O'Donnell-Luria-Rodan Syndrome

Mendelian MONDO:0032793 Pathograph 40 Show in embeddings browser Mendelian neurodevelopmental disorder Intellectual disability syndrome

O'Donnell-Luria-Rodan syndrome (ODLURO; OMIM 618512), also called KMT2E-related neurodevelopmental disorder, is an autosomal dominant neurodevelopmental disorder caused by heterozygous pathogenic variants in KMT2E or by 7q22 microdeletions that include it. Most affected children have global developmental delay with prominent speech delay, intellectual function in the low-normal to mild-to-moderate intellectual disability range, hypotonia, postnatally emerging macrocephaly and a subtle facial gestalt; about a third have autism and a minority have epilepsy. Constipation and other functional gastrointestinal symptoms and sleep disturbance are common. Most variants are protein-truncating and arise de novo, and the truncating and deletion classes are thought to act by haploinsufficiency. A small group of individuals with de novo missense variants has a more severe phenotype with infantile-onset epileptic encephalopathy and microcephaly rather than macrocephaly. Reported cohorts are male-predominant, and among individuals with truncating variants epilepsy has been more frequent in females and autism in males. Despite its family name, KMT2E appears to lack intrinsic histone methyltransferase activity; its best-characterized molecular function is reading H3K4me3 through its PHD finger.

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1
Inheritance
5
Pathophys.
40
Phenotypes
4
Hypotheses
3
Gaps
40
Pathograph
1
Genes
5
Medical Actions
2
Subtypes
3
Differentials
2
Models
1
References
1
Deep Research
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Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
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Inheritance

1
Autosomal dominant inheritance HP:0000006
Autosomal dominant. Most probands whose parents have been tested have a de novo variant; rare inherited cases come from a parent who typically has mild intellectual disability. Each child of an affected individual has a 50% chance of inheriting the variant. Expressivity varies by variant class and by sex.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (4 references)
PMID:38648332 SUPPORT Human Clinical
"KMT2E-NDD is an autosomal dominant disorder. Most probands reported to date with KMT2E-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant."
GeneReviews states the inheritance mode and the predominance of de novo variants.
PMID:38648332 SUPPORT Human Clinical
"Rarely, individuals diagnosed with KMT2E-NDD inherited a pathogenic variant from an affected parent who typically has mild intellectual disability. Each child of an individual with KMT2E-NDD has a 50% chance of inheriting the pathogenic variant."
GeneReviews documents rare transmission from mildly affected parents and the 50% recurrence risk to offspring.
PMID:34321323 SUPPORT Human Clinical
"Of all 17 variants, 13 were confirmed de novo, 2 were proven to be not inherited maternally and paternal samples were unavailable, one variant in two brothers and another variant in an unrelated patient were inherited paternally."
The second cohort quantifies de novo versus paternally transmitted variants.
+ 1 more reference
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Subtypes

2
Protein-truncating variants and KMT2E deletions
KMT2E hgnc:18541 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KMT2E (hgnc:18541). hgnc:18541 is a gene from the HUGO Gene Nomenclature Committee.
Frameshift, nonsense and canonical or cryptic splice-site variants, gene disruption by structural variants, and 7q22 deletions removing KMT2E. This is the large majority of reported individuals and is associated with the milder, macrocephalic presentation. No phenotypic difference has been found between truncating variants predicted to undergo nonsense-mediated decay and those in the last exon predicted to escape it.
Show evidence (2 references)
PMID:31079897 SUPPORT Human Clinical
"Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability."
Establishes truncating variants as the predominant class with a milder phenotype.
PMID:34321323 SUPPORT Human Clinical
"We did not detect a significant phenotypic difference between patients carrying variants predicted to lead to NMD, and patients carrying nonsense and frameshift variants in the last exon of KMT2E predicted to escape NMD."
NMD-escaping and NMD-triggering truncations are clinically indistinguishable, consistent with one loss-of-function class.
De novo missense variants
KMT2E hgnc:18541 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in KMT2E (hgnc:18541). hgnc:18541 is a gene from the HUGO Gene Nomenclature Committee.
Rare de novo missense variants. In the index cohort all four carriers had epilepsy, three with infantile-onset epileptic encephalopathy, with more severe developmental delay and microcephaly in two of three measured. The mechanism is unresolved.
Show evidence (1 reference)
PMID:31079897 SUPPORT Human Clinical
"The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group."
Defines the distinct, more severe missense-variant phenotype.
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Mechanistic Hypotheses

4
KMT2E haploinsufficiency
kmt2e_haploinsufficiency CANONICAL Loss-of-function
Evidence balance 2 support
Protein-truncating variants and deletions reduce KMT2E dosage and cause the disorder through haploinsufficiency. Support is genetic: extreme depletion of truncating variants in the general population, concordant phenotypes of intragenic truncations and gene deletions, and no difference between NMD-escaping and NMD-triggering truncations. Direct measurement of reduced KMT2E protein in patient cells has not been reported.
Pathograph links
KMT2E Haploinsufficiency -> Altered H3K4 Methylation and Transcriptional Regulation INDIRECT UNKNOWN INTERMEDIATES Link inferred from knockdown in non-neural cells; how reduced KMT2E dosage alters chromatin in developing human brain has not been measured.
Show evidence (2 references)
PMID:31079897 SUPPORT Human Clinical
"Overall, the individuals with chromosome 7q22.2-22.3 microdeletions encompassing KMT2E presented similarly to those with truncating variants, further supporting haploinsufficiency as the disease mechanism."
Phenotypic concordance of deletions and truncations supports dosage loss.
CGGV:assertion_2d0a0603-e446-4bb9-a202-4f8066a60c5a-2022-08-02T180000.000Z SUPPORT Other
"The mechanism of pathogenicity is reported to be LOF."
ClinGen records loss of function as the mechanism of pathogenicity.
Missense altered function (gain-of-function or dominant-negative)
kmt2e_missense_altered_function EMERGING Missense
Evidence balance 1 support
The more severe epileptic encephalopathy phenotype of de novo missense variants may reflect a variant-specific gain-of-function or dominant-negative effect rather than haploinsufficiency. No functional study has tested this.
Pathograph links
KMT2E Missense Altered Function -> Epileptic encephalopathy INDIRECT UNKNOWN INTERMEDIATES
KMT2E Missense Altered Function -> Microcephaly INDIRECT UNKNOWN INTERMEDIATES
KMT2E Missense Altered Function -> Severe global developmental delay INDIRECT UNKNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:31079897 SUPPORT Human Clinical
"Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation."
The index cohort proposes, and explicitly does not establish, an altered-function mechanism.
Amygdala neuronal development branch (mouse)
kmt2e_amygdala_neuronal_branch EMERGING Loss-of-function
Evidence balance 1 support
In Kmt2e heterozygous mice, social deficit and anxiety are accompanied by reduced amygdala glucose metabolism and increased numbers and soma size of amygdala neurons, proposed as the substrate of autism-like behaviour. Not yet examined in human tissue or human neuronal models.
Pathograph links
KMT2E Haploinsufficiency -> Amygdala Neuronal Development Abnormality INDIRECT UNKNOWN INTERMEDIATES
Amygdala Neuronal Development Abnormality -> Autism INDIRECT UNKNOWN INTERMEDIATES
Amygdala Neuronal Development Abnormality -> Anxiety INDIRECT UNKNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:36534336 SUPPORT Model Organism
"Our findings support a causative role of KMT2E in ASD development and suggest that amygdala neuronal development abnormality is likely a major underlying mechanism."
The mouse study proposes the amygdala branch.
Microglial phagocytosis branch (mouse)
kmt2e_microglial_branch EMERGING Loss-of-function
Evidence balance 1 support
In Mll5 (Kmt2e) haploinsufficient mice, reduced microglial phagocytosis through TREM2-SGK3-GSK3B signalling is accompanied by neuronal hyperexcitability and autism-like behaviour, and lithium chloride rescued both the phagocytosis deficit and the behaviour. Not yet examined in individuals with ODLURO.
Pathograph links
KMT2E Haploinsufficiency -> Impaired Microglial Phagocytosis INDIRECT KNOWN INTERMEDIATES
Impaired Microglial Phagocytosis -> Autism INDIRECT UNKNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:41997967 SUPPORT Model Organism
"Here, we demonstrate that Mll5 haploinsufficiency in mice impairs microglial phagocytosis, drives neuronal hyperexcitability, and recapitulates core ASD-like behaviors."
The mouse study proposes the microglial branch.
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Discussions and Knowledge Gaps

