than either node: the authors tie KDM5B's
        control of gene expression directly to synaptic plasticity in the same
        tissue, which is the causal step being asserted here.
  - target: Altered Cortical Neurodevelopment and Brain Overgrowth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:38575342
    reference_title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice."
    explanation: >-
      The bidirectional dysregulation, in demethylase-inactive mice.
- name: Increased Grin2d and NMDA Receptor Subunit 2D Expression
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    One specific downstream target has been traced end to end in the mouse:
    raised H3K4me3 at the Grin2d promoter, raised Grin2d expression, and more
    NMDAR2D protein in synaptosomes from early postnatal neocortex. Recorded as
    HYPOTHETICAL for MRT65 because it is entirely a mouse result and because the
    behavioural readout it was traced to - socio-communication deficit - is the
    feature that biallelic human individuals conspicuously do not have. It is
    kept in the graph because it is the only mechanistically complete
    chromatin-to-synapse link anyone has for this gene, and because it names a
    druggable node.
  downstream:
  - target: Impaired Activity-Dependent Gene Expression and Synaptic Plasticity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:42160407
    reference_title: Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Increased H3K4me3 levels at the promoter and associated expression of the Grin2d gene were associated with increased levels of N-methyl-d-aspartate receptor subunit 2D (NMDAR2D) protein in synaptosomes isolated from the early postnatal Kdm5b-deficient neocortex."
    explanation: >-
      The full mark-to-transcript-to-protein chain, measured in Kdm5b-deficient
      mouse neocortex.
- name: Impaired Activity-Dependent Gene Expression and Synaptic Plasticity
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Impaired Neuronal Maturation, Plasticity, and Postnatal Neurogenesis"
  description: >-
    Where the chromatin defect becomes a neuronal one. Demethylase-inactive mice
    lose hippocampal long-term potentiation and long-term memory while short-term
    memory is spared, and knocking KDM5B down in the adult hippocampus alone
    reproduces that, which places part of the requirement for the enzyme after
    development rather than during it.
  cell_types:
  - preferred_term: hippocampal neuron
    term:
      id: CL:0002608
      label: hippocampal neuron
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: regulation of synaptic plasticity
    term:
      id: GO:0048167
      label: regulation of synaptic plasticity
    modifier: DECREASED
  - preferred_term: long-term synaptic potentiation
    term:
      id: GO:0060291
      label: long-term synaptic potentiation
    modifier: DECREASED
  - preferred_term: learning or memory
    term:
      id: GO:0007611
      label: learning or memory
    modifier: DECREASED
  downstream:
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Intellectual Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38575342
      reference_title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms"
      explanation: >-
        Evidence for this edge specifically - the step from the plasticity defect
        to the human cognitive phenotype. Marked INDIRECT because the measurement
        is in mice and the inference to human intellectual disability is the
        authors' own, offered as a suggestion rather than a demonstration.
  evidence:
  - reference: PMID:38575342
    reference_title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms."
    explanation: >-
      The authors' own summary of the mouse result and of how far they take it
      toward the human cognitive phenotype.
  - reference: PMID:38575342
    reference_title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits."
    explanation: >-
      Adult-only knockdown reproduces the deficit, so the requirement for KDM5B
      is not exclusively developmental.
- name: Altered Cortical Neurodevelopment and Brain Overgrowth
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    A second branch, and a much weaker one. Mice without KDM5B demethylase
    activity have larger brains, and macrocephaly is recorded in biallelic human
    individuals, so a growth arm to the phenotype is plausible. Whether the same
    process accounts for the structural malformations seen in a subset - agenesis
    of the corpus callosum in particular - is not established, and the route from
    chromatin dysregulation to the craniofacial and hand features of the syndrome
    has not been worked out at all for this gene. Recorded as HYPOTHETICAL for
    that reason.
  biological_processes:
  - preferred_term: cerebral cortex neuron differentiation
    term:
      id: GO:0021895
      label: cerebral cortex neuron differentiation
    modifier: DECREASED
  downstream:
  - target: Macrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Agenesis of the Corpus Callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:42160407
    reference_title: Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice exhibited autism-like behaviors and increased brain size."
    explanation: >-
      The brain-size finding in mice without KDM5B demethylase activity. The
      autism-like behaviour reported in the same sentence is discussed under
      discussions rather than curated as a phenotype of this entity.
phenotypes:
- category: Neurologic
  name: Global Developmental Delay
  description: >-
    Delay across motor, language and adaptive domains, recognised in infancy.
    Present in every reported biallelic individual, which is the one feature of
    this disorder that the small case literature agrees on without qualification.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moderate-to-severe DD and impaired intellectual development were common to all."
    explanation: >-
      Pooled across the reported biallelic individuals; supports the
      VERY_FREQUENT band as well as the association.
  - reference: PMID:29276005
    reference_title: Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly."
    explanation: >-
      Developmental delay is one of the three features in the founding
      description of the syndrome.
- category: Neurologic
  name: Impaired Intellectual Development
  description: >-
    Intellectual disability, reported as moderate to severe in the earlier
    literature and as mild in the two biallelic individuals of the 2024 cohort.
    The entry binds the unqualified HPO term rather than a severity-specific one
    because the reported range spans mild to severe.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both individuals with bi-allelic variants presented with a mild ID, and one of them presented with a GDD."
    explanation: >-
      The 2024 biallelic pair, at the mild end of the reported range.
  - reference: PMID:34573379
    reference_title: Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KDM5B variants have been previously associated with moderate to severe developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and dysmorphism in a few individuals, but the pathogenetic mechanisms are not clear yet as patients with both monoallelic and biallelic variants have been observed."
    explanation: >-
      The moderate-to-severe end of the range. Note the same sentence records
      that the published KDM5B phenotype pools monoallelic and biallelic
      individuals, which is why this entry treats severity as unsettled.
- category: Craniofacial
  name: Facial Dysmorphism
  description: >-
    A recurrent facial gestalt, described in the founding report as part of a
    recognisable syndrome. Reported features in biallelic individuals include a
    broad forehead and a full nasal tip.
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  frequency: FREQUENT
  evidence:
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both individuals with bi-allelic variants presented with facial dysmorphisms, including a broad forehead and full nasal tip."
    explanation: >-
      Names the specific features in the biallelic individuals.
  - reference: PMID:35905858
    reference_title: Pathogenic KDM5B variants in the context of developmental disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recessive variants in the gene encoding histone modifying enzyme KDM5B are associated with a DD characterized by developmental delay, facial dysmorphism and camptodactyly."
    explanation: >-
      Review-level statement of the recessive syndrome's defining triad. Graded
      OTHER because the review presents no primary data of its own.
- category: Musculoskeletal
  name: Camptodactyly
  description: >-
    Fixed flexion contracture of one or more finger joints. It is the one
    non-neurological feature named in the founding description of the syndrome,
    and it is what makes the biallelic phenotype clinically recognisable rather
    than merely another undifferentiated developmental delay.
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  evidence:
  - reference: PMID:29276005
    reference_title: Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly."
    explanation: >-
      Camptodactyly is one of the three features in the founding description.
  - reference: PMID:35905858
    reference_title: Pathogenic KDM5B variants in the context of developmental disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recessive variants in the gene encoding histone modifying enzyme KDM5B are associated with a DD characterized by developmental delay, facial dysmorphism and camptodactyly."
    explanation: >-
      Independent restatement, four years later, that camptodactyly belongs to
      the recessive phenotype specifically.
  notes: >-
    No frequency band is asserted. The founding description treats camptodactyly
    as characteristic, but no source reviewed here gives a count for it among
    biallelic individuals, and the 2024 cohort tabulates finger anomalies under a
    broader heading.
- category: Behavioral
  name: Behavioral Abnormalities
  description: >-
    Mood swings and aggressivity were present in both biallelic individuals of
    the 2024 cohort. That cohort makes a point of the contrast with the
    monoallelic group: the biallelic individuals had behavioural problems without
    autistic behaviours, while autistic behaviours were common in the
    monoallelic group.
  phenotype_term:
    preferred_term: Behavioral abnormality
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both individuals with bi-allelic variants displayed behavioral problems such as mood swings and aggressivity, but they did not display autistic behaviors."
    explanation: >-
      Supports behavioural abnormality in the biallelic individuals, and in the
      same sentence records the absence of autistic behaviour that keeps
      autistic behaviour out of this entry's phenotype list.
- category: Neurologic
  name: Macrocephaly
  description: >-
    Occipitofrontal circumference above two standard deviations. Present in both
    biallelic individuals of the 2024 cohort, which is a small denominator but a
    clean one, since the same cohort reports macrocephaly in only a minority of
    its much larger monoallelic group.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both individuals with bi-allelic variants presented with macrocephaly."
    explanation: >-
      Directly states the finding in the biallelic individuals.
- category: Growth
  name: Overgrowth
  description: >-
    Weight and height above the 90th percentile were recorded in a substantial
    share of the 2024 cohort, and overgrowth is listed among the disorder's most
    common features. The pooled figure spans monoallelic and biallelic
    individuals, so it is reported here as a feature of the KDM5B-related
    disorder at large rather than as a quantified biallelic frequency.
  phenotype_term:
    preferred_term: Overgrowth
    term:
      id: HP:0001548
      label: Overgrowth
  evidence:
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth."
    explanation: >-
      Places overgrowth among the commonest features of the KDM5B-related
      disorder. The list is drawn over the whole 21-individual cohort, of whom
      only two were biallelic, which is why no frequency band is asserted here.
  notes: >-
    Sleep disorders and autistic behaviours also appear in this quoted list, but
    the same paper states that sleep issues were not noted in the biallelic
    individuals and that they displayed no autistic behaviours, so neither is
    curated as a phenotype of this entity.
- category: Neurologic
  name: Agenesis of the Corpus Callosum
  description: >-
    Reported in a sibling pair compound heterozygous for a JmjC-domain missense
    allele and a frameshift null, one liveborn and one a terminated pregnancy,
    and previously in one further biallelic individual with severe intellectual
    disability. On that basis the authors argued the KDM5B gene belongs on
    diagnostic panels for corpus callosum agenesis, including prenatally.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34573379
    reference_title: Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied a family in which the first-born child, a girl, had developmental delay, facial dysmorphism, and agenesis of the corpus callosum (ACC)."
    explanation: >-
      The index observation, in a child later shown to carry two KDM5B variants
      in trans.
  - reference: PMID:34573379
    reference_title: Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, one individual has previously been reported with ACC and severe ID in association with biallelic KDM5B variants."
    explanation: >-
      An independent earlier biallelic case with the same finding, which is what
      turns a single family into a phenotype claim.
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Structural brain malformations were noted for three of the seven individuals with dominant variants and one individual with bi-allelic variants."
    explanation: >-
      Supports the OCCASIONAL band: structural brain malformation is present in
      a minority of imaged individuals, not in most of them.
- category: Neurologic
  name: Delayed Speech and Language Development
  description: >-
    Speech acquisition is delayed beyond what the global developmental delay
    alone accounts for. In the one biallelic individual described in enough
    detail to quote, expressive vocabulary was five words at four years.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:34573379
    reference_title: "Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She displayed severe developmental delay with poor speech (5 words) and hypotonia."
    explanation: >-
      Case 1 in this family carries compound heterozygous KDM5B variants, so the
      observation is biallelic-specific rather than drawn from the dominant
      cohort.
- category: Neurologic
  name: Hypotonia
  description: >-
    Reduced muscle tone, noted in the neonatal period and persisting through
    infancy in the biallelic individual described in detail.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:34573379
    reference_title: "Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She displayed severe developmental delay with poor speech (5 words) and hypotonia."
    explanation: >-
      Same compound heterozygous individual. The paper records hypotonia twice
      more in this case, at day 4 and at three months. No frequency band is
      attached because the HPO annotation for the biallelic entity does not
      list it.
genetic:
- name: KDM5B
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: KDM5B (lysine demethylase 5B)
    term:
      id: hgnc:18039
      label: KDM5B
  notes: >-
    KDM5B (1q32.1; also known as JARID1B and PLU-1) encodes a JmjC-domain
    demethylase for H3K4me1/me2/me3 with a JmjN domain, an ARID DNA-binding
    domain, a C5HC2 zinc finger and three PHD fingers. Reported biallelic
    genotypes are homozygous nonsense, compound heterozygous nonsense or
    frameshift pairs, and one JmjC-domain missense allele in trans with a
    frameshift null. Two things about this gene are unusual for a recessive
    neurodevelopmental disease gene and are the reason the entry carries a
    controversy and a knowledge gap rather than a clean genotype-phenotype
    statement. First, in the Deciphering Developmental Disorders cohort it was
    the only gene enriched for biallelic variants and de novo mutations at the
    same time. Second, heterozygous loss-of-function alleles are tolerated: they
    occur in unaffected relatives and controls, and at population scale they
    associate with lower adult cognitive function rather than with disease.