3
Does KMT2E have intrinsic histone methyltransferase activity, and does any such activity matter for ODLURO?
CONTROVERSY OPEN kmt2e_catalytic_activity
Attached to
pathophysiology#KMT2E Haploinsufficiency pathophysiology#Altered H3K4 Methylation and Transcriptional Regulation
KMT2E is named as a lysine methyltransferase, but the crystal structure of its SET domain shows missing key residues and an obstructing loop, and the purified domain had no activity on histones or H3 peptides. An earlier study reported H3K4 mono- and di-methyltransferase activity dependent on O-GlcNAcylation of the SET domain in a myeloid cell line. The entry therefore binds the PHD-finger reader function rather than methyltransferase activity, and treats any H3K4 methylation change as indirect.
Show evidence (2 references)
PMID:27812132 SUPPORT In Vitro
"Accordingly, we show that MLL5 is devoid of any in vitro methyltransferase activity on full-length histones and histone H3 peptides."
Structural and biochemical evidence against intrinsic activity.
PMID:19377461 REFUTE In Vitro
"GlcNAcylation at Thr 440 in the MLL5 SET domain evokes its H3K4 HKMT activity and co-activates RARalpha in target gene promoters."
Reports modification-dependent H3K4 methyltransferase activity, contradicting the inactive-SET view.
What chromatin and transcriptional changes does heterozygous KMT2E loss cause in developing human neurons, and is there a KMT2E DNA methylation episignature?
KNOWLEDGE GAP OPEN kmt2e_neural_chromatin_gap
Attached to
pathophysiology#Altered H3K4 Methylation and Transcriptional Regulation
Evidence for KMT2E's chromatin function comes from myoblasts, myeloid and cancer cell lines. No patient-derived neuronal model, brain transcriptome or blood episignature for ODLURO was found (the PubMed query "(KMT2E OR MLL5) AND (episignature OR DNA methylation signature)" returned no ODLURO study), so the link from reduced dosage to the neurodevelopmental phenotype is unmeasured and the conformed module's central transcriptional node is not declared.
Show evidence (1 reference)
PMID:19264965 SUPPORT In Vitro
"We have examined the epigenetic mechanisms operating in conditional quiescence by analyzing the function of a predicted chromatin regulator mixed lineage leukemia 5 (MLL5) in a culture model of reversible arrest."
The chromatin evidence used here comes from a myoblast culture model, not neural tissue.
Is the male excess among reported individuals, and the higher epilepsy and lower autism rates in females, biological or an ascertainment effect?
OPEN QUESTION OPEN kmt2e_sex_biased_expressivity
Attached to
phenotypes#Epilepsy phenotypes#Autism
Across published loss-of-function cases 41 were male and 15 female, a significant excess. The authors raise reduced penetrance or milder expressivity in females as possible explanations but have not tested them.
Show evidence (2 references)
PMID:34321323 SUPPORT Human Clinical
"this sex distribution of 41 males to 15 females with putative loss-of-function variants (excluding 7 patients carrying missense variants with a suspected gain-of-function"
Quantifies the male excess.
PMID:31079897 SUPPORT Human Clinical
"It is possible that decreased penetrance or variable expressivity of the condition in females means that fewer female individuals with de novo protein-truncating variants come to diagnostic attention."
The index authors' proposed, untested explanation.
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Pathophysiology

5
KMT2E Haploinsufficiency
Mechanism confidence: Established
A heterozygous protein-truncating variant, splice-disrupting variant, structural variant or 7q22 deletion removes one functional copy of KMT2E. KMT2E is highly intolerant of truncating variation in gnomAD (pLI 1.0). Among the epigenetic-machinery classes of the conformed module, KMT2E is a reader rather than a writer: its PHD finger binds H3K4me3, and its SET domain is structurally and biochemically inactive (see the discussion on catalytic activity).
Amygdala neuronal development branch (mouse) KMT2E haploinsufficiency Microglial phagocytosis branch (mouse)
KMT2E hgnc:18541 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KMT2E (hgnc:18541). hgnc:18541 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context KMT2E hgnc:18541 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns KMT2E (hgnc:18541). hgnc:18541 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
histone H3K4me3 reader activity (PHD finger) GO:0140002 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone H3K4me3 reader activity (PHD finger), annotated with histone H3K4me3 reader activity (GO:0140002). GO:0140002 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Altered H3K4 Methylation and Transcriptional Regulation Link inferred from knockdown in non-neural cells; how reduced KMT2E dosage alters chromatin in developing human brain has not been measured. KMT2E haploinsufficiency
Amygdala Neuronal Development Abnormality Amygdala neuronal development branch (mouse)
Impaired Microglial Phagocytosis Microglial phagocytosis branch (mouse)
Global developmental delay
Delayed speech and language development
Intellectual disability
Motor delay
Hypotonia
Macrocephaly
Epilepsy
Autism
Sleep disturbance
Constipation
Characteristic facial gestalt
Speech articulation difficulties
Developmental regression
Attention problems
Motor stereotypies
Self-injurious behavior
Aggressive behavior
Febrile seizures
Hypoplasia of the corpus callosum
Intracranial cysts
Ventriculomegaly
Delayed CNS myelination
Gastrointestinal dysmotility
Gastroesophageal reflux
Vomiting
Show evidence (3 references)
PMID:31079897 SUPPORT Human Clinical
"KMT2E is very depleted (presumably as a result of negative selection) for protein-truncating variants; there is a probability of loss-of-function intolerance (pLI) score of 1.0 and an observed/expected ratio of 0.01"
Population constraint indicates dosage sensitivity to loss of one allele.
PMID:31079897 SUPPORT Human Clinical
"There were no significant phenotypic differences between individuals with truncating variants in the terminal exon of the gene and those with earlier-truncating variants, suggesting a probable common pathophysiology of haploinsufficiency."
Concordance of NMD-escaping and NMD-triggering truncations supports a dosage mechanism.
PMID:37157895 SUPPORT Human Clinical
"We describe a patient from the 100,000 Genomes Project with a complex de novo structural variant within KMT2E leading to O'Donnell-Luria-Rodan syndrome."
Gene disruption by a structural variant produces the same syndrome, consistent with loss of function.
Altered H3K4 Methylation and Transcriptional Regulation
Mechanism confidence: Provisional
KMT2E is recruited to H3K4me3-marked euchromatin through its PHD finger and acts as a chromatin-associated transcriptional regulator. Knockdown in myoblasts reduced H3K4 methylation globally and at a target promoter, not through intrinsic methyltransferase activity but by altering expression of other histone-modifying enzymes (LSD1, SET7/9). All of this evidence comes from non-neural cell systems; the chromatin and transcriptional consequences of heterozygous loss in developing human neurons are unknown, so this node is not connected to the neurodevelopmental phenotypes and the module's central transcriptional node is not declared.
regulation of DNA-templated transcription GO:0006355 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology. ↓ DECREASED
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.
Show evidence (4 references)
PMID:23798402 SUPPORT In Vitro
"Here, we show that MLL5 is recruited to gene-rich euchromatic regions via the interaction of its plant homeodomain finger with the histone mark H3K4me3."
Establishes KMT2E (MLL5) recruitment to H3K4me3-marked chromatin via its PHD finger.
PMID:24130829 SUPPORT In Vitro
"We further demonstrate that the PHD domain binds with similar affinity to histone H3 tail peptides di- and tri-methylated at lysine 4 (H3K4me2 and H3K4me3)"
Independent structural study confirming the PHD finger as an H3K4me2/me3 reader.
PMID:19264965 SUPPORT In Vitro
"In knockdown cells, H3K4 methylation at the CCRE is reduced, reflecting quantitative global changes in methylation."
Loss of MLL5 in cultured myoblasts reduces H3K4 methylation, the chromatin-state change this node represents.
+ 1 more reference
Amygdala Neuronal Development Abnormality
Mechanism confidence: Hypothetical
In Kmt2e heterozygous mice, amygdala glucose metabolism on FDG-PET is selectively reduced and amygdala neurons are more numerous and larger, alongside social deficit and anxiety-like behaviour. KMT2E expression in human amygdala falls after birth. Human imaging or neuropathological correlates have not been reported.
Amygdala neuronal development branch (mouse)
amygdala neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves amygdala neuron, annotated with neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
amygdala UBERON:0001876 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in amygdala (UBERON:0001876). UBERON:0001876 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Kmt2e heterozygous mouse (amygdala study) Mouse recapitulates
Downstream
Autism Amygdala neuronal development branch (mouse)
Anxiety Amygdala neuronal development branch (mouse)
Show evidence (2 references)
PMID:36534336 SUPPORT Model Organism
"Whole-brain 18F-FDG-PET analysis identified that relative amygdala glycometabolism was selectively decreased in KMT2E+/- mice compared to wild-type mice."
Imaging localizes the mouse abnormality to the amygdala.
PMID:36534336 SUPPORT Model Organism
"Additionally, KMT2E mRNA levels in human amygdala were significantly decreased after birth during brain development."
Developmental expression pattern in human amygdala reported in the same study.
Impaired Microglial Phagocytosis
Mechanism confidence: Hypothetical
Mll5 haploinsufficiency in mice reduces microglial phagocytosis through dysregulated TREM2-SGK3-GSK3B signalling, with neuronal hyperexcitability and autism-like behaviour; microglia derived from an individual with autism (not ODLURO) showed parallel reductions in MLL5 expression and phagocytosis. The GSK3B inhibitor lithium chloride rescued the deficit and the behaviour in mice. Not studied in individuals with ODLURO.
Microglial phagocytosis branch (mouse)
microglial cell CL:0000129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microglial cell (CL:0000129). CL:0000129 is a cell type from the Cell Ontology.
phagocytosis (microglial) GO:0006909 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased phagocytosis (microglial), annotated with phagocytosis (GO:0006909). GO:0006909 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Mll5 heterozygous mouse (microglia study) Mouse recapitulates
Downstream
Autism Microglial phagocytosis branch (mouse)
Show evidence (1 reference)
PMID:41997967 SUPPORT Model Organism
"By targeting this pathway, lithium chloride, a GSK3β inhibitor, rescues both microglial phagocytosis deficits and behavioral abnormalities in Mll5 haploinsufficienct mice."
Pharmacological rescue supports a causal role of the microglial pathway in the mouse behavioural phenotype.
KMT2E Missense Altered Function
Mechanism confidence: Hypothetical
De novo missense variants, which in the index cohort did not cluster (one in the PHD finger, one in the SET domain, two outside annotated domains), produce a more severe phenotype than truncating variants. Whether they act by gain of function, dominant-negative interference or another mechanism is untested. KMT2E is not constrained against missense variation in gnomAD.
Missense altered function (gain-of-function or dominant-negative)
KMT2E hgnc:18541 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KMT2E (hgnc:18541). hgnc:18541 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context KMT2E hgnc:18541 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns KMT2E (hgnc:18541). hgnc:18541 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN
Downstream
Epileptic encephalopathy Missense altered function (gain-of-function or dominant-negative)
Microcephaly Missense altered function (gain-of-function or dominant-negative)
Severe global developmental delay Missense altered function (gain-of-function or dominant-negative)
Show evidence (2 references)
PMID:31079897 SUPPORT Human Clinical
"There was no clustering of the missense variants; one is in the SET domain, one is in the PHD domain, and two are not in identified domains."
Describes the positions of the missense variants.
PMID:31079897 SUPPORT Human Clinical
"We hypothesize that the phenotype of epileptic encephalopathy could be variant specific and might relate to an alternate mechanism such as a gain-of-function or dominant-negative effect."
States the altered-function mechanism as a hypothesis.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for O'Donnell-Luria-Rodan Syndrome 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