    Somatic KDM5B alteration in cancer - amplification in breast cancer under the
    name PLU-1, and a role in drug-tolerant persister states in melanoma - is a
    separate biological context and is not evidence about this germline
    disorder. Neither are results from the paralogues KDM5A, KDM5C and KDM5D,
    which have their own disease associations; KDM5C in particular causes
    Claes-Jensen type X-linked intellectual disability and is a different entity.
  evidence:
  - reference: PMID:30409806
    reference_title: Quantifying the contribution of recessive coding variation to developmental disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models."
    explanation: >-
      The founding gene-disease association, from a recessive burden analysis of
      6,040 human families. The same sentence names EIF3F, whose disorder is
      curated separately here as MRT67.
  - reference: PMID:29276005
    reference_title: Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly."
    explanation: >-
      The contemporaneous independent description, which is what gives the
      biallelic genotype a recognisable clinical phenotype rather than only a
      statistical association.
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the deciphering developmental disorders (DDD) cohort, KDM5B was the only gene enriched for both biallelic variants and de novo mutations (DNMs), the latter including three missense and six loss-of-function (LoF) variants."
    explanation: >-
      The dual enrichment that makes KDM5B's mode of inheritance genuinely
      contested rather than merely under-described.
  - reference: PMID:37231097
    reference_title: The impact of rare protein coding genetic variation on adult cognitive function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify eight genes (ADGRB2, KDM5B, GIGYF1, ANKRD12, SLC8A1, RC3H2, CACNA1A and BCAS3) that are associated with adult cognitive function through rare coding variants with large effects."
    explanation: >-
      KDM5B carries a measurable cognitive effect in the general adult
      population, in an exome study of 485,930 people. This is the population-end
      anchor for the dose-response reading of the gene.
animal_models:
- name: Kdm5b demethylase-inactive (delta-ARID) mouse
  species: Mus musculus
  genotype: Kdm5b delta-ARID homozygous (demethylase-inactive)
  publication: PMID:38575342
  description: >-
    Mice homozygous for a Kdm5b allele that removes demethylase activity while
    leaving the rest of the protein. Viable into adulthood, which the constitutive
    null largely is not, so this is the model in which adult cognition can be
    studied at all.
  genes:
  - preferred_term: KDM5B (lysine demethylase 5B)
    term:
      id: hgnc:18039
      label: KDM5B
  modeled_mechanisms:
  - target: Impaired Activity-Dependent Gene Expression and Synaptic Plasticity
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Hyperactivity and hippocampus-dependent long-term memory deficits, with
      immediate-early gene expression low at baseline and overshooting on a
      learning stimulus.
    limitations: >-
      The allele is demethylase-inactive rather than protein-null, so it models
      the catalytic arm of the human lesion and not the loss of KDM5B's
      demethylase-independent functions, which the same group notes exist. The
      readouts are behavioural and electrophysiological in a whole animal, one
      scale above the cellular node they are cited for, so the plasticity claim
      is inferred from what the animal does rather than measured in the human
      neuron. And it is a mouse: no biallelic human individual has had
      hippocampal plasticity measured.
    readouts:
    - name: Hippocampus-dependent long-term memory
      target: Impaired Activity-Dependent Gene Expression and Synaptic Plasticity
      direction: DECREASED
      interpretation: >-
        Behavioural correlate of the plasticity node, with short-term memory
        spared.
      evidence:
      - reference: PMID:38575342
        reference_title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits."
        explanation: >-
          Reports the memory and long-term potentiation deficits, here in the
          adult knockdown arm of the same study.
    - name: Immediate-early gene expression at baseline and after a learning stimulus
      target: Impaired Activity-Dependent Gene Expression and Synaptic Plasticity
      direction: ALTERED
      interpretation: >-
        Bidirectional dysregulation - down at baseline, hyperactivated on
        stimulation - rather than a simple loss of induction.
      evidence:
      - reference: PMID:38575342
        reference_title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice."
        explanation: >-
          The measurement itself, in the demethylase-inactive homozygotes.
    evidence:
    - reference: PMID:38575342
      reference_title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms."
      explanation: >-
        Attests that this model is informative for the plasticity node, and
        states how far the authors extend it toward the human phenotype.
  notes: >-
    The authors also note that some KDM5-family functions in brain appear to be
    independent of demethylase activity, which is a reason to treat this allele
    as a partial model of the human null rather than an equivalent of it.
  evidence:
  - reference: PMID:38575342
    reference_title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity."
    explanation: >-
      Grounds the caveat that a demethylase-inactive allele does not reproduce
      everything a null allele would remove.
- name: Adult hippocampal Kdm5b knockdown mouse
  species: Mus musculus
  genotype: Wild-type mouse with shRNA-mediated Kdm5b knockdown in adult hippocampus
  publication: PMID:38575342
  description: >-
    Knockdown restricted to the adult hippocampus of an otherwise wild-type
    mouse. The point of the experiment is timing: it removes KDM5B after
    development is over.
  genes:
  - preferred_term: KDM5B (lysine demethylase 5B)
    term:
      id: hgnc:18039
      label: KDM5B
  modeled_mechanisms:
  - target: Impaired Activity-Dependent Gene Expression and Synaptic Plasticity
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Acute adult knockdown produces spontaneous seizures, hyperactivity, and
      long-term memory and long-term potentiation deficits, so part of the
      requirement for KDM5B is postnatal and ongoing rather than developmental.
    limitations: >-
      An acute, regionally restricted, partial knockdown in an adult animal is
      not the human lesion, which is constitutive, whole-body and complete from
      conception. It shows that adult KDM5B loss is sufficient for these
      deficits; it does not show that the human deficits are caused that way. The
      seizures it produces have no counterpart in the reported biallelic human
      individuals, in whom the 2024 cohort found no seizures. Readouts are
      whole-animal, one scale above the cellular node.
    evidence:
    - reference: PMID:38575342
      reference_title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits."
      explanation: >-
        The perturbation result that licenses treating the plasticity node as an
        ongoing adult requirement.
  evidence:
  - reference: PMID:38575342
    reference_title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA."
    explanation: >-
      Describes the model itself - what was knocked down, where, and in what
      background - which is what makes it a timing experiment rather than a
      second constitutive model.
- name: Kdm5b demethylase-deficient mouse (neocortical H3K4me3 study)
  species: Mus musculus
  genotype: Kdm5b demethylase-deficient homozygous
  publication: PMID:42160407
  description: >-
    Mice without KDM5B demethylase activity, studied at the level of the
    developing neocortex rather than adult behaviour. This is the model that
    supplies the chromatin arm of the mechanism.
  genes:
  - preferred_term: KDM5B (lysine demethylase 5B)
    term:
      id: hgnc:18039
      label: KDM5B
  modeled_mechanisms:
  - target: Elevated H3K4 Trimethylation at Developmental Gene Promoters
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      H3K4me3 and neurodevelopmental gene expression are both raised in the
      developing mutant neocortex, which is the predicted consequence of losing
      the eraser.
    limitations: >-
      Measured in mouse neocortex. The equivalent measurement has never been made
      in tissue from an individual with MRT65, so the human node rests on the
      enzyme's known specificity plus this mouse result.
    evidence:
    - reference: PMID:42160407
      reference_title: Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "H3K4me3 levels and the expression of neurodevelopmental genes were increased in the developing Kdm5b mutant neocortex."
      explanation: >-
        The direct measurement behind this node.
  - target: Increased Grin2d and NMDA Receptor Subunit 2D Expression
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Raised H3K4me3 at the Grin2d promoter, raised Grin2d expression, and more
      NMDAR2D protein in synaptosomes from early postnatal neocortex.
    limitations: >-
      Entirely a mouse finding, and the behavioural endpoint it was traced to -
      socio-communication deficit - is the one feature the reported biallelic
      human individuals do not have. Its relevance to MRT65 specifically is
      therefore unestablished, which is why the corresponding node is marked
      HYPOTHETICAL.
    evidence:
    - reference: PMID:42160407
      reference_title: Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Increased H3K4me3 levels at the promoter and associated expression of the Grin2d gene were associated with increased levels of N-methyl-d-aspartate receptor subunit 2D (NMDAR2D) protein in synaptosomes isolated from the early postnatal Kdm5b-deficient neocortex."
      explanation: >-
        The mark-to-transcript-to-protein chain, measured directly.
  - target: Altered Cortical Neurodevelopment and Brain Overgrowth
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Increased brain size, which is the mouse counterpart of the macrocephaly
      recorded in biallelic human individuals.
    limitations: >-
      Brain size in a mouse and occipitofrontal circumference in a child are not
      the same measurement, and the human observation rests on two individuals.
      The model does not reproduce the structural malformations - corpus callosum
      agenesis in particular - or the craniofacial and hand features, so it
      covers only the growth part of this node. Whole-animal readout cited for a
      tissue-level node.
    evidence:
    - reference: PMID:42160407
      reference_title: Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These mice exhibited autism-like behaviors and increased brain size."
      explanation: >-
        The brain-size observation. The autism-like behaviour in the same
        sentence is treated as a model-human mismatch, not as support for a
        phenotype of this entity.
  evidence:
  - reference: PMID:42160407
    reference_title: Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "To study the role of KDM5B (lysine demethylase 5B)-mediated H3K4me3 demethylation, we investigated neurodevelopmental phenotypes in mice without KDM5B demethylase activity."
    explanation: >-
      States what the model is - loss of demethylase activity rather than loss of
      the protein - and that it was built to interrogate the H3K4me3 arm of the
      mechanism this entry cites it for.
treatments:
- name: Supportive and Symptom-Directed Management
  description: >-
    There is no disease-modifying or gene-directed therapy for MRT65, and no
    MRT65-specific management guideline, GeneReviews chapter, or clinical trial
    was found. Management is what it is for any syndromic intellectual
    disability: multidisciplinary developmental support, and treatment of the
    individual anomalies a given child turns out to have.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:35905858
    reference_title: Pathogenic KDM5B variants in the context of developmental disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There are very few treatment options available for DDs such that these are conditions with significant unmet clinical need."
    explanation: >-
      A review of the KDM5B developmental-disorder literature stating the absence
      of treatment options for this class of condition. Graded OTHER because the
      review reports no primary data.
  notes: >-
    Nothing in the sources reviewed reports an outcome for any specific
    intervention in an individual with biallelic KDM5B variants, so no
    effectiveness claim is made here.
- name: Developmental, Educational and Communication Therapy
  description: >-
    Early intervention, speech and language therapy, occupational therapy and
    physical therapy, directed at the developmental delay and the hand function
    that camptodactyly may limit. This is standard care for syndromic
    intellectual disability rather than anything established for MRT65.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  notes: >-
    No evidence item is attached to this treatment. No study of any developmental
    therapy in KDM5B-related disorder exists in the sources reviewed, and citing
    a general early-intervention trial would attach evidence about a different
    population to this entry.
- name: Genetic Counseling
  description: >-
    Recurrence risk for the siblings of an affected child of two carrier parents
    is one in four on the standard recessive expectation, and prenatal or
    preimplantation testing is possible once the familial alleles are known - a
    sibling pair with corpus callosum agenesis was in fact ascertained partly
    prenatally. The counselling is harder than that arithmetic suggests, though,
    because carrier relatives of an affected child may themselves carry a
    heterozygous loss-of-function allele whose consequences are contested, and
    the 2024 cohort says plainly that variant interpretation in this gene is
    difficult in the light of reduced penetrance.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genotypic interpretation remains difficult in the light of reduced penetrance."
    explanation: >-
      The authors' own statement of what makes counselling for this gene
      difficult, and the reason this entry does not present a clean recessive
      counselling message.
prevalence:
- population: Worldwide, published biallelic KDM5B cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence or incidence estimate exists for MRT65. The disorder
    is known from a case literature of roughly ten individuals with biallelic
    KDM5B variants: the founding descriptions in 2018, a compound heterozygous
    sibling pair in 2021, and two further individuals in the 2024
    genotype-phenotype cohort. The 2024 paper is internally inconsistent about
    the running total - its discussion counts four previously described biallelic
    cases attributable to the two 2018 reports, while its literature-comparison
    table uses a denominator of eight - so "roughly ten" is the honest figure and
    a precise count is not asserted here. No numeric rate is recorded. A
    theoretical birth incidence near 1 in 1.3 million appears in one of the
    committed deep-research reports, but it is a calculation from an assumed
    carrier frequency and an assumed complete penetrance, not a measurement, and
    it is not curated as a prevalence value here.
  evidence:
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four cases of bi-allelic KDM5B variants with intellectual developmental disorder autosomal recessive-65 (MRT65) (OMIM: 618109) have been described in the literature"
    explanation: >-
      The published case count attributed to the two founding reports, which is
      what places this disorder in the ultra-rare band and rules out any
      population-rate claim.
diagnosis:
- name: Exome or Genome Sequencing
  description: >-
    Sequencing is how every reported case was found and is effectively the only
    diagnostic route. Camptodactyly with a recognisable facial gestalt and
    developmental delay may raise the question, but the phenotype is not
    distinctive enough to reach the gene without sequencing, and with about ten
    individuals published no clinician can be expected to recognise it.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  markers: Two disruptive KDM5B alleles in trans - nonsense, frameshift, canonical
    splice-site, or a JmjC-domain missense allele opposite a null. A single heterozygous
    loss-of-function allele does not establish this diagnosis, since such alleles
    occur in unaffected relatives and population controls.
  evidence:
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65."
    explanation: >-
      Names the variant classes a sequencing report must show, and that they must
      be biallelic.
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives."
    explanation: >-
      Why phasing matters diagnostically: a single disruptive KDM5B allele is
      found in unaffected people, so a monoallelic finding does not make this
      diagnosis.
- name: Brain Magnetic Resonance Imaging
  description: >-
    Imaging is worth doing because agenesis of the corpus callosum has been found
    in biallelic individuals, including prenatally, and the authors of that
    report argued on that basis for putting KDM5B on diagnostic panels for
    corpus callosum agenesis. It is not a screening test for the diagnosis:
    structural malformation was present in only one of the biallelic individuals
    imaged in the 2024 cohort.
  diagnosis_term:
    preferred_term: brain magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:34573379
    reference_title: Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Together with the observations in this family, this suggests that agenesis of the corpus callosum may be part of the phenotypic spectrum associated with KDM5B variants and that the KDM5B gene should be included in gene panels to clarify the etiology of ACC both in the prenatal and postnatal setting."
    explanation: >-
      The authors' recommendation, and the reason imaging findings feed back into
      the genetic differential rather than only into prognosis.
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Structural brain malformations were noted for three of the seven individuals with dominant variants and one individual with bi-allelic variants."
    explanation: >-
      Sets expectations: a normal scan does not argue against the diagnosis.
discussions:
- discussion_id: kdm5b_dominant_disorder_existence
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is there a distinct dominant, monoallelic KDM5B neurodevelopmental disorder,
    or is MRT65 the only KDM5B disease and heterozygous loss of function merely a
    quantitative shift in cognitive function?
  attaches_to:
  - genetic#KDM5B
  - inheritance#Autosomal recessive inheritance
  - disease#Intellectual Disability Autosomal Recessive 65
  rationale: >-
    The literature has argued both sides and has not settled. On one side, a 2018
    functional study of splice variants concluded flatly that KDM5B
    haploinsufficiency is not a mechanism in intellectual disability and that the
    KDM5B loss-of-function disorder is recessive; the same paper notes that
    de novo loss-of-function and missense KDM5B variants have been found in
    unaffected individuals as well as in patients. On the other, a 2024
    genotype-phenotype study of 21 individuals - nineteen of them monoallelic -
    describes a monoallelic phenotype in detail and argues for the pathogenicity
    of certain dominant missense variants. Its own framing is that there is "a
    spectrum of recessiveness" in KDM5B disease.


    The population data are what make this hard rather than merely
    under-reported. Heterozygous KDM5B protein-truncating variants are common
    enough in the general adult population to be studied at biobank scale, where
    they associate with a measurable downward shift in cognitive function - a
    quantitative effect, not a disease. That is compatible either with a dominant
    disorder of very reduced penetrance or with no dominant disorder at all and a
    dose-response relationship whose lower end is subclinical.


    What this entry does about it: it scopes itself to the biallelic genotype,
    which is what MONDO:0020850 and OMIM 618109 name and what every source agrees
    is disease-causing. It does not curate a dominant KDM5B entity, and it does
    not import monoallelic phenotype frequencies into the biallelic phenotype
    list. If a dominant entity is eventually accepted with its own MONDO term, it
    should be a separate entry, not a subtype here.
  evidence:
  - reference: PMID:30217758
    reference_title: "Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data reinforces the recent observation that the KDM5B haploinsufficiency is not a mechanism involved in intellectual disability and that KDM5B disorder associated with LOF variants is a recessive disorder."
    explanation: >-
      The recessive-only position, stated explicitly.
  - reference: PMID:30217758
    reference_title: "Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, de novo loss-of-function and missense variants in KDM5B were identified in patients with intellectual disability (ID) and autism spectrum disorder (ASD) but also in unaffected individuals."
    explanation: >-
      The observation that drives the recessive-only position: the same de novo
      alleles appear in affected and unaffected people.
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In our opinion, there is a spectrum of recessiveness in KDM5B-related diseases"
    explanation: >-
      Graded REFUTE against the strict recessive-only position quoted above: this
      cohort argues that monoallelic KDM5B variants can be pathogenic and that
      the recessive-versus-dominant question is not binary. It does not refute
      the biallelic disease claim, which this paper affirms elsewhere in the
      entry.
  - reference: PMID:37231097
    reference_title: The impact of rare protein coding genetic variation on adult cognitive function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans."
    explanation: >-
      The dose-response framing that reconciles the two positions without
      settling them. Graded HUMAN_CLINICAL because the study is a human exome
      analysis of 485,930 adults; its mouse arm is a secondary component of the
      same sentence and cannot be split out of one quote.
- discussion_id: kdm5b_biallelic_penetrance_unmeasured
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What is the penetrance of the biallelic KDM5B loss-of-function genotype? No
    study has estimated it, and the reduced penetrance that the KDM5B literature
    repeatedly documents belongs to the heterozygous state.
  attaches_to:
  - inheritance#Autosomal recessive inheritance
  - genetic#KDM5B
  rationale: >-
    Every published individual with two disruptive KDM5B alleles has been
    affected. That is a real observation and it is why the entry does not record
    incomplete penetrance. But all of them were ascertained through an affected
    proband in a literature of about ten cases, so it cannot separate complete
    penetrance from the ascertainment that produced the case series, and no
    source reviewed here reports an unaffected homozygous or compound
    heterozygous relative. Penetrance is therefore recorded as UNKNOWN rather
    than COMPLETE.


    The reason the question is live rather than pedantic is the gene's behaviour
    one dose up. Heterozygous loss-of-function alleles are tolerated well enough
    to sit in population reference data at an observed-to-expected ratio near
    0.57, which the 2024 cohort reads as partial penetrance, and they do not
    segregate with disease in families. A gene whose heterozygous null state is
    that permissive is exactly the kind of gene where an unaffected biallelic
    individual would be worth actively looking for.


    Resolving it needs population-scale data rather than more case reports: a
    genotype-first search of a large biobank or a consanguineous-population
    cohort for biallelic KDM5B loss-of-function individuals, with phenotyping
    that does not presuppose they were referred for developmental delay.
  proposed_experiments:
  - experiment_id: kdm5b_genotype_first_biallelic_ascertainment
    name: Genotype-first ascertainment of biallelic KDM5B loss-of-function carriers
    description: >-
      Search large unselected exome or genome cohorts, weighted toward
      populations with high autozygosity, for individuals homozygous or compound
      heterozygous for KDM5B protein-truncating alleles, then phenotype them
      through linked health records and direct cognitive assessment rather than
      through the referral route that produced the existing case series.
    decision_criterion: >-
      Whether any ascertained biallelic individual lacks developmental delay or
      intellectual disability on direct assessment.
    would_support:
    - inheritance#Autosomal recessive inheritance
    supporting_outcome:
    - Every biallelic individual found by genotype-first ascertainment has
      developmental delay or intellectual disability, which would move penetrance
      from UNKNOWN toward COMPLETE.
    refuting_outcome:
    - Unaffected or minimally affected biallelic individuals are found, which
      would establish incomplete penetrance for the biallelic genotype and change
      both the recurrence-risk counselling and the diagnostic weight of a
      biallelic finding.
  evidence:
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is in line with a partial penetrance of heterozygous LoF KDM5B variants."
    explanation: >-
      The documented partial penetrance, stated for the heterozygous genotype.
      This is the claim that must not be transferred to the biallelic genotype.
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moderate-to-severe DD and impaired intellectual development were common to all."
    explanation: >-
      All reported biallelic individuals were affected, which is the observation
      the gap is about: it is consistent with complete penetrance and equally
      consistent with ascertainment.
- discussion_id: kdm5b_mouse_autism_vs_human_biallelic
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Mice without KDM5B demethylase activity show autism-like behaviour, yet the
    reported biallelic human individuals do not have autistic behaviours. Is the
    NMDAR2D mechanism traced in the mouse relevant to MRT65 at all, or is it a
    model of the monoallelic human phenotype?
  attaches_to:
  - pathophysiology#Increased Grin2d and NMDA Receptor Subunit 2D Expression
  - animal_models#Kdm5b demethylase-deficient mouse (neocortical H3K4me3 study)
  - phenotypes#Behavioral Abnormalities
  rationale: >-
    This is a mismatch of the specific kind the HUMAN_MODEL_MISMATCH label exists
    for: the model evidence is strong and the human evidence is not absent, they
    simply point different ways. The mouse chain is unusually complete for a
    chromatinopathy - raised H3K4me3 at the Grin2d promoter, raised transcript,
    raised NMDAR2D protein in synaptosomes, socio-communication deficits, and
    rescue of the vocalisation deficit by memantine. But the endpoint it lands on
    is the feature the biallelic human individuals do not have. The 2024 cohort
    states that both of its biallelic individuals had behavioural problems
    without autistic behaviours, and notes the same monoallelic-versus-biallelic
    split for autistic behaviour that it had previously reported for another
    epigenetic regulator.


    Two readings survive. Either the mouse models the monoallelic end of the
    human dose-response, in which case its mechanism is about the contested
    dominant disorder and not about MRT65; or autistic behaviour in biallelic
    humans is simply undercounted at a denominator of two plus a small pooled
    literature. Nothing in the sources distinguishes them, and the entry does not
    pick: the Grin2d node is retained with mechanism_confidence HYPOTHETICAL, and
    autistic behaviour is not curated as a phenotype of this entity.
  evidence:
  - reference: PMID:42160407
    reference_title: Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice exhibited autism-like behaviors and increased brain size."
    explanation: >-
      The model phenotype, in mice without KDM5B demethylase activity.
  - reference: PMID:39202393
    reference_title: A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Both individuals with bi-allelic variants displayed behavioral problems such as mood swings and aggressivity, but they did not display autistic behaviors."
    explanation: >-
      Graded REFUTE against the proposition that the mouse autism-like phenotype
      corresponds to a feature of the biallelic human disorder. It is the human
      observation that creates the mismatch.
- discussion_id: kdm5b_nmdar_antagonism_as_target
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  prompt: >-
    Does NMDA receptor antagonism have any therapeutic potential in KDM5B-related
    neurodevelopmental disorder, given that memantine rescued a vocalisation
    deficit in demethylase-deficient mice?
  attaches_to:
  - pathophysiology#Increased Grin2d and NMDA Receptor Subunit 2D Expression
  - treatments#Supportive and Symptom-Directed Management
  rationale: >-
    This is recorded as a hypothesis and nothing more. A single mouse study
    reports that memantine rescued ultrasonic vocalisation deficits in mice
    lacking KDM5B demethylase activity, downstream of raised Grin2d expression.
    That is a mechanistically motivated result, and it names a drug that is
    already licensed for other indications, which is why it is worth recording at
    all. Against it: the rescued endpoint is a mouse vocalisation deficit whose
    human counterpart is a socio-communication phenotype that the reported
    biallelic individuals do not have; no human has been treated; and no trial
    exists. The entry does not list memantine as a treatment, and this discussion
    should not be read as suggesting it be used.
  evidence:
  - reference: PMID:42160407
    reference_title: Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Treating mice with the NMDAR antagonist memantine rescued deficits in ultrasonic vocalizations."
    explanation: >-
      The rescue result. Mouse only, and the endpoint is a vocalisation measure.
- discussion_id: kdm5b_developmental_versus_ongoing_requirement
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is the cognitive impairment in MRT65 fixed at the end of development, or does
    part of it reflect an ongoing adult requirement for KDM5B that might in
    principle remain modifiable?
  attaches_to:
  - pathophysiology#Impaired Activity-Dependent Gene Expression and Synaptic Plasticity
  - animal_models#Adult hippocampal Kdm5b knockdown mouse
  rationale: >-
    Knocking Kdm5b down in the adult mouse hippocampus alone - after development
    is complete - produces long-term memory and long-term potentiation deficits.
    That is a genuinely interesting result for a disorder that is otherwise
    described as a static developmental disability, because it separates the
    developmental requirement for the gene from a continuing one. Whether any
    part of the human phenotype has the same character is unknown: no
    longitudinal cognitive data exist for biallelic individuals, and the oldest
    reported individual is described only cross-sectionally. The question is
    recorded because it bears directly on whether a postnatal intervention window
    could exist at all, not because any intervention is available.
  evidence:
  - reference: PMID:38575342
    reference_title: The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits."
    explanation: >-
      Adult-restricted knockdown is sufficient for the deficits, which is what
      raises the question of an ongoing rather than purely developmental
      requirement.
notes: >-
  Curation scope and sourcing. This entry covers the biallelic KDM5B genotype
  named by MONDO:0020850 and OMIM 618109. It draws on eight primary sources plus
  one review, and on two deep-research reports committed alongside it. The
  requested falcon provider returned HTTP 402; the recorded fallback produced an
  openscientist report, and a claude_code report was run in parallel while that
  one was outstanding. Both are committed. They agree on the disease definition,
  the causal gene, the mechanism and the absence of any disease-modifying
  therapy, and both were read before the entry was finalised.


  Where the two reports disagree with this entry, and with each other.
  Penetrance: the openscientist report calls the biallelic genotype fully or
  highly penetrant, qualified as "based on limited cohorts". This entry records
  UNKNOWN instead, for the reason set out in the inheritance block - every
  reported biallelic individual was ascertained through an affected proband, so
  a case series of about ten cannot separate complete penetrance from
  ascertainment, and no source reviewed states a penetrance estimate for the
  biallelic genotype. gnomAD constraint: the 2024 cohort quoted in this entry
  reports a loss-of-function observed-to-expected ratio of about 0.57 from
  gnomAD non-neuro v2.1.2, while the openscientist report gives 0.74 with LOEUF
  0.855 from a current gnomAD query. Both readings support the same conclusion -
  that heterozygous KDM5B loss of function is tolerated - and the entry quotes
  only the figure that has a citable source behind it. Incidence: the
  openscientist report offers a carrier frequency near 1 in 570 and a birth
  incidence near 1 in 1.3 million, and flags both as theoretical calculations
  assuming random mating and complete penetrance. Neither is curated, because
  neither is an observation and the second is derived from the penetrance
  assumption this entry declines to make.


  Claims present in the deep-research report but deliberately not curated here,
  because they could not be verified against a cached source: the specific
  variant list from the founding cohort, the 96.89-fold enrichment of homozygous
  protein-truncating variants, the absence of homozygous KDM5B knockouts among
  3,222 consanguineous reference individuals, and the constitutive Kdm5b-null
  mouse phenotype including perinatal lethality and exencephaly. All of those sit
  in the full text of PMID:29276005, which is cached as abstract only, so no
  exact quote is available for them. They are recorded here as unverified leads,
  not as entry content. The report also gave hgnc:29332 for KDM5B and HP:0002510
  for moderate intellectual disability; both are wrong - the gene is hgnc:18039
  and HP:0002510 is Spastic tetraplegia - and neither was used.


  Not curated for lack of a quotable biallelic-specific source: feeding
  difficulties, dolichocephaly, cardiac septal defect, genitourinary anomalies,
  hernias, supernumerary nipple, optic nerve hypoplasia and pectus excavatum.
  Speech and language delay was on this list in an earlier revision and should
  not have been: PMID:34573379 describes its Case 1, a compound heterozygote,
  with poor speech at four years, which is a quotable biallelic-specific
  sentence, and the HPO annotation for OMIM:618109 lists HP:0000750 as frequent.
  It is now curated, as is the hypotonia in the same sentence. What remains
  correct is the exclusion of the 7-of-13 speech figure in PMID:39202393, which
  is explicitly a count over that paper's dominant cohort. Each appears in the deep-research report,
  usually as a single-patient observation traceable to the full text of a source
  that is cached as abstract only. Sleep disturbance and autistic behaviour are
  omitted for the opposite reason: the 2024 cohort, which is the best source for
  both, reports them absent in its biallelic individuals while common in its
  monoallelic ones.


  The pathophysiology chain leaves facial dysmorphism and camptodactyly
  unconnected. That is not an oversight. No source reviewed here traces a route
  from KDM5B loss through chromatin to the craniofacial or hand phenotype, and
  drawing an edge to fill the gap would assert a mechanism nobody has shown.


  Module conformance. Three nodes conform to the epigenetic machinery
  neurodevelopmental dysregulation module. The initiating node deliberately does
  not: that module's first node is haploinsufficiency of a dosage-sensitive
  chromatin component, and this disorder is biallelic complete loss. The
  direction of the chromatin change is also inverted relative to the module's
  worked conformers - most of them lose a writer and lose a permissive mark,
  whereas losing KDM5B removes an eraser and the permissive H3K4me3 mark
  accumulates. The conserved middle of the module, chromatin imbalance to
  dysregulated neurodevelopmental transcription to impaired neuronal maturation,
  holds either way, which is why conformance is declared from the second node on.
datasets: []
📚

References & Deep Research

References

9
PMID:29276005
Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders.
No top-level findings curated for this source.
PMID:30409806
Quantifying the contribution of recessive coding variation to developmental disorders.
No top-level findings curated for this source.
PMID:30217758
Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences.
No top-level findings curated for this source.
PMID:34573379
Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants.
No top-level findings curated for this source.
PMID:35905858
Pathogenic KDM5B variants in the context of developmental disorders.
No top-level findings curated for this source.
PMID:37231097
The impact of rare protein coding genetic variation on adult cognitive function.
No top-level findings curated for this source.
PMID:38575342
The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.
No top-level findings curated for this source.
PMID:39202393
A Genotype/Phenotype Study of KDM5B-Associated Disorders Suggests a Pathogenic Effect of Dominantly Inherited Missense Variants.
No top-level findings curated for this source.
PMID:42160407
Autism-like phenotypes and increased NMDAR2D expression in mice with KDM5B histone lysine demethylase deficiency.
No top-level findings curated for this source.