40
Digestive 4
Constipation OCCASIONAL HP:0002019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34321323 SUPPORT Human Clinical
"Constipation | 8/18 (44%) | 5/27 (19%) | 13/45 (29%)"
Combined frequency 13/45.
PMID:38648332 SUPPORT Human Clinical
"Constipation is the most frequent gastrointestinal issue, although gastroesophageal reflux, vomiting, and/or reduced bowel motility have been reported in almost half of affected individuals."
GeneReviews ranks constipation as the leading gastrointestinal issue.
Gastrointestinal dysmotility FREQUENT HP:0002579 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal dysmotility (HP:0002579). HP:0002579 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38648332 SUPPORT Human Clinical
"Constipation is the most frequent gastrointestinal issue, although gastroesophageal reflux, vomiting, and/or reduced bowel motility have been reported in almost half of affected individuals."
Almost half have reflux, vomiting or dysmotility.
PMID:31079897 SUPPORT Human Clinical
"Many of the individuals were reported to have gastrointestinal symptoms, including reflux, vomiting, or bowel motility issues; these are issues commonly seen in individuals with hypotonia."
Index cohort description of functional gastrointestinal symptoms.
Gastroesophageal reflux OCCASIONAL HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Gastro-oesophageal reflux | 1/18 (6%) | 2/27 (7%) | 3/45 (7%)"
Combined frequency 3/45.
Vomiting OCCASIONAL HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Vomiting | 3/18 (18%) | 1/27 (4%) | 4/45 (9%)"
Combined frequency 4/45 (the published cell reads 3/18 as 18%).
Ear 1
Small ears OCCASIONAL Microtia HP:0008551 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small ears, annotated with Microtia (HP:0008551). HP:0008551 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Small ears | 4/17 (24%) | n/q"
Frequency in the second cohort.
Eye 1
Deeply set eyes FREQUENT HP:0000490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deep-set eyes, annotated with Deeply set eye (HP:0000490). HP:0000490 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Deep-set eyes | 7/17 (41%) | n/q"
Frequency in the second cohort.
Head and Neck 10
Macrocephaly FREQUENT HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256), qualified as infantile onset. HP:0000256 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (3 references)
PMID:34321323 SUPPORT Human Clinical
"Macrocephaly | 10/18 (56%) | 18/33 (55%) | 28/51 (55%)"
Combined frequency 28/51.
PMID:38648332 SUPPORT Human Clinical
"Growth parameters are typically in the normal range for length/height and weight, although about half of affected individuals have macrocephaly or relative macrocephaly."
GeneReviews summary; somatic growth is otherwise normal.
PMID:39709003 SUPPORT Human Clinical
"By a systematic review of the previously reported series, we also discuss previously unappreciated findings, including progressive macrocephaly, apraxia, and higher risk of bone fractures."
Notes that macrocephaly can be progressive.
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31079897 SUPPORT Human Clinical
"Missense Total | 4 | 100% (3/3) | 33% (1/3) | 100% (4/4) | 0% (0/3) | 66% (2/3)"
Microcephaly in 2/3 and macrocephaly in 0/3 of the missense group.
Characteristic facial gestalt Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31079897 SUPPORT Human Clinical
"Consistent facial features include dolichocephaly, large foreheads, and deep-set eyes, often with down-slanting palpebral fissures, periorbital fullness, prominent cheeks, and prominent nasolacrimal folds."
Index cohort description of the facial gestalt.
Large forehead FREQUENT High forehead HP:0000348 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large or high forehead, annotated with High forehead (HP:0000348). HP:0000348 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34321323 SUPPORT Human Clinical
"Large forehead | 10/17 (59%) | n/q"
Frequency in the second cohort.
PMID:31079897 SUPPORT Human Clinical
"Comparison of the facial features of eleven of the individuals in our cohort suggests some commonalities, including macrocephaly, dolichocephaly, high forehead, deep-set eyes, periorbital fullness, prominent cheeks, and prominent nasolabial folds (Figures 2 and 4)."
The index cohort describes the forehead as high.
Full cheeks FREQUENT HP:0000293 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Full cheeks (HP:0000293). HP:0000293 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Full cheeks | 9/17 (53%) | n/q"
Frequency in the second cohort.
Epicanthus FREQUENT HP:0000286 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epicanthal folds, annotated with Epicanthus (HP:0000286). HP:0000286 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Epicanthal folds | 7/17 (41%) | n/q"
Frequency in the second cohort.
Dolichocephaly OCCASIONAL HP:0000268 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dolichocephaly (HP:0000268). HP:0000268 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Dolichocephaly | 2/17 (12%) | n/q"
Frequency in the second cohort.
Prominent nasolabial fold OCCASIONAL HP:0005272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent nasolabial folds, annotated with Prominent nasolabial fold (HP:0005272). HP:0005272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Prominent nasolabial folds | 3/17 (18%) | n/q"
Frequency in the second cohort.
Downslanted palpebral fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31079897 SUPPORT Human Clinical
"Consistent facial features include dolichocephaly, large foreheads, and deep-set eyes, often with down-slanting palpebral fissures, periorbital fullness, prominent cheeks, and prominent nasolacrimal folds."
Index cohort facial description.
Periorbital fullness HP:0000629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periorbital fullness (HP:0000629). HP:0000629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31079897 SUPPORT Human Clinical
"Consistent facial features include dolichocephaly, large foreheads, and deep-set eyes, often with down-slanting palpebral fissures, periorbital fullness, prominent cheeks, and prominent nasolacrimal folds."
Index cohort facial description.
Limbs 1
Clinodactyly OCCASIONAL HP:0030084 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clinodactyly (HP:0030084). HP:0030084 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Clinodactyly | 4/17 (24%) | n/q"
Frequency in the second cohort.
Musculoskeletal 2
Hypotonia FREQUENT 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:34321323 SUPPORT Human Clinical
"Muscular hypotonia | 8/18 (44%) | 15/27 (56%) | 23/45 (51%)"
Combined frequency 23/45.
Recurrent fractures HP:0002757 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone fractures, annotated with Recurrent fractures (HP:0002757). HP:0002757 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39709003 SUPPORT Human Clinical
"By a systematic review of the previously reported series, we also discuss previously unappreciated findings, including progressive macrocephaly, apraxia, and higher risk of bone fractures."
Reports increased fracture risk as a newly recognized finding.
Nervous System 21
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), qualified as infantile onset. HP:0001263 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (2 references)
PMID:38648332 SUPPORT Human Clinical
"KMT2E-related neurodevelopmental disorder (KMT2E-NDD) is a condition characterized by global developmental delay, variable intellectual disability (typically in the mild-to-moderate range), and hypotonia."
GeneReviews lists global developmental delay as a defining feature.
PMID:33111303 SUPPORT Human Clinical
"The common features were global developmental delay (97%) followed by macrocephaly (35%), seizures (30%), and autism (25%)."
Pooled literature review (40 published plus 2 new cases) gives the very-frequent band.
Delayed speech and language development VERY_FREQUENT 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 (2 references)
PMID:34321323 SUPPORT Human Clinical
"Speech delay | 17/18 (94%) | 21/28 (75%) | 38/46 (83%)"
Combined frequency 38/46 across both loss-of-function cohorts.
PMID:38648332 SUPPORT Human Clinical
"The majority of affected individuals are verbal but experience speech delays with or without articulation problems."
GeneReviews summary of the language phenotype.
Speech articulation difficulties FREQUENT HP:0009088 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Speech articulation difficulties (HP:0009088). HP:0009088 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31079897 SUPPORT Human Clinical
"Although this information is not available for all individuals, 14 (out of 17) individuals are verbal, but seven are noted to speak poorly or to have articulation problems."
Seven of 14 verbal individuals had articulation problems.
PMID:39709003 SUPPORT Human Clinical
"By a systematic review of the previously reported series, we also discuss previously unappreciated findings, including progressive macrocephaly, apraxia, and higher risk of bone fractures."
A later cohort and review identifies apraxia as a feature; the abstract does not specify its type or frequency.
Motor delay FREQUENT HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34321323 SUPPORT Human Clinical
"Motor delay | 13/18 (72%) | 18/27 (67%) | 31/45 (69%)"
Combined frequency 31/45.
PMID:38648332 SUPPORT Human Clinical
"All reported individuals who are older than infants have been able to obtain independent ambulation."
Motor delay does not preclude independent walking.
Intellectual disability FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability, mostly mild, annotated with Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:34321323 SUPPORT Human Clinical
"Intellectual disability | 6/12 (50%) | 17/20 (85%) | 23/32 (72%)"
Combined frequency 23/32 of assessed individuals.
PMID:31079897 SUPPORT Human Clinical
"Intelligence quotient (IQ) data were available for only seven out of the 29 individuals: the mean IQ was 74 (range 62-98)."
Quantifies the typical low-normal to mild range.
PMID:40616444 SUPPORT Human Clinical
"Wilcoxon paired tests showed verbal reasoning was stronger than non-verbal reasoning skills (p = 0.04)."
Characterizes the cognitive profile (verbal greater than nonverbal reasoning).
Severe global developmental delay HP:0011344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe global developmental delay (HP:0011344). HP:0011344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31079897 SUPPORT Human Clinical
"Only two of the four individuals can walk independently, and none of the individuals were verbal at most recent follow-up (Figure 3)."
Severity of delay in the missense group.
Developmental regression OCCASIONAL HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Regression | 2/18 (11%) | 4/33 (12%) | 6/51 (12%)"
Combined frequency 6/51.
Autism FREQUENT HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism spectrum disorder, annotated with Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
Show evidence (5 references)
PMID:34321323 SUPPORT Human Clinical
"Autism spectrum disorder | 7/17 (41%) | 8/31 (26%) | 15/48 (31%)"
Combined frequency 15/48.
PMID:38648332 SUPPORT Human Clinical
"Similarly, about one third of affected individuals have an autism spectrum disorder diagnosis, of which most to date are male."
GeneReviews summary including the male predominance.
PMID:31079897 SUPPORT Human Clinical
"Male | 22 | 82% (9/11) | 35% (7/20) | 5% (1/19) | 52% (11/21) | 0% (0/21)"
Autism in 7/20 males with truncating variants.
+ 2 more references
Anxiety FREQUENT HP:0000739 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anxiety (HP:0000739). HP:0000739 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41137515 SUPPORT Human Clinical
"Findings show prominent behavioral features in ODLURO include problems with anxiety (33%), attention (67%), and executive function (50%) (working memory, cognitive inflexibility)"
Quantifies anxiety problems in a neurobehavioral series.
Attention problems FREQUENT Short attention span HP:0000736 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention problems, annotated with Short attention span (HP:0000736). HP:0000736 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:41137515 SUPPORT Human Clinical
"Findings show prominent behavioral features in ODLURO include problems with anxiety (33%), attention (67%), and executive function (50%) (working memory, cognitive inflexibility)"
Attention problems in two-thirds of a neurobehavioral series.
PMID:40616444 SUPPORT Human Clinical
"Over half of respondents rated their children in the at-risk to clinically significant range for attention problems and hyperactivity."
Independent series (n=10) with the same finding.
PMID:34321323 SUPPORT Human Clinical
"ADHD | 1/18 (6%) | 2/34 (6%) | 3/52 (6%)"
Formal ADHD diagnoses are much less frequent than rated attention problems.
Motor stereotypies OCCASIONAL Motor stereotypy HP:0000733 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stereotypical behaviour, annotated with Motor stereotypy (HP:0000733). HP:0000733 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Stereotypical behaviour | 6/18 (33%) | 3/34 (9%) | 9/52 (17%)"
Combined frequency 9/52.
Self-injurious behavior OCCASIONAL HP:0100716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Self-injurious behavior (HP:0100716). HP:0100716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Self-injurious behaviour | 2/18 (11%) | 1/34 (3%) | 3/52 (6%)"
Combined frequency 3/52.
Aggressive behavior OCCASIONAL HP:0000718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aggressive behavior (HP:0000718). HP:0000718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Aggressive behaviour | 1/18 (6%) | 2/34 (6%) | 3/52 (6%)"
Combined frequency 3/52.
Sleep disturbance FREQUENT HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:34321323 SUPPORT Human Clinical
"Sleep disturbances | 8/17 (47%) | n/s"
Frequency in the second cohort; not systematically recorded in the index cohort.
PMID:34321323 SUPPORT Human Clinical
"The reported sleep disturbances in our cohort consisted of frequent awakening and difficulty falling asleep with prolonged sleep latency."
Describes the type of sleep disturbance.
PMID:41137515 SUPPORT Human Clinical
"Sleep disturbances are common in ODLURO (85%) and associated with behavior regulation difficulties, highlighting the importance of early screening/intervention."
Higher frequency in a dedicated neurobehavioral series.
Epilepsy OCCASIONAL Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epilepsy, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (5 references)
PMID:34321323 SUPPORT Human Clinical
"Epilepsy | 0/18 (0%) | 7/30 (23%) | 7/48 (15%)"
Combined frequency 7/48 in the loss-of-function cohorts.
PMID:31079897 SUPPORT Human Clinical
"Although the rates of intellectual disability and macrocephaly were similar, interestingly, epilepsy was seen in 43% of females but in only 5% of males (p = 0.047, Fisher's exact test)"
Sex difference in epilepsy among truncating-variant carriers.
PMID:38648332 SUPPORT Human Clinical
"About one third of affected individuals develop seizures, with no consistent seizure semiology or epilepsy syndrome. However, females may be more likely to develop seizures compared to males."
GeneReviews all-class estimate and sex difference.
+ 2 more references
Febrile seizures OCCASIONAL Febrile seizure (within the age range of 3 months to 6 years) HP:0002373 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Febrile seizures, annotated with Febrile seizure (within the age range of 3 months to 6 years) (HP:0002373). HP:0002373 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Febrile seizures | 2/18 (11%) | n/s"
Frequency in the second cohort.
Epileptic encephalopathy HP:0200134 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infantile-onset epileptic encephalopathy, annotated with Epileptic encephalopathy (HP:0200134), qualified as infantile onset. HP:0200134 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (3 references)
PMID:31079897 SUPPORT Human Clinical
"Individuals 34, 35, and 36 all presented with infantile epileptic encephalopathy."
Three of four missense carriers had infantile epileptic encephalopathy.
PMID:31079897 SUPPORT Human Clinical
"The initial EEG in individual 35 showed burst suppression and subsequently evolved into hypsarrhythmia. The EEG in individual 36 also showed hypsarrhythmia."
EEG pattern in the missense group.
PMID:40070083 SUPPORT Human Clinical
"The patient presented with spasmodic seizures and developmental delay at 6 months of age. The video electroencephalogram (EEG) displayed hypsarrhythmia."
West syndrome with a de novo KMT2E splice variant.
Hypoplasia of the corpus callosum OCCASIONAL HP:0002079 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the corpus callosum (HP:0002079). HP:0002079 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Corpus callosum hypoplasia | 3/14 (21%) | 4/22 (18%) | 7/36 (19%)"
Combined frequency 7/36 imaged.
Intracranial cysts OCCASIONAL Intracranial cystic lesion HP:0010576 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intracranial cysts, annotated with Intracranial cystic lesion (HP:0010576). HP:0010576 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Cerebral cysts | 3/14 (21%) | 4/22 (18%) | 7/36 (19%)"
Combined frequency 7/36 imaged.
Ventriculomegaly OCCASIONAL HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Ventriculomegaly | 2/14 (14%) | 3/22 (14%) | 5/36 (14%)"
Combined frequency 5/36 imaged.
Delayed CNS myelination OCCASIONAL HP:0002188 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed CNS myelination (HP:0002188). HP:0002188 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Delayed myelination | 4/14 (29%) | 1/22 (5%) | 5/36 (14%)"
Combined frequency 5/36 imaged.
🧬