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Curation scope and sourcing. This entry covers the biallelic KDM5B genotype named by MONDO:0020850 and OMIM 618109. It draws on eight primary sources plus one review, and on two deep-research reports committed alongside it. The requested falcon provider returned HTTP 402; the recorded fallback produced an openscientist report, and a claude_code report was run in parallel while that one was outstanding. Both are committed. They agree on the disease definition, the causal gene, the mechanism and the absence of any disease-modifying therapy, and both were read before the entry was finalised. Where the two reports disagree with this entry, and with each other. Penetrance: the openscientist report calls the biallelic genotype fully or highly penetrant, qualified as "based on limited cohorts". This entry records UNKNOWN instead, for the reason set out in the inheritance block - every reported biallelic individual was ascertained through an affected proband, so a case series of about ten cannot separate complete penetrance from ascertainment, and no source reviewed states a penetrance estimate for the biallelic genotype. gnomAD constraint: the 2024 cohort quoted in this entry reports a loss-of-function observed-to-expected ratio of about 0.57 from gnomAD non-neuro v2.1.2, while the openscientist report gives 0.74 with LOEUF 0.855 from a current gnomAD query. Both readings support the same conclusion - that heterozygous KDM5B loss of function is tolerated - and the entry quotes only the figure that has a citable source behind it. Incidence: the openscientist report offers a carrier frequency near 1 in 570 and a birth incidence near 1 in 1.3 million, and flags both as theoretical calculations assuming random mating and complete penetrance. Neither is curated, because neither is an observation and the second is derived from the penetrance assumption this entry declines to make. Claims present in the deep-research report but deliberately not curated here, because they could not be verified against a cached source: the specific variant list from the founding cohort, the 96.89-fold enrichment of homozygous protein-truncating variants, the absence of homozygous KDM5B knockouts among 3,222 consanguineous reference individuals, and the constitutive Kdm5b-null mouse phenotype including perinatal lethality and exencephaly. All of those sit in the full text of PMID:29276005, which is cached as abstract only, so no exact quote is available for them. They are recorded here as unverified leads, not as entry content. The report also gave hgnc:29332 for KDM5B and HP:0002510 for moderate intellectual disability; both are wrong - the gene is hgnc:18039 and HP:0002510 is Spastic tetraplegia - and neither was used. Not curated for lack of a quotable biallelic-specific source: feeding difficulties, dolichocephaly, cardiac septal defect, genitourinary anomalies, hernias, supernumerary nipple, optic nerve hypoplasia and pectus excavatum. Speech and language delay was on this list in an earlier revision and should not have been: PMID:34573379 describes its Case 1, a compound heterozygote, with poor speech at four years, which is a quotable biallelic-specific sentence, and the HPO annotation for OMIM:618109 lists HP:0000750 as frequent. It is now curated, as is the hypotonia in the same sentence. What remains correct is the exclusion of the 7-of-13 speech figure in PMID:39202393, which is explicitly a count over that paper's dominant cohort. Each appears in the deep-research report, usually as a single-patient observation traceable to the full text of a source that is cached as abstract only. Sleep disturbance and autistic behaviour are omitted for the opposite reason: the 2024 cohort, which is the best source for both, reports them absent in its biallelic individuals while common in its monoallelic ones. The pathophysiology chain leaves facial dysmorphism and camptodactyly unconnected. That is not an oversight. No source reviewed here traces a route from KDM5B loss through chromatin to the craniofacial or hand phenotype, and drawing an edge to fill the gap would assert a mechanism nobody has shown. Module conformance. Three nodes conform to the epigenetic machinery neurodevelopmental dysregulation module. The initiating node deliberately does not: that module's first node is haploinsufficiency of a dosage-sensitive chromatin component, and this disorder is biallelic complete loss. The direction of the chromatin change is also inverted relative to the module's worked conformers - most of them lose a writer and lose a permissive mark, whereas losing KDM5B removes an eraser and the permissive H3K4me3 mark accumulates. The conserved middle of the module, chromatin imbalance to dysregulated neurodevelopmental transcription to impaired neuronal maturation, holds either way, which is why conformance is declared from the second node on.

Create: Intellectual_Disability_Autosomal_Recessive_65 · 2026-09-07T22:25:22Z · View source

Created the MRT65 (biallelic KDM5B, MONDO:0020850) entry from the stub, and deleted the stub. Lump/split: DISEASE. The stub carried one causal gene (hgnc:18039 KDM5B), no MONDO descendants, and a single MONDO parent (MONDO:0019502), which is the leaf signature; the literature treats MRT65 as one entity keyed to the biallelic genotype (OMIM 618109), so no grouping or subtype call was warranted. Deep research provider chain: falcon was requested and returned HTTP 402 (Edison account out of credits); the recorded --fallback run fell back to openscientist, which completed in 1283s and produced research/Intellectual_Disability_Autosomal_Recessive_65-deep-research-openscientist.md (reference_validation 9/9 resolved, 3/3 quotes valid, 8/9 on topic; term_validation 26/29 verified, 0 not found, needs_review true; just preflight-dr PASS). Because a sibling agent's openscientist run had been cancelled server-side after 3600s, a claude_code run was launched in parallel while the fallback was outstanding and completed first in 290s, producing research/Intellectual_Disability_Autosomal_Recessive_65-deep-research-claude_code.md (reference_validation 8/8 resolved, 0 unresolved, 7/8 on topic; term_validation needs_review true with 12 mislabelled terms, mostly frequency strings written into the label slot; just preflight-dr WARN, whose flagged rival gene was the HP ontology prefix, a false positive, and whose second OMIM id 617773 belongs to RUSC2-related Alwadei syndrome, which that report names explicitly as a differential rather than confusing with MRT65). Both reports are committed and both were read. They agree on disease definition, causal gene, mechanism and the absence of disease-modifying therapy. Where they disagree with the entry - the openscientist report calls biallelic penetrance full or high, and offers a theoretical 1-in-1.3-million birth incidence - the entry declines both and says so in its notes. Two errors in the claude_code report were caught and not used: hgnc:29332 for KDM5B (correct is hgnc:18039, verified against the HGNC REST API) and HP:0002510 offered as moderate intellectual disability (that CURIE is Spastic tetraplegia; the entry binds the unqualified HP:0001249 because the reported severity spans mild to severe). That report also attributes PMID:39202393 to Chong et al.; it is Borroto et al. The openscientist report gives the gene CURIE correctly as HGNC:18039. Penetrance was the substantive curation question and the answer went against the working assumption in the task prompt. The reduced penetrance repeatedly documented in the KDM5B literature is a property of the HETEROZYGOUS state - unaffected relatives and controls carrying single loss-of-function alleles, non-segregation of dominant variants within families, and a gnomAD loss-of-function observed/expected ratio of about 0.57 that Borroto et al. read as partial penetrance. No source reviewed reports an unaffected homozygous or compound heterozygous individual; every reported biallelic individual was affected, and all were ascertained through affected probands. Inheritance.penetrance is therefore set to UNKNOWN (not INCOMPLETE, which would import a finding about a different genotype; not COMPLETE, which a ~10-case ascertained series cannot support), with expressivity VARIABLE (mild ID in the 2024 biallelic pair versus moderate-to-severe in the earlier literature). The reasoning is in the inheritance description, and the gap is recorded as a KNOWLEDGE_GAP discussion with a genotype-first ascertainment experiment. Evidence: nine references, all PMIDs, 63/63 snippets verified. Snippets were extracted programmatically from references_cache rather than retyped. Discussions cover the contested dominant/monoallelic KDM5B entity (CONTROVERSY), unmeasured biallelic penetrance (KNOWLEDGE_GAP), the mouse autism-like phenotype against its absence in biallelic humans (HUMAN_MODEL_MISMATCH), memantine/NMDAR antagonism as a preclinical lead (EMERGING_HYPOTHESIS), and the developmental-versus-ongoing requirement for KDM5B (OPEN_QUESTION). Three pathophysiology nodes conform to epigenetic_machinery_neurodevelopmental_dysregulation. The initiating node deliberately does not: that module node is haploinsufficiency of a dosage-sensitive component, whereas this disorder is biallelic complete loss, and the direction of the chromatin change is inverted (an eraser is lost, so the permissive H3K4me3 mark accumulates). Validation run to completion: just validate (pass), just count-verified-snippets (63/63), just validate-terms (pass), just check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-reference-titles, check-term-cache-integrity, just normalize-cache, and finally just validate-disorders (pass, 63/63). just qc as an aggregate was not run; it exceeds the session tool timeout.

Claude Code ▸
Intellectual Disability, Autosomal Recessive 65 (MRT65): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 12 citations 2026-09-07T22:07:42.172137

Intellectual Disability, Autosomal Recessive 65 (MRT65): Comprehensive Research Report

1. Disease Information

Overview. Intellectual Developmental Disorder, Autosomal Recessive 65 (MRT65) is a rare Mendelian neurodevelopmental disorder caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in KDM5B (lysine demethylase 5B), located on chromosome 1q32.1. It is characterized by moderate-to-severe intellectual disability, global developmental delay, characteristic facial dysmorphism, and camptodactyly, with onset in infancy (OMIM #618109; MalaCards).

Key identifiers: - OMIM: #618109 (phenotype); 605393 (KDM5B gene locus) - MONDO: MONDO:0020850 - Gene: KDM5B, HGNC (HGNC:29332), NCBI Gene, chromosome 1q32.1 - Related Orphanet entries: KDM5B is listed as causal for "Autosomal recessive non-syndromic intellectual disability" (ORPHA:88616) and as a candidate gene for autosomal dominant non-syndromic intellectual disability (ORPHA:178469) (Orphanet gene page) - Synonyms:* MRT65; Intellectual disability, autosomal recessive 65; KDM5B-related recessive intellectual disability syndrome; KDM5B-associated developmental delay with facial dysmorphism and camptodactyly

Note on nomenclature confusion (important for curation): MRT65/KDM5B-biallelic disease is distinct from "Alwadei syndrome" (also loosely called MRT61 in some lay sources), which is caused by biallelic RUSC2 variants on chromosome 9p13.3 (OMIM #617773) and is a separate, phenotypically overlapping but genetically unrelated autosomal recessive ID syndrome (Wikipedia summary of Alwadei syndrome, citing Alwadei et al. 2016, Dev Med Child Neurol). Some tertiary aggregator pages conflate the two; this should not be repeated in a curated entry.

Source of information: Nearly all clinical description derives from aggregated case-series/cohort publications (not large-scale EHR data) — a small number of published families/probands (originally 3, now up to ~10–11 published biallelic cases across multiple reports), supplemented by structured databases (OMIM, ClinVar, Orphanet, gnomAD) and model-organism data.

2. Etiology

Disease Causal Factors

MRT65 is a monogenic, purely genetic disorder — no environmental, infectious, or acquired mechanism is implicated. Disease results from biallelic loss-of-function (LoF) variants in KDM5B: nonsense, frameshift, and canonical splice-site variants that are predicted to trigger nonsense-mediated decay or truncate the protein before/within critical catalytic domains, as well as at least one compound-heterozygous case pairing a damaging missense variant (p.Ala635Thr, in the catalytic JmjC domain) with a frameshift null allele (Martin syndrome case report, PMC8467522).

Genetic Risk Factors

  • Causal variants (original cohort, Faundes et al. 2018, Am J Hum Genet 102(1):175-187, PMID:29276005):
  • Patient 12: homozygous c.4109T>G, p.(Leu1370Ter)
  • Patient 13: compound heterozygous c.2475-2A>G (splice acceptor) / c.895C>T, p.(Arg299Ter)
  • Patient 14: compound heterozygous c.3906delC, p.(Asn1302LysfsTer45) / c.622dupT, p.(Tyr208LeufsTer5)
  • Additional reported variant (ClinVar, RCV001764151): c.3424-2A>G, a splice-acceptor variant
  • Compound heterozygous missense + frameshift in siblings with agenesis of the corpus callosum: c.1903G>A p.(Ala635Thr) [CADD 28.8, JmjC domain, conserved across KDM5 paralogues] with c.3463del p.(Ser1155AlafsTer4) (PMC8467522)
  • Statistical evidence of pathogenicity: Fisher's exact test showed a 96.89-fold enrichment of homozygous protein-truncating variants (PTVs) in affected cohorts versus gnomAD background (95% CI 3.95–2,378.87; p=0.03); no homozygous KDM5B knockouts were observed among 3,222 adults from a high-consanguinity reference cohort, consistent with strong purifying selection against biallelic LoF (Faundes et al. 2018).
  • Cumulative literature: A 2024 genotype/phenotype study (Chong et al., Genes 15(8):1033, PMC11353349) catalogs 2 newly reported plus ~8 previously published biallelic cases (total ~10), all with LoF-type variants (nonsense/frameshift), contrasted against 19 individuals (18 novel) with monoallelic (dominant) KDM5B variants including 8 missense, 3 nonsense, 2 splice-site, 4 frameshift, and 1 whole-gene deletion (PMC11353349).
  • Modifier genes: None established.
  • Consanguinity: Multiple reported homozygous cases arise in the setting of parental consanguinity or regions of homozygosity, consistent with an autosomal recessive founder-type mechanism in some families (not formally reported as a specific founder allele/population to date).

Environmental Risk Factors

None identified; this is a Mendelian disorder with no reported environmental/lifestyle contribution to causation.

Protective Factors

None specifically described for the recessive form. Population data show that heterozygous (single-allele) LoF carriers are largely unaffected or mildly affected — heterozygous PTVs are common enough in the population (and in unaffected relatives/controls) to be associated only with subtle cognitive effects (see below), implying the wild-type allele in trans provides substantial functional buffering in carriers.

Gene-Environment Interactions

Not reported; no GxE data available for this ultra-rare monogenic disorder.

3. Phenotypes

Below are the principal reported phenotypes, aggregated primarily from Faundes et al. 2018 (original 3 patients), the sibling agenesis-of-corpus-callosum report (PMC8467522), and the 2024 genotype/phenotype cohort (PMC11353349).

Phenotype Type Onset Frequency (biallelic cohort) Suggested HPO term
Global developmental delay Sign Infancy ~100% (all reported cases) HP:0001263
Intellectual disability (moderate–severe) Sign Recognized in childhood 100% HP:0002510 (moderate)/HP:0010864 (severe)
Delayed walking (achieved age 2–4 y) Sign Infancy/toddler Most patients HP:0031936 (Delayed ability to walk)
Delayed/limited speech Sign Infancy/toddler Most patients (e.g., "5 words" at age 4 in one case) HP:0000750
Neonatal/infantile feeding difficulties Sign Neonatal Reported in original 3 patients HP:0011968
Poor overall growth / mild postnatal growth deficiency Sign Infancy Mild, in a subset HP:0001510
Dolichocephaly Physical sign Congenital Present in a subset HP:0000268
Prominent/broad metopic ridge or forehead Physical sign Congenital Common HP:0000348 / HP:0011220
Square face Physical sign — Some patients HP:0000321
Dysplastic/low-set ears Physical sign Congenital Some patients HP:0008551 / HP:0000369
High nasal bridge, bulbous nasal tip, smooth philtrum, thin lips Physical signs Congenital Recurrent facial gestalt across cases HP:0000426, HP:0000414, HP:0000319, HP:0000219
Camptodactyly (fixed flexion, typically digits 4–5) Physical sign Congenital Present in majority (hallmark feature) HP:0012385
Joint hypermobility / hand abnormalities Physical sign — ~50% in 2024 cohort HP:0001382
Behavioral problems (nonspecific) Behavioral Childhood Present in all biallelic cases assessed HP:0000708
Agenesis/hypoplasia of corpus callosum Structural brain anomaly Congenital Reported in multiple biallelic cases (Patient 12; sibling pair) HP:0001274 (agenesis) / HP:0002079 (hypoplasia)
Camptodactyly with cardiac defects (atrial septal defect) Sign Congenital One patient HP:0001631
Cryptorchidism, hypospadias Sign Congenital One patient (male) HP:0000028, HP:0000047
Inguinal hernia / umbilical hernia Sign Infancy Individual patients HP:0000023 / HP:0001537
Supernumerary nipple Sign Congenital One patient HP:0002558
Optic nerve hypoplasia Sign Congenital One patient (sibling case) HP:0000609
Pectus excavatum Sign Congenital One patient HP:0000767

Notably absent in the biallelic (recessive) cohort, in contrast to the monoallelic/dominant KDM5B phenotype: autism spectrum disorder and seizures were not observed in the 2024 systematic genotype/phenotype study's recessive cases, whereas ASD (53–64%) and sleep disorders (47%) are common in dominant KDM5B disease (PMC11353349).

Progression/severity: Developmental milestones are markedly delayed but generally achieved (walking and speech onset between 2–4 years in the original cohort); the disorder is considered a static/stable neurodevelopmental disability rather than a progressive neurodegenerative process, though hippocampal/memory-related deficits demonstrated in mouse models raise the possibility of an ongoing (not purely developmental) component to the cognitive phenotype (see Mechanism section).

Quality of life impact: Not formally studied with standardized instruments (EQ-5D, SF-36) in this ultra-rare population; qualitatively, affected individuals require lifelong support for intellectual disability, communication impairment, and (in a subset) structural brain and congenital anomalies requiring surgical/medical management.

4. Genetic/Molecular Information

Causal gene: KDM5B (also known as JARID1B, PLU1, RBBP2H1A, CT31), OMIM *605393, chromosome 1q32.1.

Gene product/domain architecture: KDM5B contains 7 annotated domains: JmjN domain, catalytic JmjC domain, ARID (DNA-binding) domain, C5HC2 zinc finger, and three PHD (plant homeodomain) fingers (PHD1–3) (Sci Rep 2019, molecular architecture paper; Functions and Interactions of Mammalian KDM5 Demethylases, PMC9309374).

Molecular function: KDM5B is an Fe(II)/2-oxoglutarate-dependent JmjC-domain histone demethylase that removes methyl groups from trimethylated, dimethylated, and monomethylated lysine 4 of histone H3 (H3K4me3/me2/me1) — a promoter-proximal mark generally associated with transcriptional activation. Catalysis proceeds via decarboxylation of 2-oxoglutarate to succinate + CO₂ coupled to hydroxylation of the methylated lysine, yielding an unstable hemiaminal that spontaneously decomposes to release formaldehyde and demethylated lysine. KDM5B additionally regulates RNA polymerase II initiation/elongation rates and alternative splicing.

Variant classification (ACMG/AMP) in the recessive disease: Reported biallelic variants are predominantly classified pathogenic/likely pathogenic loss-of-function alleles: - Nonsense: p.(Leu1370Ter), p.(Arg299Ter) - Frameshift: p.(Asn1302LysfsTer45), p.(Tyr208LeufsTer5), p.(Ser1155AlafsTer4) - Canonical splice-site: c.2475-2A>G, c.3424-2A>G (ClinVar RCV000678688, RCV001764151) - One missense (p.Ala635Thr, JmjC domain, CADD 28.8) reported in trans with a frameshift null, in a family with corpus callosum agenesis; classified as likely pathogenic on the basis of conservation, domain location, and segregation (PMC8467522)

Population allele frequency (gnomAD): The pathogenic missense variant (p.Ala635Thr) was observed in a single gnomAD heterozygote; the frameshift null was absent from gnomAD, consistent with strong selection against biallelic loss-of-function. No homozygous KDM5B PTV carriers were found among 3,222 highly consanguineous individuals in reference data. KDM5B shows strong constraint against loss-of-function in gnomAD generally (specific pLI/LOEUF values were not independently verifiable via the sources retrieved in this session and should be confirmed directly against the gnomAD browser before curation).

Somatic vs. germline: All reported disease-causing variants are germline; KDM5B is separately studied as a somatically amplified oncogene in some cancers (breast, prostate), but that is a distinct biological context from the germline recessive ID disorder.

Functional consequences: Loss-of-function variants are predicted/demonstrated to cause haploinsufficiency-on-a-null-background — i.e., the recessive disease requires near-complete loss of KDM5B demethylase activity from both alleles, since heterozygous LoF carriers are generally unaffected or only mildly affected (see Section 2). This is mechanistically consistent with the semi-dominant/dosage-sensitive biology of KDM5 family demethylases.

Modifier genes: None established.

Epigenetic information: KDM5B is itself a chromatin-modifying enzyme; its loss is predicted to cause genome-wide dysregulation of the H3K4me3 landscape, particularly at promoters of activity-dependent and developmentally regulated genes (directly demonstrated in mouse hippocampal models — see Mechanism section). No human DNA methylation/EWAS "episignature" for MRT65 was identified in the sources reviewed in this session.

Chromosomal abnormalities: No microdeletion/microduplication syndrome mechanism is described for MRT65; disease arises from intragenic sequence variants, not copy-number rearrangement (in contrast to some dominant KDM5B cases, one of which involved a whole-gene deletion).

Suggested ontology bindings: - Gene: hgnc:29332 (KDM5B) - GO Molecular Function: GO:0032454 (histone H3-K9 demethylase activity — not correct; correct term is GO:0032453, "histone H3K4 demethylase activity, trimethyl-H3K4-specific") — verify exact GO ID against OAK/AmiGO before binding - GO Biological Process: GO:0016575 (histone deacetylation — not applicable); more precisely, "negative regulation of gene expression, epigenetic" GO:0045814, or "histone H3-K4 demethylation" (verify exact CURIE)

5. Environmental Information

No environmental factors, lifestyle exposures, or infectious agents are implicated in causation of MRT65. This is a purely monogenic Mendelian disorder.

6. Mechanism / Pathophysiology

Causal chain (ordered, from molecular lesion to clinical phenotype)

  1. Biallelic KDM5B loss-of-function or damaging missense variant (nonsense, frameshift, canonical splice-site, or a JmjC-domain missense in trans with a null allele) leads to near-complete loss of functional KDM5B protein or catalytic activity in the affected individual (demonstrated statistically by enrichment of homozygous PTVs over population background; PMID:29276005).
  2. Loss of KDM5B H3K4 demethylase activity leads to failure to remove trimethyl/dimethyl/monomethyl marks from histone H3 lysine 4 at target gene promoters, resulting in genome-wide dysregulation of the H3K4me3 chromatin landscape — this step is demonstrated directly in a demethylase-dead mouse model (Kdm5bΔARID/ΔARID), which shows abnormal baseline H3K4me3 accumulation in hippocampal neurons (PMID:38575342/PMC11079963). This mouse-model step is inferred to translate to human neurons; it has not been directly demonstrated in human tissue.
  3. Dysregulated H3K4me3 leads to abnormal baseline transcription of activity-dependent immediate-early genes (Egr1, Npas4, cFos are downregulated at baseline) and, upon a learning/activity stimulus, hyperactivated and pathologically prolonged transcription of the same genes (persisting ~3 hours vs. transient in controls) — a bidirectional dysregulation of neuronal activity-dependent gene programs (model-organism evidence, PMC11079963).
  4. Dysregulated activity-dependent transcription leads to impaired postsynaptic long-term potentiation (LTP) stability in hippocampal CA1 neurons following theta-burst stimulation, with intact presynaptic release and short-term plasticity — i.e., a selective postsynaptic synaptic-plasticity defect (model-organism evidence).
  5. Impaired synaptic plasticity leads to deficits in long-term (but not short-term) spatial memory consolidation, demonstrated behaviorally in Morris water maze and object-location memory tasks in mice, while short-term memory and cognitive flexibility are preserved (model-organism evidence).
  6. In humans, this cascade is inferred (by analogy/extrapolation from the mouse mechanistic data, not directly demonstrated) to manifest as global developmental delay and moderate-to-severe intellectual disability, with a possible ongoing (not purely developmental) memory-consolidation component — raising the hypothesis that some cognitive deficits could remain modifiable in postnatal/adult life, a claim explicitly framed as therapeutically speculative by the authors (PMC11079963).
  7. In parallel, independent of the neuronal/synaptic branch, KDM5B's broader role in regulating cell differentiation, developmental gene expression programs, and (in mouse knockouts) cranial neural crest/skeletal and craniofacial development leads to the syndromic congenital anomalies seen in humans — camptodactyly, characteristic facial dysmorphism (broad forehead/metopic prominence, high nasal bridge, bulbous nasal tip, thin lips), and in a subset, structural brain malformation (corpus callosum agenesis/hypoplasia) and other congenital anomalies (cardiac septal defects, genitourinary anomalies, hernias). This branch is supported by Kdm5b-null mouse phenotypes: disorganized cranial nerves, eye developmental defects, exencephaly, and skeletal anomalies, with most homozygous-null pups dying within the first postnatal day (perinatal lethality), and surviving pups showing developmental defects into adulthood (PMID:29276005; MGI:1922855).
  8. A distinct, dosage-dependent branch: heterozygous (monoallelic) KDM5B protein-truncating variants, insufficient to cause the full recessive syndrome, are nonetheless associated with measurably reduced educational attainment, slower reaction time, and worse verbal-numerical reasoning at the population level, and are enriched among individuals with ADHD in two independent large case-control sequencing studies — indicating a dose-dependent (semi-dominant) relationship between KDM5B function and cognitive/behavioral phenotype severity, from mild population-level cognitive effects (heterozygous LoF) through syndromic dominant disease (heterozygous disruptive or missense variants with more severe/penetrant effects, including ASD and renal/dermatologic anomalies) to the fully penetrant recessive syndrome described here (biallelic LoF) (PMC10260403; PMC11353349; medRxiv 2025.01.14.25320294; Nat Commun 2024, 10.1038/s41467-024-50247-7).

Molecular pathways

Histone H3K4 methylation/demethylation cycle (writers: SET1/MLL family KMTs; erasers: KDM5 family, including KDM5A/B/C/D); RNA Pol II transcriptional initiation/elongation regulation; alternative splicing regulation.

Cellular processes

Neuronal activity-dependent transcription (immediate-early gene induction), synaptic plasticity (LTP), neural differentiation, cranial neural crest-derived craniofacial/skeletal development.

Protein dysfunction

Loss of catalytic JmjC-domain demethylase activity (nonsense/frameshift → truncated/degraded protein via NMD; missense in JmjC domain → predicted catalytic impairment).

Cell types and biological processes implicated (suggested ontology terms)

  • Cell types: hippocampal pyramidal neuron (CL:0002614 or more specific CA1 pyramidal neuron term), cranial neural crest cell (CL:0000333)
  • GO Biological Process candidates: "histone H3-K4 demethylation," "regulation of synaptic plasticity" (GO:0048167), "positive regulation of transcription by RNA polymerase II" (GO:0045944), "long-term memory" (GO:0007616), "neural crest cell development" (GO:0014032) — all CURIEs should be verified against OAK before binding.

Single-cell / omics data

No human single-cell, spatial transcriptomic, or multi-omic dataset specific to MRT65 patient tissue was identified in this session's searches. The relevant "omics" evidence base is exclusively mouse hippocampal transcriptomic (RNA-seq of immediate-early and late-response genes) and ChIP-based H3K4me3 profiling from the 2024 J Neurosci study (PMC11079963), plus a related 2024/2025 preprint on autism-like phenotypes and increased NMDAR2D expression in KDM5B-deficient mice (Sci Adv, PMC13189110) describing altered glutamatergic signaling gene expression.

7. Anatomical Structures Affected

Organ level: - Primary: central nervous system (intellectual disability, developmental delay; structural anomaly — corpus callosum agenesis/hypoplasia, absent interthalamic adhesion, hypoplastic anterior commissure in severe cases; optic nerve hypoplasia) - Secondary: musculoskeletal system (camptodactyly, joint hypermobility), craniofacial skeleton (dolichocephaly, metopic prominence, facial dysmorphism), cardiovascular system (atrial septal defect in one patient), genitourinary system (cryptorchidism, hypospadias in one patient), abdominal wall (inguinal/umbilical hernia) - Body systems: nervous, skeletal, craniofacial, cardiovascular (occasional), genitourinary (occasional)

Tissue/cell level: Neurons (particularly hippocampal), cranial neural crest-derived mesenchyme/craniofacial tissue, developing corpus callosum axonal tracts (with Probst bundle formation in complete agenesis — anomalous longitudinally-oriented axon bundles that fail to cross the midline).

Subcellular level: Nucleus (chromatin/nucleosome — GO Cellular Component: "nucleus" GO:0005634; more specifically chromatin, GO:0000785), consistent with KDM5B's role as a chromatin-modifying nuclear enzyme.

Localization/UBERON suggestions: brain (UBERON:0000955), corpus callosum (UBERON:0002336), hippocampus (UBERON:0002421), hand digit / phalanx (for camptodactyly — UBERON:0002389 or more specific digit terms), face (UBERON:0001456).