Genetic Associations

1
KMT2E
Gene: KMT2E hgnc:18541 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KMT2E (hgnc:18541). hgnc:18541 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
CGGV:assertion_2d0a0603-e446-4bb9-a202-4f8066a60c5a-2022-08-02T180000.000Z SUPPORT Other
"KMT2E | HGNC:18541 | complex neurodevelopmental disorder | MONDO:0100038 | AD | Definitive"
ClinGen Definitive gene-disease validity for autosomal dominant disease.
CGGV:assertion_2d0a0603-e446-4bb9-a202-4f8066a60c5a-2022-08-02T180000.000Z SUPPORT Other
"Complex neurodevelopmental disorder in relation to variants in KMT2E was originally termed as O'Donnell-Luria-Rodan syndrome (ODLURO)"
ClinGen equates its lumped disease term with ODLURO.
PMID:31079897 SUPPORT Human Clinical
"This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported)."
Index cohort variant spectrum.
+ 2 more references
💊

Medical Actions

5
Antiseizure medication
Category: Therapeutic Action: Anticonvulsant therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticonvulsant therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticonvulsant Therapy NCIT:C64172
Platform: Small molecule
Seizures are treated with standard antiseizure medications chosen by seizure type; no drug has been studied specifically in ODLURO. In the index cohort, epilepsy with truncating variants was controlled with medication in almost all, whereas missense-variant epileptic encephalopathy was treatment resistant (a ketogenic diet did not help in one child). In a systematic review of cases with epilepsy, about 70% of those with medication records needed two or more drugs.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:31079897 SUPPORT Human Clinical
"Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all."
Treatment response in the truncating-variant group.
PMID:40048818 SUPPORT Human Clinical
"Among ten individuals with a record of antiseizure medication, approximately 70% required two or more antiseizure medications."
Polytherapy was often needed among cases ascertained for epilepsy.
PMID:31079897 SUPPORT Human Clinical
"Individual 34 was started on the ketogenic diet at 14 months of age, but this diet did not improve seizure control."
Single-case negative experience with the ketogenic diet in the missense group.
Developmental and educational therapies
Category: Therapeutic Action: Speech language therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is 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
Standard early intervention, speech-language, physical and occupational therapy and educational support for developmental delay and intellectual disability, per GeneReviews management guidance. Not studied specifically in ODLURO.
Target Phenotypes: Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology. 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.
Show evidence (1 reference)
PMID:38648332 SUPPORT Human Clinical
"Standard treatment for developmental delay / intellectual disability, neuropsychiatric issues, seizures, constipation, gastroesophageal reflux/dysmotility, vomiting, and sleep disturbance."
GeneReviews recommends standard developmental treatment.
Symptomatic management of gastrointestinal and sleep problems
Category: Therapeutic Action: Supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Standard management of constipation, reflux and dysmotility, vomiting and sleep disturbance, per GeneReviews. Not studied specifically in ODLURO.
Target Phenotypes: Constipation HP:0002019 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology. Sleep disturbance HP:0002360 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38648332 SUPPORT Human Clinical
"Standard treatment for developmental delay / intellectual disability, neuropsychiatric issues, seizures, constipation, gastroesophageal reflux/dysmotility, vomiting, and sleep disturbance."
GeneReviews recommends standard symptomatic treatment.
Surveillance
Category: Monitoring Action: Supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
At each visit: growth parameters including head circumference, new neurologic manifestations and seizure monitoring, developmental progress and educational needs, behaviour (anxiety, ADHD, aggression, self-injury), and chronic vomiting, constipation and sleep.
Show evidence (1 reference)
PMID:38648332 SUPPORT Human Clinical
"At each visit, measure growth parameters (including head circumference); assess for new neurologic manifestations and monitor those with seizures as clinically indicated; monitor developmental progress and educational need; assess for behavioral issues, including anxiety, ADHD, aggression, and..."
GeneReviews surveillance recommendations.
Genetic counseling
Category: Counseling / Informational Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counseling on autosomal dominant inheritance, the predominance of de novo variants, the 50% risk to offspring of an affected individual, testing of parents who may be mildly affected, and prenatal or preimplantation testing once the familial variant is known.
Show evidence (1 reference)
PMID:38648332 SUPPORT Human Clinical
"Each child of an individual with KMT2E-NDD has a 50% chance of inheriting the pathogenic variant. Once the KMT2E pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
GeneReviews counseling content.
🔬