Lateralization: Not reported as asymmetric; anomalies (corpus callosum agenesis, camptodactyly) are typically bilateral/midline.

8. Temporal Development

  • Onset: Congenital/infantile — feeding difficulties and dysmorphic features present from birth or early infancy; developmental delay recognized in infancy.
  • Onset pattern: Insidious/developmental rather than acute.
  • Progression: The intellectual disability and developmental delay are generally considered a static (non-progressive) neurodevelopmental disability once diagnosed, though affected individuals continue to acquire skills at a delayed rate (walking and first words achieved between ages 2–4 years in the original cohort). No degenerative course has been reported.
  • Disease course pattern: Stable/lifelong; no remission.
  • Critical periods: Mouse mechanistic data suggest KDM5B has functions in both prenatal neurodevelopment and ongoing adult synaptic plasticity/memory consolidation (demonstrated via adult hippocampal knockdown reproducing memory deficits) — raising the hypothesis of a postnatal "window of continued relevance" for gene function, distinct from a purely prenatal critical period, though this remains an extrapolation from animal data with unproven human therapeutic implications (PMC11079963).

9. Inheritance and Population

Epidemiology: MRT65 is an ultra-rare disorder. As of the original description, only 3 unrelated patients (all boys) had been reported (Faundes et al. 2018); by the 2024 genotype/phenotype study, roughly 10 biallelic cases total were catalogued in the literature (PMC11353349). No formal population prevalence or incidence estimate exists; this would be classified prevalence_class: NOT_YET_DOCUMENTED or an ultra-rare qualitative tier per dismech convention, sourced to measure_type: CASES_IN_LITERATURE.

Inheritance pattern: Autosomal recessive (biallelic KDM5B variants — homozygous or compound heterozygous).

Penetrance: Appears fully penetrant for the biallelic LoF genotype based on reported cases, though ascertainment bias in an ultra-rare, case-report-driven literature cannot be excluded.

Expressivity: Variable — e.g., presence/absence of craniofacial dysmorphism, corpus callosum anomalies, cardiac/genitourinary anomalies differ among the reported patients despite shared biallelic LoF mechanism (Patient 13 notably lacked craniofacial dysmorphism).

Genetic anticipation: Not applicable/not reported (not a repeat-expansion disorder).

Germline mosaicism: Not specifically reported for KDM5B.

Founder effects: Not established; however, several published families are consanguineous, consistent with the general expectation for an ultra-rare autosomal recessive disorder.

Consanguinity role: Multiple reported homozygous cases arose from consanguineous unions; the population-genetics analysis in Faundes et al. specifically leveraged highly consanguineous reference cohorts (3,222 individuals) to show absence of homozygous PTV carriers as pathogenicity evidence.

Carrier frequency: Not established for MRT65 specifically; heterozygous KDM5B PTVs are present in the general population at a frequency sufficient to be studied for population-level cognitive/ADHD associations (i.e., not vanishingly rare), consistent with a modest carrier frequency, though a precise number was not identified in this session's sources — verify via gnomAD before curation.

Population demographics: All three original patients were male (boys), though this is very likely an ascertainment artifact from a small case series rather than a true sex-linked susceptibility, since the gene is autosomal. No specific ethnic/geographic enrichment has been reported; cases described in the literature originate from genetically heterogeneous ascertainment (Deciphering Developmental Disorders (DDD)-type cohorts and clinical case reports internationally).

Sex ratio: Not formally established (small sample skewed male in original description; not confirmed as a true biological sex bias).

10. Diagnostics

Genetic testing (primary diagnostic modality): - Whole exome sequencing (WES) or whole genome sequencing (WGS) — the diagnostic method by which essentially all reported cases were identified (via trio-based DDD-type cohorts or diagnostic clinical WES), given the ultra-rare and clinically non-specific nature of the phenotype. - Gene panel testing for intellectual disability/developmental delay panels that include KDM5B (e.g., Genomics England PanelApp Intellectual Disability panel, green/confidence level 10 — well-established gene-disease association) (PanelApp). - Single-gene KDM5B sequencing reasonable only when phenotype (camptodactyly + facial gestalt + developmental delay) is strongly suggestive, given the rarity. - Chromosomal microarray — not the primary diagnostic tool for this sequence-variant-driven disorder (as opposed to dominant cases with a reported whole-gene deletion), but useful to exclude CNV-based differentials. - RNA/splicing studies: Used in at least one report to functionally validate splice-site variants ("Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences," ScienceDirect/ResearchGate) — demonstrating aberrant transcript products from canonical splice-site variants.

Clinical/imaging tests: - Brain MRI — recommended given the reported association with corpus callosum agenesis/hypoplasia, absent interthalamic adhesion, hypoplastic anterior commissure, and optic nerve hypoplasia in a subset of patients; prenatal fetal MRI has also identified partial corpus callosum agenesis (splenium absence) at 22 weeks gestation in one case. - Cardiac echocardiogram — indicated given a reported atrial septal defect. - Skeletal/hand examination — camptodactyly assessment. - Developmental/cognitive assessment — standardized developmental and IQ testing to characterize the moderate-to-severe intellectual disability.

Differential diagnosis: Other genetic causes of syndromic intellectual disability with camptodactyly and/or corpus callosum anomalies, including but not limited to other chromatin-modifier-related neurodevelopmental disorders (KMT2D/Kabuki syndrome spectrum, other KDM5-family disorders — KDM5A, KDM5C [X-linked, Claes-Jensen syndrome], KDM5D), and RUSC2-related Alwadei syndrome (biallelic, overlapping ID + facial dysmorphism + occasional corpus callosum hypoplasia phenotype, OMIM #617773) — this is a genuine differential to flag given surface-level phenotypic overlap and nomenclature confusion in secondary sources.

Screening: No population or newborn screening program exists for this ultra-rare disorder; diagnosis is reactive, prompted by clinical developmental delay/dysmorphism evaluation.

11. Outcome/Prognosis

  • Survival/mortality: No mortality directly attributable to MRT65 itself has been reported in surviving liveborn patients (oldest reported patient in the 2024 cohort was 28 years old); one reported pregnancy was electively terminated at 24 weeks for severe prenatal brain malformation (partial corpus callosum agenesis), reflecting reproductive-decision outcomes rather than a mortality statistic of the postnatal disease.
  • Morbidity/function: Lifelong moderate-to-severe intellectual disability with need for ongoing developmental, educational, and adaptive support; camptodactyly may require orthopedic/hand-therapy management; structural brain anomalies (when present) correlate with more severe neurological phenotype.
  • Complications: Congenital anomalies in a subset (cardiac septal defect, cryptorchidism/hypospadias, hernias) may require surgical correction.
  • Recovery potential: No cure; supportive management only. The mouse memory-consolidation data (PMC11079963) raise a speculative, not yet clinically validated, hypothesis that some adult cognitive deficits could theoretically remain responsive to intervention beyond the developmental period — this should be flagged in any curated entry as a HUMAN_MODEL_MISMATCH-type caveat rather than an established human therapeutic avenue.
  • Prognostic factors: Presence/severity of structural brain anomaly (corpus callosum agenesis) appears to correlate with greater phenotypic severity in the small reported series, though this is not statistically established given sample size.

12. Treatment

No disease-specific or targeted pharmacotherapy exists. Management is entirely supportive and symptom-directed:

  • Supportive care / multidisciplinary developmental management: NCIT:C15747 (Supportive Care)
  • Early intervention / developmental therapies: physical therapy (NCIT:C15302), occupational therapy (NCIT:C121351), speech therapy (NCIT:C159273) — addressing motor delay, camptodactyly-related hand function, and speech/communication delay
  • Special education / behavioral support for intellectual disability and behavioral problems
  • Orthopedic surgical procedure (NCIT:C16186) — potential management of camptodactyly if functionally limiting
  • Cardiac surgical correction — for structural cardiac anomalies (atrial septal defect) if hemodynamically significant, NCIT:C15329 (Surgical Procedure)
  • Genetic counseling (NCIT:C15240) — essential given autosomal recessive inheritance and 25% recurrence risk for future pregnancies of carrier parents; prenatal diagnosis is feasible once the familial variants are known (as demonstrated by the prenatal case detected via fetal MRI/genetic testing).

Experimental/clinical trials: No KDM5B/MRT65-specific clinical trials were identified in ClinicalTrials.gov searches performed in this session; none should be assumed to exist without direct verification.

Genotype-guided considerations: None currently established; the disorder is too rare for stratified precision-medicine approaches to have been developed.

13. Prevention

  • Primary prevention: Not applicable (no modifiable risk factor); genetic counseling for known carrier couples (e.g., after an affected child) regarding 25% recurrence risk in future pregnancies.
  • Secondary prevention: Prenatal diagnosis via chorionic villus sampling/amniocentesis for known familial variants once identified in a proband, as illustrated by the prenatal detection case (partial corpus callosum agenesis on fetal MRI, followed by molecular confirmation) (PMC8467522). Preimplantation genetic diagnosis (PGD) is a theoretical option for known carrier couples, though not specifically documented as used in the literature reviewed.
  • Tertiary prevention: Early developmental intervention services to optimize functional outcomes once diagnosed.
  • Population/genetic screening: No population carrier-screening panel currently includes KDM5B as a routine component (it is not among common expanded-carrier-screening panel genes at this time), consistent with its very recent (2018) disease-gene establishment and ultra-rare status.

14. Other Species / Natural Disease

No naturally occurring veterinary/companion-animal disease caused by biallelic KDM5B loss-of-function has been reported in the sources reviewed (no OMIA entry identified). KDM5B orthologs are broadly conserved (mouse Kdm5b, MGI:1922855; Drosophila kdm5/lid; and other KDM5-family members across vertebrates), but disease association is currently a human/laboratory-model finding rather than a recognized natural veterinary disease.

15. Model Organisms

Mouse models (primary model system used): - Constitutive Kdm5b knockout mice (MGI:1922855): Homozygous knockout causes postnatal lethality in the majority of pups, most dying within the first 24 hours of life; surviving pups develop normally into adulthood but show increased incidence of exencephaly, eye developmental defects, disorganized cranial nerves, and skeletal anomalies — recapitulating several structural/congenital features of the human syndrome, but with far greater lethality than seen in humans, indicating the mouse null is not a fully faithful model of viable human biallelic loss (relevant for a FAILS_TO_RECAPITULATE/PARTIALLY_RECAPITULATES model-link annotation, fidelity: LOW–MODERATE, with a SPECIES_MISMATCH or BOUNDARY_OMISSION divergence given the survival discrepancy) (PMID:29276005; MGI:1922855). - Kdm5bΔARID/ΔARID mice (demethylase-catalytically-dead, but not full protein-null): viable, adult-survivable model used to study postnatal/adult hippocampal function — hyperactivity, long-term (but not short-term) spatial memory deficits, impaired hippocampal LTP, and dysregulated activity-dependent immediate-early gene transcription (PMID:38575342/PMC11079963). This model partially recapitulates the human cognitive phenotype at the behavioral/circuit level (RECAPITULATES for memory/behavioral readouts) but does not model the congenital/dysmorphic features of the human syndrome, since it preserves partial protein structure and is not a full LoF-null. - Adult hippocampal shRNA knockdown (CA1-targeted, wild-type mice): Demonstrates that postnatal/adult-only knockdown is sufficient to cause spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory/LTP deficits — showing the phenotype is not exclusively attributable to developmental loss, supporting a model where ongoing adult gene function is separately required (PMC11079963). - Mouse model of autism-like phenotypes: A 2024–2025 study (Science Advances, PMC13189110) reports KDM5B-deficient mice show autism-like behavioral phenotypes and increased NMDAR2D (Grin2d) expression, suggesting altered glutamatergic signaling as an additional mechanistic branch — this maps more directly to the dominant/monoallelic human KDM5B-ASD phenotype than to the biallelic MRT65 phenotype (which notably lacks ASD in the 2024 clinical cohort), and should be flagged as a model-to-phenotype scale/relevance mismatch if used to support the recessive MRT65 entry specifically.

Invertebrate models: Drosophila KDM5 (fly ortholog, "lid") knockdown/mutant studies demonstrate roles in synaptic structure and function at the neuromuscular junction, larval growth, and chromatin insulator activity in the brain — supporting deep evolutionary conservation of KDM5's neurodevelopmental role, but these are invertebrate systems with substantial biological distance from the human CNS phenotype (fidelity: LOW, useful mechanistically but not for direct phenotype recapitulation claims).

Model limitations (general): No existing animal model — including the closest available (Kdm5bΔARID/ΔARID) — reproduces the full human MRT65 syndromic phenotype (camptodactyly, characteristic facial dysmorphism, corpus callosum agenesis) together with viable adult survival; the constitutive null best matches structural/congenital features but is embryonic/perinatal lethal in the majority of animals, while the catalytically-dead ARID model best matches the cognitive/memory phenotype but lacks the structural and craniofacial anomalies. This split strongly suggests the human syndrome as a whole has never been fully modeled in one animal system to date, an appropriate HUMAN_MODEL_MISMATCH discussion point for curation.

Summary of Key Primary Citations

PMID/Source Citation Contribution
29276005 Faundes V, et al. Am J Hum Genet. 2018 Jan 4;102(1):175-187. Original description establishing biallelic KDM5B LoF as cause of recessive ID syndrome (3 patients); population-genetics pathogenicity evidence; mouse KO phenotype summary
PMC8467522 Case report, compound het missense/frameshift KDM5B, sibling pair Corpus callosum agenesis phenotype, prenatal detection, expands allelic spectrum
PMC11353349 (Chong et al.) Genes 2024;15(8):1033 Genotype/phenotype study contrasting biallelic vs. monoallelic KDM5B disease; ~10 biallelic cases catalogued
35905858 Harrington et al. review, Biochim Biophys Acta Gene Regul Expr. 2022 Comprehensive review of pathogenic KDM5B variant spectrum, recessive vs dominant
38575342 / PMC11079963 J Neurosci. 2024;44(19):e1544232024 Mouse mechanistic model: hippocampal H3K4me3 dysregulation, memory consolidation deficits
PMC13189110 (Sci Adv) Autism-like phenotypes/NMDAR2D in KDM5B-deficient mice Mechanistic link to glutamatergic signaling (relevant mainly to dominant/ASD phenotype)
PMC10260403 Rare protein-coding variation and adult cognitive function Population-level heterozygous KDM5B PTV effect on cognition
OMIM #618109 Clinical synopsis, MRT65 Curated phenotype/gene summary

Curation caveats to flag explicitly: (1) The disorder is defined by an extremely small published case count (~10 biallelic patients across all literature to date) — treat prevalence as CASES_IN_LITERATURE/undocumented, not a population rate. (2) Distinguish this recessive entry sharply from dominant/monoallelic KDM5B disease and from RUSC2-related Alwadei syndrome, both of which are conflated in some secondary/tertiary web sources. (3) Mouse mechanistic data (hippocampal memory consolidation, autism-like NMDAR2D findings) come from models that do not fully recapitulate the human biallelic-null phenotype and should be evidence-graded MODEL_ORGANISM with explicit HUMAN_MODEL_MISMATCH/divergence annotations rather than treated as directly confirmed human mechanism. (4) Several ontology CURIEs suggested above (GO terms in particular) are provisional and must be verified against OAK/live ontology lookup before binding, per this repository's term-validation policy.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 7
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 59
Resolved 54
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 4
Terms whose name was checked 23
Terms named correctly 9
Terms named as a different term 12
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0001263 (1 mention) - the report calls it "~100% (all reported cases)"; HP calls it Global developmental delay
  • HP:0000750 (1 mention) - the report calls it "Most patients (e.g., "5 words" at age 4 in one case)"; HP calls it Delayed speech and language development
  • HP:0001510 (1 mention) - the report calls it "Mild, in a subset"; HP calls it Growth delay
  • HP:0000268 (1 mention) - the report calls it "Present in a subset"; HP calls it Dolichocephaly
  • HP:0012385 (1 mention) - the report calls it "Present in majority (hallmark feature)"; HP calls it Camptodactyly
  • HP:0001382 (1 mention) - the report calls it "~50% in 2024 cohort"; HP calls it Joint hypermobility
  • HP:0000708 (1 mention) - the report calls it "Present in all biallelic cases assessed"; HP calls it Atypical behavior
  • HP:0001631 (1 mention) - the report calls it "One patient"; HP calls it Atrial septal defect
  • HP:0002558 (1 mention) - the report calls it "One patient"; HP calls it Supernumerary nipple
  • HP:0000609 (1 mention) - the report calls it "One patient (sibling case)"; HP calls it Optic nerve hypoplasia
  • HP:0000767 (1 mention) - the report calls it "One patient"; HP calls it Pectus excavatum
  • NCIT:C15302 (1 mention) - the report calls it "Early intervention / developmental therapies: physical therapy"; NCIT calls it Physical Therapy**

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0016575 (obsolete histone deacetylation) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0000321 (1 mention) - the report calls it "Some patients"; HP calls it Square face, and lists "Square facies" among its other names
  • GO:0016575 (1 mention) - the report calls it "histone deacetylation — not applicable"; GO calls it obsolete histone deacetylation

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.

OpenScientist ▸
Intellectual Disability, Autosomal Recessive 65 (MRT65): A Comprehensive Disease Report
openscientist-autonomous 6 citations 2026-09-07T22:23:22.871147

Intellectual Disability, Autosomal Recessive 65 (MRT65): A Comprehensive Disease Report

Disease: Intellectual disability, autosomal recessive 65 (MRT65) MONDO ID: MONDO:0020850 · OMIM: #618109 · Causal gene: KDM5B (1q32.1) Category: Mendelian, autosomal recessive neurodevelopmental disorder ("chromatinopathy")

Summary

Intellectual disability, autosomal recessive 65 (MRT65) is an ultra-rare, autosomal-recessive neurodevelopmental disorder caused by biallelic (homozygous or compound-heterozygous) loss-of-function variants in KDM5B, a gene on chromosome 1q32.1 encoding a histone H3K4 (tri-/di-/mono-methyl) demethylase. Because KDM5B is a chromatin-modifying enzyme, MRT65 belongs to the growing family of "chromatinopathies" — Mendelian disorders of the epigenetic machinery that disrupt developmental and activity-dependent gene transcription in the brain. The disorder was first delineated by Faundes and colleagues in 2018, who described "a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly" (PMID: 29276005).

The core clinical picture combines global developmental delay and moderate intellectual disability, delayed speech and motor milestones, behavioral/autistic features, craniofacial dysmorphism (square face, smooth philtrum, thin vermilion border, prominent nasal bridge, bulbous nose), finger camptodactyly (contractures of the 4th/5th proximal interphalangeal joints), and structural brain abnormalities, most notably corpus callosum hypoplasia/partial agenesis. Onset is neonatal to infantile. Importantly, the same gene shows a striking dosage relationship: KDM5B is loss-of-function–tolerant in the general population (gnomAD pLI ≈ 0, LOEUF 0.855), which mechanistically explains why a single pathogenic allele is generally insufficient for the full syndrome and why disease requires biallelic hits — although heterozygous protein-truncating variants are associated with modestly reduced population-level cognition.

MRT65 is ultra-rare: from gnomAD v4 we estimate a pathogenic-carrier frequency of roughly 1 in 570 and a theoretical random-mating birth incidence near 1 in 1.3 million (higher in consanguineous populations). There is no disease-specific or curative therapy; management is entirely supportive (early developmental intervention, physical/occupational/speech therapy, and management of dysmorphism-related and systemic complications). Mouse models recapitulate cognitive and autism-like deficits and implicate dysregulation of NMDA-receptor and immediate-early/activity-dependent gene expression, providing the mechanistic bridge from H3K4-demethylase loss to the neurobehavioral phenotype.

Key Findings

Finding 1 — MRT65 is caused by biallelic loss-of-function variants in KDM5B

MONDO:0020850 maps unambiguously to OMIM:618109, DOID:0081226, and MedGen C4748219. The NCBI MedGen→Gene link resolves to Gene ID 10765 = KDM5B (lysine demethylase 5B; aliases JARID1B, PLU1, and — reflecting this disorder — "MRT65"), HGNC:18039, Ensembl ENSG00000117139, located at chr1q32.1 (GRCh38 chr1:202,724,495–202,808,487). The disorder was first described by Faundes et al. 2018 (Am J Hum Genet), who reported "a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly" (PMID: 29276005). A subsequent genotype/phenotype study explicitly confirmed that "bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65" (PMID: 39202393).

KDM5B encodes a JmjC-domain histone H3K4 demethylase that removes tri-, di-, and mono-methyl marks from lysine 4 of histone H3 — a key activating mark at promoters and enhancers. Its loss therefore perturbs the epigenetic control of gene transcription. Suggested annotations: HGNC:18039 (KDM5B); GO:0032453 (histone H3-K4 demethylation); GO:0006325 (chromatin organization); MONDO:0020850.

Finding 2 — KDM5B is not haploinsufficient, consistent with the recessive mechanism

Population constraint data explain the recessive inheritance. gnomAD constraint for KDM5B (ENSG00000117139) shows pLI ≈ 0 (7.9×10⁻³⁶), an observed/expected LoF ratio of 0.74 (90% CI 0.65–0.86; LOEUF 0.855), and missense Z = 0.53. These metrics indicate that KDM5B tolerates heterozygous loss-of-function in the general population. A single pathogenic allele is therefore generally insufficient to cause disease, and the fully penetrant MRT65 syndrome requires biallelic (homozygous or compound-heterozygous) LoF. This is a clean genotype–constraint–phenotype concordance: a LoF-tolerant gene produces a recessive, not dominant, Mendelian disorder. Notably, heterozygous protein-truncating KDM5B variants are nonetheless associated with modestly reduced population-level cognitive function, indicating a subtle dosage effect below the threshold for the full syndrome.

Finding 3 — Mouse models recapitulate cognitive/autism-like deficits and implicate NMDAR/immediate-early gene dysregulation

Two independent mouse studies bridge the molecular lesion to neurobehavior. Kdm5b^ΔARID/ΔARID mice (lacking demethylase activity) show hyperactivity and hippocampus-dependent long-term memory deficits, with downregulated baseline and hyperactivated post-learning immediate-early/activity-dependent gene expression (Pérez-Sisqués et al., J Neurosci 2024, PMID: 38575342). This paper confirms that "the histone lysine demethylase KDM5B is implicated in recessive intellectual" disability and directly probes hippocampal memory function. A companion study reports that KDM5B-deficient mice display autism-like phenotypes with increased NMDAR2D (Grin3b/GRIN2D) expression (Pérez-Sisqués et al., Sci Adv 2026, PMID 42160407). Together these provide a mechanistic link from H3K4me3 demethylase loss → impaired transcriptional control of synaptic/learning ("plasticity") genes → cognitive and autism-like deficits.

Suggested annotations: GO:0007613 (memory); GO:0007611 (learning or memory); GO:0050804 (modulation of chemical synaptic transmission); NMDA receptor complex components (GRIN2D/GRIN3B).

Finding 4 — ClinVar documents a predominantly truncating biallelic variant spectrum (NM_006618.5)

ClinVar (accessed 2026) contains 590 total KDM5B variant records, of which 219 are classified pathogenic/likely-pathogenic and 98 are explicitly linked to "Intellectual disability, autosomal recessive 65." The pathogenic spectrum is dominated by protein-truncating variants. Representative pathogenic/likely-pathogenic alleles (reference transcript NM_006618.5) include:

Variant (cDNA) Protein consequence Class
c.394C>T p.(Gln132Ter) Nonsense
c.1457G>A p.(Trp486Ter) Nonsense
c.2345T>G p.(Leu782Ter) Nonsense
c.4198C>T p.(Arg1400Ter) Nonsense
c.2049_2050insA p.(Leu684fs) Frameshift
c.3151del p.(Val1051fs) Frameshift
c.2401_2405del p.(Arg801fs) Frameshift
c.1612G>C p.(Ala538Pro) Missense (typically VUS)

Most pathogenic alleles are nonsense, frameshift, or splice-site (predicted to trigger nonsense-mediated decay or produce non-functional protein). Missense variants are generally classified as variants of uncertain significance (VUS) under ACMG/AMP criteria, reflecting the loss-of-function mechanism where truncation is more confidently deleterious than single amino-acid substitutions.

Finding 5 — Kdm5b-null mice show lethality/growth/neurological phenotypes; no MRT65-specific trials exist

IMPC genotype–phenotype data for mouse Kdm5b (NCBI Gene 75605) homozygous nulls show preweaning lethality with incomplete penetrance, decreased body length (growth/size phenotype), and absent pinna reflex (neurological/behavioral phenotype) — a constellation consistent with an essential developmental regulator. A ClinicalTrials.gov API query (2026) returned no interventional trials for MRT65/KDM5B intellectual disability; KDM5B appears only in observational autism/genetics registries (e.g., Simons SPARK, NCT01238250). Small-molecule KDM5B inhibitors exist but only in oncology contexts (e.g., PMID 42324589) and are mechanistically inappropriate for a loss-of-function disorder — inhibiting an already-lost enzyme cannot restore function. Consequently, MRT65 management remains entirely supportive.

Finding 6 — HPO annotations define the full, frequency-tagged phenotype spectrum

The HPO disease annotation for OMIM:618109 (gene KDM5B/NCBIGene:10765; autosomal recessive; source PMID:29276005) comprises 37 terms, with frequencies expressed as n/3 biallelic individuals from the original cohort. The phenotype spectrum:

Domain Phenotype (HPO term) Frequency (original cohort)
Neurodevelopment Intellectual disability, moderate (HP:0002342) Core feature
Global developmental delay (HP:0001263) Moderate 2/3, severe 1/3
Delayed speech and language development (HP:0000750) Frequent
Delayed ability to walk (HP:0031936) Frequent
Gait ataxia / unsteady gait (HP:0002066) Present
Aggressive behavior (HP:0000718) 1/3
Brain MRI Hypoplasia of the corpus callosum (HP:0002079) Present
Partial agenesis of the corpus callosum (HP:0001338) 1/3
Craniofacial Square face (HP:0000321) 2/3
Smooth philtrum, thin vermilion border, prominent nasal bridge, bulbous nose, downslanted palpebral fissures, dolichocephaly, prominent metopic ridge Variable
Digits Camptodactyly of 4th/5th fingers, PIP-joint contractures (HP:0009276 / HP:0009185) Characteristic
Eyes Myopia (HP:0000545) 2/3
Astigmatism, ptosis, strabismus Variable
Other Feeding difficulties (HP:0011968) 2/3
Cryptorchidism, hypospadias, inguinal hernia, supernumerary nipple, secundum atrial septal defect, abnormal pinna Individual cases

Onset: neonatal in 2/3 and infantile in 1/3.

Finding 7 — Carrier frequency ~1 in 570; theoretical birth incidence ~1 in 1.3 million

Using gnomAD v4 (8,525 KDM5B variants), high-confidence (LOFTEE HC) rare (allele frequency <0.1%) predicted loss-of-function alleles across 411 sites sum to a pathogenic allele frequency q ≈ 8.8×10⁻⁴. This gives:

  • Carrier frequency 2q ≈ 0.0018 (≈ 1 in 567)
  • Theoretical random-mating homozygous/compound-heterozygous birth incidence q² ≈ 7.8×10⁻⁷ (≈ 1 in 1.3 million)

A methodological caveat surfaced during this estimate: the single common "LoF"-annotated allele (a frameshift at AF 0.185) is LOFTEE low-confidence (LC) — i.e., not a true LoF. Its naive inclusion inflated the estimate ~100-fold, underscoring the necessity of LOFTEE/quality filtering for constraint- and incidence-based calculations. The true incidence will be substantially higher in consanguineous populations, where autosomal-recessive disorders are enriched.

Mechanistic Model / Interpretation

MRT65 is best understood as a transcriptional/epigenetic disorder of neurodevelopment. The causal chain runs from an epigenetic enzyme defect to dysregulated activity-dependent gene programs to the clinical phenotype:

1.  Biallelic LoF variants in KDM5B (nonsense / frameshift / splice)
│  leads to
▼
2.  Nonsense-mediated decay / truncated non-functional protein
│  results in
▼
3.  Loss of H3K4me3/me2/me1 demethylase activity (JmjC + ARID domains)
│  leads to
▼
4.  Aberrant H3K4-methylation landscape at promoters/enhancers
│  results in
▼
5.  Dysregulated developmental + activity-dependent transcription
│  (immediate-early genes down at baseline, hyperactivated post-learning;
│   NMDAR subunit GRIN2D/GRIN3B up — shown in mouse)   [model organism]
├─────────────► Brain: impaired synaptic plasticity / hippocampal memory
│                        └► intellectual disability, developmental delay,
│                           autistic/behavioral features, gait ataxia
├─────────────► Neuroanatomy: corpus callosum hypoplasia / partial agenesis
├─────────────► Craniofacial morphogenesis → dysmorphism
└─────────────► Limb/digit development → camptodactyly (4th/5th PIP contractures)

Upstream vs downstream. The upstream initiating lesion is the KDM5B biallelic LoF genotype; the proximate molecular consequence is loss of H3K4 demethylase activity and a shifted chromatin state; the downstream manifestations are the transcriptional dysregulation of neuronal plasticity and developmental genes and the multi-organ developmental phenotype. The mouse data (Finding 3) provide the strongest mechanistic evidence for the neuronal branch — linking demethylase loss to immediate-early gene and NMDA-receptor dysregulation and hippocampus-dependent memory deficits — but the craniofacial, callosal, and digit branches are currently inferred from human phenotype–genotype correlation rather than demonstrated mechanistically.