Diagnosis

1
Molecular genetic testing
Diagnosis is established by a heterozygous pathogenic KMT2E variant in a proband with suggestive findings. Intragenic variants are found by exome or genome sequencing and deletions by chromosomal microarray. There are no consensus clinical diagnostic criteria. Complex structural variants can be missed by standard exome and genome pipelines and have been found on reanalysis of genome data.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A heterozygous pathogenic KMT2E variant or a deletion including KMT2E establishes the diagnosis.
Show evidence (3 references)
PMID:38648332 SUPPORT Human Clinical
"The diagnosis of KMT2E-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in KMT2E identified by molecular genetic testing."
GeneReviews diagnostic criterion.
PMID:31079897 SUPPORT Human Clinical
"Microdeletions were detected by chromosomal microarrays in some individuals, whereas all other individuals were found to have variants in KMT2E via exome or genome sequencing."
Testing modalities by variant class.
PMID:37157895 SUPPORT Human Clinical
"This case expands the mutational spectrum for this syndrome and highlights the importance of revisiting unsolved cases using better SV prioritisation tools and updated gene panels."
A cryptic structural variant was found only on dedicated structural-variant reanalysis.
📈

Progression

3
Infancy
Age: Birth to 2 years
Pregnancy and birth are usually uncomplicated. Head circumference is often high-normal at birth and crosses the 97th percentile within the first year. In the missense group, epileptic encephalopathy began in the neonatal period or by 6 months.
Show evidence (3 references)
PMID:34321323 SUPPORT Human Clinical
"In our cohort, the more common presentation of macrocephaly was that of a high-normal occipitofrontal circumference (OFC) at birth, crossing the 97th percentile within the first year of life, although this was not universal"
Describes postnatal emergence of macrocephaly during infancy.
PMID:34321323 SUPPORT Human Clinical
"Pregnancy and birth history were generally uncomplicated for these patients, except for the youngest patient of our cohort (patient 2)."
Perinatal course in the second cohort.
PMID:31079897 SUPPORT Human Clinical
"Individual 34 developed seizures at 6 months of age, and individuals 35 and 36 both developed seizures in the neonatal period."
Seizure onset timing in the missense-variant group.
Early childhood
Age: 1 to 5 years
In the index truncating-variant group, mean ages of independent walking and of first words were each 20 months (range 12 to 48 months), and all individuals eventually walked independently.
Show evidence (2 references)
PMID:31079897 SUPPORT Human Clinical
"The mean age of independent walking in this group was 20 months (range 12 to 48 months, Figure 3). All individuals are currently able to walk independently."
Motor milestone timing in the protein-truncating variant group.
PMID:31079897 SUPPORT Human Clinical
"The mean age of acquired first word in this group was 20 months (range 12 to 48 months, Figure 3)."
Language milestone timing in the protein-truncating variant group.
Adolescence and adulthood
Few adolescents and adults have been described, so long-term outcome and adult-onset complications are not characterized.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Since there is so far only a smaller number of reports on teenagers and adults (10 patients in total, including the father/daughter/son trio in previous work7), conclusions about patients' long-term development and possible late-onset health problems in adulthood remain speculative at best."
States that adult natural history is essentially undescribed.
📊

Prevalence

1
Worldwide (published case series)
Cases In Literature
No population-based prevalence or birth-prevalence estimate exists. The second multinational cohort brought the published total to 63 individuals within about two years of the first description and argued that the disorder may be a relatively common single-gene cause of developmental delay and autism; that is an inference from ascertainment, not a measured rate.
Show evidence (1 reference)
PMID:34321323 SUPPORT Human Clinical
"Shortly after the systematic description of ODLURO in 2019, our report now brings the number of known patients to 63."
Case count in the literature at the time of the second cohort.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from O'Donnell-Luria-Rodan Syndrome:

PTEN hamartoma tumor syndrome
Overlapping Features Macrocephaly with developmental delay or autism prompts PTEN testing; PTEN was tested and excluded in one ODLURO patient before KMT2E was found, and a child in the index cohort had pathogenic variants in both KMT2E and PTEN.
Distinguishing Features
  • Molecular testing; a PTEN result does not exclude KMT2E and vice versa.
Show evidence (2 references)
PMID:37157895 SUPPORT Human Clinical
"The large OFC at 11 years prompted Sanger sequencing and MLPA analysis of PTEN but no pathogenic variants were identified."
PTEN was the first diagnostic consideration for macrocephaly in an ODLURO patient.
PMID:31079897 SUPPORT Human Clinical
"Individual 6 also had a de novo pathogenic PTEN (GenBank: NM_000314.6, MIM: 601728) c.493G>A (p.Gly165Arg) variant, which can also account for his macrocephaly."
Dual KMT2E and PTEN diagnosis in the index cohort.
🐁

Animal Models

2
Kmt2e heterozygous mouse (amygdala study)
Heterozygous mice show social deficit and anxiety-like behaviour, reduced relative amygdala glucose metabolism on FDG-PET, and increased numbers and soma size of amygdala neurons. Developmental delay, macrocephaly and seizures are not reported in the abstract.
Social deficit Anxiety-like behaviour Reduced amygdala glucose metabolism Increased amygdala neuron number and soma size
Species
Mouse
Genotype
Kmt2e+/- (constitutive heterozygous)
Genes
KMT2E hgnc:18541 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns KMT2E (hgnc:18541). hgnc:18541 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:36534336
Pathograph links
Amygdala Neuronal Development Abnormality recapitulates fidelity: unknown observes: tissue
Limitations: The amygdala finding has no reported human counterpart, so fidelity to the human disorder cannot be assessed.
Show evidence (1 reference)
PMID:36534336 SUPPORT Model Organism
"The numbers and soma sizes of amygdala neurons in KMT2E+/- mice were prominently increased."
The model is the source of this node.
Show evidence (1 reference)
PMID:36534336 SUPPORT Model Organism
"Behavioral results revealed that KMT2E haploinsufficiency was sufficient to produce social deficit, accompanied by anxiety in mice."
Behavioural phenotype of the heterozygous mouse.
Mll5 heterozygous mouse (microglia study)
Haploinsufficient mice show impaired microglial phagocytosis through TREM2-SGK3-GSK3B signalling, neuronal hyperexcitability and autism-like behaviours; lithium chloride rescued the microglial and behavioural abnormalities.
Impaired microglial phagocytosis Neuronal hyperexcitability Autism-like behaviours
Species
Mouse
Genotype
Mll5 (Kmt2e) haploinsufficient
Genes
KMT2E hgnc:18541 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns KMT2E (hgnc:18541). hgnc:18541 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:41997967
Pathograph links
Impaired Microglial Phagocytosis recapitulates fidelity: unknown observes: cellular
Limitations: Microglial phagocytosis has not been studied in individuals with ODLURO; the human comparison in the study used microglia from an individual with autism, not with ODLURO.
Show evidence (1 reference)
PMID:41997967 SUPPORT Model Organism
"Furthermore, microglia derived from individual with ASD exhibit parallel reductions in MLL5 expression and phagocytic function."
The only human correlate comes from autism, not ODLURO.
Show evidence (1 reference)
PMID:41997967 SUPPORT Model Organism
"Here, we demonstrate that Mll5 haploinsufficiency in mice impairs microglial phagocytosis, drives neuronal hyperexcitability, and recapitulates core ASD-like behaviors."
Summary of the model phenotype.
{ }

Source YAML

click to show 
name: O'Donnell-Luria-Rodan Syndrome
creation_date: "2026-09-23T00:00:00Z"
references:
- reference: PMID:38648332
  title: "KMT2E-Related Neurodevelopmental Disorder."
  tags:
  - GeneReviews
category: Mendelian
disease_term:
  preferred_term: O'Donnell-Luria-Rodan syndrome
  term:
    id: MONDO:0032793
    label: O'Donnell-Luria-Rodan syndrome
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      A neurodevelopmental disorder whose core manifestations (global
      developmental delay, intellectual disability, hypotonia, autism and
      epilepsy) are neurologic.
    evidence:
    - reference: PMID:38648332
      reference_title: "KMT2E-Related Neurodevelopmental Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        KMT2E-related neurodevelopmental disorder (KMT2E-NDD) is a condition
        characterized by global developmental delay, variable intellectual
        disability (typically in the mild-to-moderate range), and hypotonia.
      explanation: >-
        GeneReviews defines the condition as a neurodevelopmental disorder,
        supporting the neurologic Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Autosomal dominant Mendelian disorder caused by heterozygous KMT2E
      variants; ClinGen classifies the KMT2E gene-disease relationship as
      Definitive.
    evidence:
    - reference: CGGV:assertion_2d0a0603-e446-4bb9-a202-4f8066a60c5a-2022-08-02T180000.000Z
      reference_title: "KMT2E / complex neurodevelopmental disorder (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "KMT2E | HGNC:18541 | complex neurodevelopmental disorder | MONDO:0100038 | AD | Definitive"
      explanation: >-
        ClinGen gene-disease validity row establishing a definitive autosomal
        dominant monogenic basis.
parents:
- Mendelian neurodevelopmental disorder
- Intellectual disability syndrome
synonyms:
- ODLURO
- KMT2E-related neurodevelopmental disorder
- KMT2E-NDD
description: >-
  O'Donnell-Luria-Rodan syndrome (ODLURO; OMIM 618512), also called
  KMT2E-related neurodevelopmental disorder, is an autosomal dominant
  neurodevelopmental disorder caused by heterozygous pathogenic variants in
  KMT2E or by 7q22 microdeletions that include it. Most affected children have
  global developmental delay with prominent speech delay, intellectual function
  in the low-normal to mild-to-moderate intellectual disability range,
  hypotonia, postnatally emerging macrocephaly and a subtle facial gestalt;
  about a third have autism and a minority have epilepsy. Constipation and
  other functional gastrointestinal symptoms and sleep disturbance are common.
  Most variants are protein-truncating and arise de novo, and the truncating
  and deletion classes are thought to act by haploinsufficiency. A small group
  of individuals with de novo missense variants has a more severe phenotype
  with infantile-onset epileptic encephalopathy and microcephaly rather than
  macrocephaly. Reported cohorts are male-predominant, and among individuals
  with truncating variants epilepsy has been more frequent in females and
  autism in males. Despite its family name, KMT2E appears to lack intrinsic
  histone methyltransferase activity; its best-characterized molecular
  function is reading H3K4me3 through its PHD finger.
notes: >-
  Lump/split. MONDO (MONDO:0032793) and OMIM (618512) carry a single concept for
  all KMT2E variant classes, and this entry follows them. The phenotypic
  divergence between protein-truncating variants and gene deletions on one hand
  and de novo missense variants on the other is represented as two allelic
  has_subtypes rather than as separate entries, because the missense group is
  small (four individuals in the index cohort) and its distinct mechanism is a
  hypothesis the original authors flag as requiring validation. Large
  7q22.2-q22.3 deletions that also remove neighbouring genes are included under
  the loss-of-function subtype; they were associated with greater developmental
  delay than intragenic variants, which the index cohort attributes in part to
  the additional deleted genes. No Orphanet disorder record for this syndrome
  was found in the Orphadata product 1 file (searched for "Donnell" and
  "KMT2E"), and MONDO carries no ORPHA cross-reference for it.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  description: >-
    Autosomal dominant. Most probands whose parents have been tested have a de
    novo variant; rare inherited cases come from a parent who typically has
    mild intellectual disability.
    Each child of an affected individual has a 50% chance of inheriting the
    variant. Expressivity varies by variant class and by sex.
  evidence:
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KMT2E-NDD is an autosomal dominant disorder. Most probands reported to
      date with KMT2E-NDD whose parents have undergone molecular genetic testing
      have the disorder as the result of a de novo pathogenic variant.
    explanation: GeneReviews states the inheritance mode and the predominance of de novo variants.
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rarely, individuals diagnosed with KMT2E-NDD inherited a pathogenic
      variant from an affected parent who typically has mild intellectual
      disability. Each child of an individual with KMT2E-NDD has a 50% chance of
      inheriting the pathogenic variant.
    explanation: GeneReviews documents rare transmission from mildly affected parents and the 50% recurrence risk to offspring.
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of all 17 variants, 13 were confirmed de novo, 2 were proven to be not
      inherited maternally and paternal samples were unavailable, one variant in
      two brothers and another variant in an unrelated patient were inherited
      paternally.
    explanation: The second cohort quantifies de novo versus paternally transmitted variants.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than 70% of the individuals were male, and expressivity was variable
      by sex; epilepsy was more common in females and autism more common in
      males.
    explanation: The index cohort reports sex-dependent variable expressivity.
prevalence:
- population: Worldwide (published case series)
  measure_type: CASES_IN_LITERATURE
  notes: >-
    No population-based prevalence or birth-prevalence estimate exists. The
    second multinational cohort brought the published total to 63 individuals
    within about two years of the first description and argued that the
    disorder may be a relatively common single-gene cause of developmental
    delay and autism; that is an inference from ascertainment, not a measured
    rate.
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shortly after the systematic description of ODLURO in 2019, our report now
      brings the number of known patients to 63.
    explanation: Case count in the literature at the time of the second cohort.
progression:
- phase: Infancy
  age_range: Birth to 2 years
  notes: >-
    Pregnancy and birth are usually uncomplicated. Head circumference is often
    high-normal at birth and crosses the 97th percentile within the first year.
    In the missense group, epileptic encephalopathy began in the neonatal
    period or by 6 months.
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our cohort, the more common presentation of macrocephaly was that of a
      high-normal occipitofrontal circumference (OFC) at birth, crossing the
      97th percentile within the first year of life, although this was not
      universal
    explanation: Describes postnatal emergence of macrocephaly during infancy.
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pregnancy and birth history were generally uncomplicated for these
      patients, except for the youngest patient of our cohort (patient 2).
    explanation: Perinatal course in the second cohort.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual 34 developed seizures at 6 months of age, and individuals 35
      and 36 both developed seizures in the neonatal period.
    explanation: Seizure onset timing in the missense-variant group.
- phase: Early childhood
  age_range: 1 to 5 years
  notes: >-
    In the index truncating-variant group, mean ages of independent walking and
    of first words were each 20 months (range 12 to 48 months), and all
    individuals eventually walked independently.
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mean age of independent walking in this group was 20 months (range 12
      to 48 months, Figure 3). All individuals are currently able to walk
      independently.
    explanation: Motor milestone timing in the protein-truncating variant group.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mean age of acquired first word in this group was 20 months (range 12
      to 48 months, Figure 3).
    explanation: Language milestone timing in the protein-truncating variant group.
- phase: Adolescence and adulthood
  notes: >-
    Few adolescents and adults have been described, so long-term outcome and
    adult-onset complications are not characterized.
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since there is so far only a smaller number of reports on teenagers and
      adults (10 patients in total, including the father/daughter/son trio in
      previous work7), conclusions about patients' long-term development and
      possible late-onset health problems in adulthood remain speculative at
      best.
    explanation: States that adult natural history is essentially undescribed.
has_subtypes:
- name: Loss-of-function
  display_name: Protein-truncating variants and KMT2E deletions
  description: >-
    Frameshift, nonsense and canonical or cryptic splice-site variants, gene
    disruption by structural variants, and 7q22 deletions removing KMT2E. This
    is the large majority of reported individuals and is associated with the
    milder, macrocephalic presentation. No phenotypic difference has been found
    between truncating variants predicted to undergo nonsense-mediated decay and
    those in the last exon predicted to escape it.
  genes:
  - preferred_term: KMT2E
    term:
      id: hgnc:18541
      label: KMT2E
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Almost all variants occurred de novo, and most were truncating. Most
      affected individuals with protein-truncating variants presented with mild
      intellectual disability.
    explanation: Establishes truncating variants as the predominant class with a milder phenotype.
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We did not detect a significant phenotypic difference between patients
      carrying variants predicted to lead to NMD, and patients carrying
      nonsense and frameshift variants in the last exon of KMT2E predicted to
      escape NMD.
    explanation: NMD-escaping and NMD-triggering truncations are clinically indistinguishable, consistent with one loss-of-function class.
- name: Missense
  display_name: De novo missense variants
  description: >-
    Rare de novo missense variants. In the index cohort all four carriers had
    epilepsy, three with infantile-onset epileptic encephalopathy, with more
    severe developmental delay and microcephaly in two of three measured. The
    mechanism is unresolved.
  genes:
  - preferred_term: KMT2E
    term:
      id: hgnc:18541
      label: KMT2E
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The group of four individuals with missense variants in KMT2E presented
      with the most severe developmental delays. Epilepsy was present in all
      individuals with missense variants, often manifesting as
      treatment-resistant infantile epileptic encephalopathy. Microcephaly was
      also common in this group.
    explanation: Defines the distinct, more severe missense-variant phenotype.
mechanistic_hypotheses:
- hypothesis_group_id: kmt2e_haploinsufficiency
  hypothesis_label: KMT2E haploinsufficiency
  status: CANONICAL
  applies_to_subtypes:
  - Loss-of-function
  description: >-
    Protein-truncating variants and deletions reduce KMT2E dosage and cause the
    disorder through haploinsufficiency. Support is genetic: extreme depletion
    of truncating variants in the general population, concordant phenotypes of
    intragenic truncations and gene deletions, and no difference between
    NMD-escaping and NMD-triggering truncations. Direct measurement of reduced
    KMT2E protein in patient cells has not been reported.
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, the individuals with chromosome 7q22.2-22.3 microdeletions
      encompassing KMT2E presented similarly to those with truncating variants,
      further supporting haploinsufficiency as the disease mechanism.
    explanation: Phenotypic concordance of deletions and truncations supports dosage loss.
  - reference: CGGV:assertion_2d0a0603-e446-4bb9-a202-4f8066a60c5a-2022-08-02T180000.000Z
    reference_title: "KMT2E / complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity is reported to be LOF."
    explanation: ClinGen records loss of function as the mechanism of pathogenicity.
- hypothesis_group_id: kmt2e_missense_altered_function
  hypothesis_label: Missense altered function (gain-of-function or dominant-negative)
  status: EMERGING
  applies_to_subtypes:
  - Missense
  description: >-
    The more severe epileptic encephalopathy phenotype of de novo missense
    variants may reflect a variant-specific gain-of-function or dominant-negative
    effect rather than haploinsufficiency. No functional study has tested this.
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Haploinsufficiency versus gain-of-function or dominant-negative effects
      specific to these missense variants in KMT2E might explain this divergence
      in phenotype, but requires independent validation.
    explanation: The index cohort proposes, and explicitly does not establish, an altered-function mechanism.
- hypothesis_group_id: kmt2e_amygdala_neuronal_branch
  hypothesis_label: Amygdala neuronal development branch (mouse)
  status: EMERGING
  applies_to_subtypes:
  - Loss-of-function
  description: >-
    In Kmt2e heterozygous mice, social deficit and anxiety are accompanied by
    reduced amygdala glucose metabolism and increased numbers and soma size of
    amygdala neurons, proposed as the substrate of autism-like behaviour. Not
    yet examined in human tissue or human neuronal models.
  evidence:
  - reference: PMID:36534336
    reference_title: "KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our findings support a causative role of KMT2E in ASD development and
      suggest that amygdala neuronal development abnormality is likely a major
      underlying mechanism.
    explanation: The mouse study proposes the amygdala branch.
- hypothesis_group_id: kmt2e_microglial_branch
  hypothesis_label: Microglial phagocytosis branch (mouse)
  status: EMERGING
  applies_to_subtypes:
  - Loss-of-function
  description: >-
    In Mll5 (Kmt2e) haploinsufficient mice, reduced microglial phagocytosis
    through TREM2-SGK3-GSK3B signalling is accompanied by neuronal
    hyperexcitability and autism-like behaviour, and lithium chloride rescued
    both the phagocytosis deficit and the behaviour. Not yet examined in
    individuals with ODLURO.
  evidence:
  - reference: PMID:41997967
    reference_title: "Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we demonstrate that Mll5 haploinsufficiency in mice impairs
      microglial phagocytosis, drives neuronal hyperexcitability, and
      recapitulates core ASD-like behaviors.
    explanation: The mouse study proposes the microglial branch.
pathophysiology:
- name: KMT2E Haploinsufficiency
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Epigenetic Machinery Component Haploinsufficiency"
  role: trigger
  mechanism_confidence: ESTABLISHED
  biological_scale: MOLECULAR
  subtypes:
  - Loss-of-function
  description: >-
    A heterozygous protein-truncating variant, splice-disrupting variant,
    structural variant or 7q22 deletion removes one functional copy of KMT2E.
    KMT2E is highly intolerant of truncating variation in gnomAD (pLI 1.0).
    Among the epigenetic-machinery classes of the conformed module, KMT2E is a
    reader rather than a writer: its PHD finger binds H3K4me3, and its SET
    domain is structurally and biochemically inactive (see the discussion on
    catalytic activity).
  gene:
    preferred_term: KMT2E
    term:
      id: hgnc:18541
      label: KMT2E
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    gene:
      preferred_term: KMT2E
      term:
        id: hgnc:18541
        label: KMT2E
  molecular_functions:
  - preferred_term: histone H3K4me3 reader activity (PHD finger)
    term:
      id: GO:0140002
      label: histone H3K4me3 reader activity
    modifier: DECREASED
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KMT2E is very depleted (presumably as a result of negative selection) for
      protein-truncating variants; there is a probability of loss-of-function
      intolerance (pLI) score of 1.0 and an observed/expected ratio of 0.01
    explanation: Population constraint indicates dosage sensitivity to loss of one allele.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There were no significant phenotypic differences between individuals with
      truncating variants in the terminal exon of the gene and those with
      earlier-truncating variants, suggesting a probable common pathophysiology
      of haploinsufficiency.
    explanation: Concordance of NMD-escaping and NMD-triggering truncations supports a dosage mechanism.
  - reference: PMID:37157895
    reference_title: "Genome sequencing identifies KMT2E-disrupting cryptic structural variant in a female with O'Donnell-Luria-Rodan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a patient from the 100,000 Genomes Project with a complex de
      novo structural variant within KMT2E leading to O'Donnell-Luria-Rodan
      syndrome.
    explanation: Gene disruption by a structural variant produces the same syndrome, consistent with loss of function.
  downstream:
  - target: Altered H3K4 Methylation and Transcriptional Regulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Link inferred from knockdown in non-neural cells; how reduced KMT2E dosage
      alters chromatin in developing human brain has not been measured.
    hypothesis_groups:
    - kmt2e_haploinsufficiency
  - target: Amygdala Neuronal Development Abnormality
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - kmt2e_amygdala_neuronal_branch
    evidence:
    - reference: PMID:36534336
      reference_title: "KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The numbers and soma sizes of amygdala neurons in KMT2E+/- mice were
        prominently increased.
      explanation: Heterozygous loss of Kmt2e alters amygdala neuronal development in mice.
  - target: Impaired Microglial Phagocytosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - kmt2e_microglial_branch
    evidence:
    - reference: PMID:41997967
      reference_title: "Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We also show that Mll5 acts as an epigenetic regulator, modulating
        microglial phagocytosis via the TREM2-SGK3-GSK3β signaling axis, which
        is associated with deficient glucose metabolism.
      explanation: Names the signalling intermediates between Mll5 dosage and the microglial deficit in mice.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38648332
      reference_title: "KMT2E-Related Neurodevelopmental Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        KMT2E-related neurodevelopmental disorder (KMT2E-NDD) is a condition
        characterized by global developmental delay, variable intellectual
        disability (typically in the mild-to-moderate range), and hypotonia.
      explanation: Developmental delay is the core consequence of KMT2E disruption; intermediates are unknown.
  - target: Delayed speech and language development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31079897
      reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most affected individuals with protein-truncating variants presented
        with mild intellectual disability.
      explanation: Links the truncating (loss-of-function) class to intellectual disability.
  - target: Motor delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Macrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31079897
      reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Protein-Truncating Variants Total | 30 | 81% (13/16) | 26% (7/27) | 15% (4/26) | 55% (16/29) | 0% (0/29)"
      explanation: >-
        Macrocephaly in 55% and microcephaly in none of the truncating-variant
        group links macrocephaly to the loss-of-function class; the growth
        mechanism is unknown.
  - target: Epilepsy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sleep disturbance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Constipation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Characteristic facial gestalt
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Speech articulation difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Developmental regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Attention problems
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Motor stereotypies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Self-injurious behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Aggressive behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Febrile seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypoplasia of the corpus callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intracranial cysts
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ventriculomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed CNS myelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Gastrointestinal dysmotility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Gastroesophageal reflux
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Vomiting
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Altered H3K4 Methylation and Transcriptional Regulation
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Permissive-Repressive Chromatin State Imbalance"
  role: amplifier
  mechanism_confidence: PROVISIONAL
  biological_scale: MOLECULAR
  description: >-
    KMT2E is recruited to H3K4me3-marked euchromatin through its PHD finger and
    acts as a chromatin-associated transcriptional regulator. Knockdown in
    myoblasts reduced H3K4 methylation globally and at a target promoter, not
    through intrinsic methyltransferase activity but by altering expression of
    other histone-modifying enzymes (LSD1, SET7/9). All of this evidence comes
    from non-neural cell systems; the chromatin and transcriptional
    consequences of heterozygous loss in developing human neurons are unknown,
    so this node is not connected to the neurodevelopmental phenotypes and the
    module's central transcriptional node is not declared.
  cellular_components:
  - preferred_term: chromatin
    term:
      id: GO:0000785
      label: chromatin
  biological_processes:
  - preferred_term: regulation of DNA-templated transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: DECREASED
  evidence:
  - reference: PMID:23798402
    reference_title: "Molecular basis for chromatin binding and regulation of MLL5."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that MLL5 is recruited to gene-rich euchromatic regions via
      the interaction of its plant homeodomain finger with the histone mark
      H3K4me3.
    explanation: Establishes KMT2E (MLL5) recruitment to H3K4me3-marked chromatin via its PHD finger.
  - reference: PMID:24130829
    reference_title: "Solution NMR structure and histone binding of the PHD domain of human MLL5."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We further demonstrate that the PHD domain binds with similar affinity to
      histone H3 tail peptides di- and tri-methylated at lysine 4 (H3K4me2 and
      H3K4me3)
    explanation: Independent structural study confirming the PHD finger as an H3K4me2/me3 reader.
  - reference: PMID:19264965
    reference_title: "MLL5, a trithorax homolog, indirectly regulates H3K4 methylation, represses cyclin A2 expression, and promotes myogenic differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In knockdown cells, H3K4 methylation at the CCRE is reduced, reflecting
      quantitative global changes in methylation.
    explanation: Loss of MLL5 in cultured myoblasts reduces H3K4 methylation, the chromatin-state change this node represents.
  - reference: PMID:19264965
    reference_title: "MLL5, a trithorax homolog, indirectly regulates H3K4 methylation, represses cyclin A2 expression, and promotes myogenic differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MLL5 appears to lack intrinsic histone methyl transferase activity, but
      regulates expression of histone-modifying enzymes LSD1 and SET7/9,
      suggesting an indirect mechanism.
    explanation: The H3K4 methylation change is indirect, through other chromatin enzymes.