Cell types and processes. The affected biological processes center on chromatin organization (GO:0006325), histone H3-K4 demethylation (GO:0032453), and learning/memory (GO:0007611, GO:0007613). Implicated cell types are principally neurons (CL:0000540), including hippocampal/glutamatergic neurons, with subcellular localization in the nucleus (GO:0005634) and chromatin (GO:0000785), consistent with a nuclear chromatin-modifying enzyme.

Why recessive. Finding 2 ties the genetics together: because KDM5B is LoF-tolerant (pLI ≈ 0, LOEUF 0.855), one functional allele suffices for near-normal development, so only biallelic loss crosses the disease threshold — a textbook example of constraint metrics predicting inheritance mode.

Section-by-Section Detail

1. Disease Information

MRT65 is an ultra-rare autosomal-recessive neurodevelopmental chromatinopathy. Identifiers: MONDO:0020850; OMIM #618109; DOID:0081226; MedGen C4748219. Synonyms: "Intellectual developmental disorder, autosomal recessive 65"; "MRT65." Dedicated ICD-10/ICD-11 and MeSH codes are not specifically assigned; it falls under generic intellectual-disability rubrics. Information is derived from aggregated disease-level resources (OMIM, HPO, ClinVar) and small published patient cohorts (originally 3 families/biallelic individuals), not from large EHR datasets.

2. Etiology

Primary cause: genetic — biallelic loss-of-function variants in KDM5B. Genetic risk factors: homozygous or compound-heterozygous LoF alleles; consanguinity substantially increases risk (as for all AR disorders). No established environmental risk or protective factors and no infectious etiology. Genetic protective/modifier factors: none specifically characterized; the residual function of hypomorphic (e.g., some missense) alleles may modulate severity, and heterozygous carriers show only subclinical cognitive effects. Gene–environment interactions: none documented.

3. Phenotypes

See Finding 6 table. Phenotype types span clinical signs (dysmorphism, camptodactyly), neurodevelopmental/behavioral changes (ID, autism features, aggression), and structural findings (corpus callosum anomalies on MRI). Onset is neonatal-to-infantile; severity is typically moderate for ID with variable expressivity; course is stable/non-progressive (a developmental, not neurodegenerative, disorder). Quality-of-life impact is dominated by lifelong intellectual disability, communication limitations, and dependency in daily functioning; formal QoL instrument data specific to MRT65 are not available.

4. Genetic / Molecular Information

Causal gene: KDM5B (HGNC:18039; gene MIM 605393; Ensembl ENSG00000117139). Variant classes: predominantly nonsense, frameshift, and splice-site (pathogenic/likely-pathogenic); missense generally VUS (Finding 4). Reference transcript: NM_006618.5. Population frequency: pathogenic LoF alleles are individually rare (AF <0.1%). Origin: germline (no somatic disease role). Functional consequence: loss of function (haploinsufficiency tolerated; disease requires biallelic loss). Epigenetic dimension: the disorder is itself an epigenetic-machinery defect — loss of a histone H3K4 demethylase alters the genome-wide methylation landscape rather than acting through a single-locus methylation change. Chromosomal abnormalities:* none characteristic; diagnosis is at the sequence-variant level.

5. Environmental Information

No environmental, lifestyle, or infectious contributors are implicated. MRT65 is a monogenic Mendelian disorder.

6. Mechanism / Pathophysiology

See the causal-chain diagram above and Findings 1–3. Molecular pathway: chromatin/H3K4-methylation regulation; downstream, NMDAR signaling and immediate-early gene programs (model-organism evidence). No metabolic, immune, or classic tissue-injury (oxidative/ischemic/fibrotic) mechanisms are involved; the pathology is developmental/transcriptional.

7. Anatomical Structures Affected

Primary organ/system: central nervous system (brain, UBERON:0000955; nervous system, UBERON:0001016), with corpus callosum (UBERON:0002336) hypoplasia/partial agenesis. Secondary/associated: craniofacial skeleton (dysmorphism), digits/hands (camptodactyly), eyes (myopia, astigmatism, ptosis, strabismus), genitourinary (cryptorchidism, hypospadias, inguinal hernia), and heart (secundum atrial septal defect) in individual cases. Cell type: neurons (CL:0000540). Subcellular: nucleus/chromatin (GO:0005634 / GO:0000785). Lateralization: brain findings are midline (callosal); other features generally bilateral.

8. Temporal Development

Onset: congenital/neonatal (2/3) to infantile (1/3). Pattern: chronic, static developmental disorder — non-progressive and lifelong. There are no remission patterns; the critical window for intervention is early childhood developmental support.

9. Inheritance and Population

Inheritance: autosomal recessive. Penetrance: high/complete for biallelic LoF (based on limited cohorts). Expressivity: variable (severity and non-neurological features differ between individuals). Carrier frequency: ≈ 1 in 570; theoretical birth incidence: ≈ 1 in 1.3 million under random mating (Finding 7), higher with consanguinity. No anticipation (not a repeat-expansion disorder). Founder effects/geographic clustering: none established, though consanguineous populations are enriched. Sex ratio: no strong skew expected (autosomal); some reported features (cryptorchidism/hypospadias) are male-specific.

10. Diagnostics

Genetic testing is diagnostic. Recommended approach: exome or genome sequencing (often as an intellectual-disability/neurodevelopmental gene panel of 1,000+ genes), which detects the causative biallelic SNV/indels. Long-read genome sequencing can add value for phasing biallelic variants in autosomal-recessive genes and resolving structural/complex variants (PMID: 41514368). Confirmation: ClinVar-referenced pathogenic classification and parental segregation (trans configuration for compound heterozygotes). Supportive workup: brain MRI (corpus callosum assessment), ophthalmologic exam, developmental/cognitive assessment. No specific biochemical biomarker exists. Differential diagnosis: other chromatinopathies and ID syndromes — notably KDM4B-related disorders (autosomal dominant IDD from heterozygous KDM4B LoF, and a reported biallelic KDM4B case) which share developmental delay, brain anomalies, and digital findings (PMID: 37526414); metabolic ID mimics should be excluded when biochemical clues are present.

11. Outcome / Prognosis

MRT65 is a non-lethal, non-progressive developmental disorder in humans (contrast with murine preweaning lethality, Finding 5). Life expectancy is not established but is not intrinsically shortened by the neurodevelopmental phenotype; systemic malformations (e.g., cardiac septal defect) may modify individual prognosis. Morbidity is dominated by lifelong intellectual disability and dependency. No prognostic biomarkers are defined; residual gene function (hypomorphic alleles) is the plausible principal modifier of severity.

12. Treatment

No disease-specific or curative therapy exists (Finding 5). Management is supportive and rehabilitative: early developmental intervention, special education, physical, occupational, and speech therapy, management of behavioral features, ophthalmologic correction (refractive error), orthopedic/hand management of camptodactyly, and surgical correction of associated malformations (cryptorchidism, hernia, ASD) as indicated. KDM5B small-molecule inhibitors developed for oncology are contraindicated in concept for a loss-of-function disorder. No pharmacogenomic or gene/RNA-based therapies are available. Suggested NCIT-type intervention categories: rehabilitation therapy, occupational therapy, speech/language therapy, supportive care.

13. Prevention

No primary prevention beyond genetic counseling and reproductive options for at-risk (e.g., consanguineous or carrier) couples: carrier testing, prenatal diagnosis, and preimplantation genetic testing are applicable once familial variants are known. There is no vaccine, no environmental intervention, and no population newborn-screening test for MRT65. Cascade carrier testing in families is appropriate after a proband is identified.

14. Other Species / Natural Disease

Orthologue: mouse Kdm5b (NCBI Gene 75605). No naturally occurring companion-animal/wildlife disease is catalogued for KDM5B (no OMIA entry noted). The gene and its H3K4-demethylase function are evolutionarily conserved, supporting cross-species mechanistic study. No zoonotic dimension (non-infectious disorder).

15. Model Organisms

The principal model is the mouse. Informative genetic models: (1) Kdm5b^ΔARID/ΔARID (demethylase-dead) mice recapitulate hyperactivity, hippocampal memory deficits, and activity-dependent/immediate-early gene dysregulation (PMID: 38575342); (2) KDM5B-deficient mice with autism-like phenotypes and increased NMDAR (GRIN2D/GRIN3B) expression (Sci Adv 2026, PMID 42160407); and (3) IMPC Kdm5b-null mice with preweaning lethality (incomplete penetrance), reduced body length, and absent pinna reflex (Finding 5). Phenotype recapitulation: strong for the cognitive/behavioral axis. Limitations: homozygous-null lethality in mice exceeds the human phenotype, so demethylase-dead/conditional models better model the viable human disorder. Resources: MGI, IMPC.

Evidence Base

PMID Title (abbrev.) Evidence type Role in this report
29276005 Recessive H3K4-methylation defect / KDM5B syndrome (Faundes et al., 2018) Human clinical Foundational — defines MRT65 and its causal biallelic KDM5B mechanism and core triad (DD, dysmorphism, camptodactyly); source of HPO annotations
39202393 Genotype/phenotype study of KDM5B Human clinical Confirms biallelic disruptive (nonsense/frameshift/splice) KDM5B variants cause AR IDD type 65
38575342 Kdm5b and hippocampal memory (Pérez-Sisqués et al., J Neurosci 2024) Model organism (mouse) Links demethylase loss to memory deficits and immediate-early/activity-dependent gene dysregulation
PMID 42160407 KDM5B-deficient mice, autism-like, NMDAR2D up (Sci Adv 2026) Model organism (mouse) Extends mechanism to NMDAR (GRIN2D/GRIN3B) and autism-like phenotype
37526414 Biallelic KDM4B frameshift phenotype Human clinical Differential diagnosis — related histone-demethylase (KDM4B) chromatinopathy; distinguishes from KDM5B
41514368 Long-read GS in pediatric neurological disorders Human diagnostics Supports genome sequencing (incl. phasing biallelic AR variants) as first-line diagnostic
40088508 Genetic epilepsies, consanguinity, India Human epidemiology Contextual — AR disorders enriched under consanguinity; WES diagnostic yield

Data resources underpinning the quantitative findings: OMIM/MONDO/MedGen (identifier mapping), ClinVar (variant spectrum, Finding 4), gnomAD v4 (constraint and carrier/incidence, Findings 2 & 7), HPO (phenotype annotation, Finding 6), IMPC and ClinicalTrials.gov API (mouse phenotypes and trial landscape, Finding 5).

Limitations and Knowledge Gaps

  1. Small human cohort. The HPO frequencies derive from only 3 biallelic individuals in the original report; frequencies (n/3) are imprecise and the full phenotypic range is likely broader than currently annotated. The 2024 genotype/phenotype study (PMID 39202393) expands this, but MRT65 remains defined by tens, not hundreds, of patients.
  2. Mechanistic branches inferred, not proven. The neuronal branch (memory, NMDAR, immediate-early genes) is supported by mouse data; the craniofacial, corpus callosum, and digit branches remain genotype–phenotype correlations without direct mechanistic demonstration.
  3. Genotype–phenotype correlation. It is not yet clear whether missense/hypomorphic alleles produce milder disease than complete truncation; missense variants are largely VUS.
  4. Incidence estimate is theoretical. The 1-in-1.3-million figure assumes random mating and complete penetrance; real incidence is unknown and higher in consanguineous populations. No formal prevalence study exists.
  5. Model organism discordance. Mouse homozygous nulls are preweaning-lethal, unlike viable human patients — limiting the null model and favoring demethylase-dead/conditional models.
  6. No natural-history, QoL, or long-term outcome data, and no biomarker for diagnosis or prognosis.

Proposed Follow-up Experiments / Actions

  1. Aggregate a larger patient registry (GeneMatcher/MatchmakerExchange) to refine phenotype frequencies, expressivity, and genotype–phenotype correlations (truncating vs missense).
  2. Functional characterization of missense VUS — demethylase activity assays and H3K4me3 ChIP in patient/edited cells to reclassify VUS under ACMG PS3/BS3 evidence.
  3. Patient-derived iPSC neurons/organoids to test whether human neurons reproduce the murine immediate-early/NMDAR transcriptional dysregulation and to map the affected gene programs (analogous iPSC modeling has proven informative in other AR neuro disorders, e.g., PMID: 39617394).
  4. Conditional/demethylase-dead brain-region-specific mouse models with staged (developmental vs adult) inactivation to define critical windows and test reversibility.
  5. Epigenomic profiling (H3K4me3 CUT&RUN/ChIP-seq, RNA-seq) across neuronal, craniofacial, and limb-bud lineages to test the non-neuronal mechanistic branches.
  6. Refine carrier-frequency and incidence estimates using targeted, LOFTEE-filtered analyses across ancestrally diverse and consanguineous cohorts.
  7. Standardize supportive-care guidance (developmental intervention, ophthalmology, orthopedics, cardiology) into a GeneReviews-style clinical management outline.

Report compiled from a 5-iteration autonomous investigation integrating OMIM/MONDO/MedGen mapping, ClinVar, gnomAD v4, HPO, IMPC, ClinicalTrials.gov, and primary literature. Evidence types are labeled human clinical, model organism, or computational throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 3
Quoted claims found in source 3
Quoted claims not found in source 0
References weighed for topical relevance 9
On topic 8
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 29
Resolved 26
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 17
Terms named correctly 15
Terms named as a different term 0
Terms whose name is worth a second look 2

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0032453 (2 mentions) - the report calls it "histone H3-K4 demethylation"; GO calls it histone H3K4 demethylase activity, and lists "histone H3-K4 demethylase activity" among its other names
  • HP:0002066 (1 mention) - the report calls it "Gait ataxia / unsteady gait"; HP calls it Gait ataxia

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, NCBIGene.

26 of 29 terms resolved to a current term; the rest could not be looked up either way.