- name: Amygdala Neuronal Development Abnormality
  role: downstream_mechanism
  mechanism_confidence: HYPOTHETICAL
  biological_scale: TISSUE
  subtypes:
  - Loss-of-function
  description: >-
    In Kmt2e heterozygous mice, amygdala glucose metabolism on FDG-PET is
    selectively reduced and amygdala neurons are more numerous and larger,
    alongside social deficit and anxiety-like behaviour. KMT2E expression in
    human amygdala falls after birth. Human imaging or neuropathological
    correlates have not been reported.
  cell_types:
  - preferred_term: amygdala neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: amygdala
    term:
      id: UBERON:0001876
      label: amygdala
  evidence:
  - reference: PMID:36534336
    reference_title: "KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Whole-brain 18F-FDG-PET analysis identified that relative amygdala
      glycometabolism was selectively decreased in KMT2E+/- mice compared to
      wild-type mice.
    explanation: Imaging localizes the mouse abnormality to the amygdala.
  - reference: PMID:36534336
    reference_title: "KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Additionally, KMT2E mRNA levels in human amygdala were significantly
      decreased after birth during brain development.
    explanation: Developmental expression pattern in human amygdala reported in the same study.
  downstream:
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - kmt2e_amygdala_neuronal_branch
    evidence:
    - reference: PMID:36534336
      reference_title: "KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Behavioral results revealed that KMT2E haploinsufficiency was sufficient
        to produce social deficit, accompanied by anxiety in mice.
      explanation: Social deficit in the same mice is the proposed behavioural readout of the amygdala change.
  - target: Anxiety
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - kmt2e_amygdala_neuronal_branch

- name: Impaired Microglial Phagocytosis
  role: downstream_mechanism
  mechanism_confidence: HYPOTHETICAL
  biological_scale: CELLULAR
  subtypes:
  - Loss-of-function
  description: >-
    Mll5 haploinsufficiency in mice reduces microglial phagocytosis through
    dysregulated TREM2-SGK3-GSK3B signalling, with neuronal hyperexcitability
    and autism-like behaviour; microglia derived from an individual with
    autism (not ODLURO) showed parallel reductions in MLL5 expression and
    phagocytosis. The GSK3B inhibitor lithium chloride rescued the deficit and
    the behaviour in mice. Not studied in individuals with ODLURO.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: phagocytosis (microglial)
    term:
      id: GO:0006909
      label: phagocytosis
    modifier: DECREASED
  evidence:
  - reference: PMID:41997967
    reference_title: "Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      By targeting this pathway, lithium chloride, a GSK3β inhibitor, rescues
      both microglial phagocytosis deficits and behavioral abnormalities in Mll5
      haploinsufficienct mice.
    explanation: Pharmacological rescue supports a causal role of the microglial pathway in the mouse behavioural phenotype.
  downstream:
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - kmt2e_microglial_branch
    evidence:
    - reference: PMID:41997967
      reference_title: "Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we demonstrate that Mll5 haploinsufficiency in mice impairs
        microglial phagocytosis, drives neuronal hyperexcitability, and
        recapitulates core ASD-like behaviors.
      explanation: Connects the microglial deficit to autism-like behaviour in mice.

- name: KMT2E Missense Altered Function
  role: trigger
  mechanism_confidence: HYPOTHETICAL
  biological_scale: MOLECULAR
  subtypes:
  - Missense
  description: >-
    De novo missense variants, which in the index cohort did not cluster (one
    in the PHD finger, one in the SET domain, two outside annotated domains),
    produce a more severe phenotype than truncating variants. Whether they act
    by gain of function, dominant-negative interference or another mechanism is
    untested. KMT2E is not constrained against missense variation in gnomAD.
  gene:
    preferred_term: KMT2E
    term:
      id: hgnc:18541
      label: KMT2E
  genetic_context:
    functional_impact_category: UNKNOWN
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    gene:
      preferred_term: KMT2E
      term:
        id: hgnc:18541
        label: KMT2E
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was no clustering of the missense variants; one is in the SET
      domain, one is in the PHD domain, and two are not in identified domains.
    explanation: Describes the positions of the missense variants.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We hypothesize that the phenotype of epileptic encephalopathy could be
      variant specific and might relate to an alternate mechanism such as a
      gain-of-function or dominant-negative effect.
    explanation: States the altered-function mechanism as a hypothesis.
  downstream:
  - target: Epileptic encephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - kmt2e_missense_altered_function
    evidence:
    - reference: PMID:31079897
      reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whereas, in our cohort, only approximately 14% of the individuals with
        protein-truncating variants have epilepsy, all of the individuals we
        report as having missense variants have epilepsy. This association met
        statistical significance (p = 0.0026, Fisher's exact test).
      explanation: Statistically links the missense class to epilepsy.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - kmt2e_missense_altered_function
  - target: Severe global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - kmt2e_missense_altered_function

phenotypes:
- name: Global developmental delay
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Developmental delay across motor and language domains, evident in infancy.
    Pooled across 42 published individuals of all variant classes, 97% had
    global developmental delay.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KMT2E-related neurodevelopmental disorder (KMT2E-NDD) is a condition
      characterized by global developmental delay, variable intellectual
      disability (typically in the mild-to-moderate range), and hypotonia.
    explanation: GeneReviews lists global developmental delay as a defining feature.
  - reference: PMID:33111303
    reference_title: "Clinical Characteristics and Genotype-Phenotype Correlation in Children with KMT2E Gene-Related Neurodevelopmental Disorders: Report of Two New Cases and Review of Published Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The common features were global developmental delay (97%) followed by
      macrocephaly (35%), seizures (30%), and autism (25%).
    explanation: Pooled literature review (40 published plus 2 new cases) gives the very-frequent band.
- name: Delayed speech and language development
  category: Neurological
  frequency: VERY_FREQUENT
  description: >-
    Speech delay is the most consistent developmental feature: 38/46 (83%) in
    the combined loss-of-function cohorts. Most affected individuals become
    verbal. Language regression occurred in a few children.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Speech delay | 17/18 (94%) | 21/28 (75%) | 38/46 (83%)"
    explanation: Combined frequency 38/46 across both loss-of-function cohorts.
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of affected individuals are verbal but experience speech
      delays with or without articulation problems.
    explanation: GeneReviews summary of the language phenotype.
- name: Speech articulation difficulties
  category: Neurological
  frequency: FREQUENT
  description: >-
    In the index truncating-variant group, 14 of 17 individuals with data were
    verbal, and 7 of them spoke poorly or had articulation problems. Apraxia
    has also been highlighted in a later cohort review.
  phenotype_term:
    preferred_term: Speech articulation difficulties
    term:
      id: HP:0009088
      label: Speech articulation difficulties
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although this information is not available for all individuals, 14 (out
      of 17) individuals are verbal, but seven are noted to speak poorly or to
      have articulation problems.
    explanation: Seven of 14 verbal individuals had articulation problems.
  - reference: PMID:39709003
    reference_title: "Molecular and clinical Insights into KMT2E-Related O'Donnell-Luria-Rodan syndrome in a novel patient cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By a systematic review of the previously reported series, we also discuss
      previously unappreciated findings, including progressive macrocephaly,
      apraxia, and higher risk of bone fractures.
    explanation: A later cohort and review identifies apraxia as a feature; the abstract does not specify its type or frequency.
- name: Motor delay
  category: Neurological
  frequency: FREQUENT
  description: >-
    Motor delay in 31/45 (69%) of the combined loss-of-function cohorts. Mean
    age of independent walking was 20 months in the index truncating group and
    all eventually walked.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Motor delay | 13/18 (72%) | 18/27 (67%) | 31/45 (69%)"
    explanation: Combined frequency 31/45.
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All reported individuals who are older than infants have been able to
      obtain independent ambulation.
    explanation: Motor delay does not preclude independent walking.
- name: Intellectual disability
  category: Neurological
  frequency: FREQUENT
  description: >-
    Intellectual disability in 23/32 (72%) of formally assessed individuals in
    the combined loss-of-function cohorts, usually mild; some function in the
    low-normal range (mean IQ 74, range 62-98, in seven tested individuals of
    the index truncating group). Neuropsychological testing in ten individuals
    showed relatively preserved verbal reasoning and expressive vocabulary
    against weaker nonverbal reasoning, working memory, reading and
    mathematics.
  phenotype_term:
    preferred_term: Intellectual disability, mostly mild
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability | 6/12 (50%) | 17/20 (85%) | 23/32 (72%)"
    explanation: Combined frequency 23/32 of assessed individuals.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intelligence quotient (IQ) data were available for only seven out of the
      29 individuals: the mean IQ was 74 (range 62-98).
    explanation: Quantifies the typical low-normal to mild range.
  - reference: PMID:40616444
    reference_title: "Delineating the Cognitive Profile of ODLURO Syndrome: Emergent Clues on the Endophenotype Across KMT2 Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wilcoxon paired tests showed verbal reasoning was stronger than non-verbal
      reasoning skills (p = 0.04).
    explanation: Characterizes the cognitive profile (verbal greater than nonverbal reasoning).
- name: Severe global developmental delay
  category: Neurological
  subtype: Missense
  description: >-
    Individuals with de novo missense variants had the most severe delays; at
    last follow-up two of four walked independently and none was verbal.
  phenotype_term:
    preferred_term: Severe global developmental delay
    term:
      id: HP:0011344
      label: Severe global developmental delay
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only two of the four individuals can walk independently, and none of the
      individuals were verbal at most recent follow-up (Figure 3).
    explanation: Severity of delay in the missense group.
- name: Developmental regression
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    Regression, mainly loss of previously acquired words, in 6/51 (12%) of the
    combined loss-of-function cohorts; in the second cohort both children with
    language regression also had autism.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regression | 2/18 (11%) | 4/33 (12%) | 6/51 (12%)"
    explanation: Combined frequency 6/51.
- name: Autism
  category: Behavioral
  frequency: FREQUENT
  description: >-
    Autism spectrum disorder in 15/48 (31%) of the combined loss-of-function
    cohorts, predominantly in males (in the index truncating group 7/20 males
    and 0/7 females). Parent ratings in a later series showed most difficulty
    in restricted and repetitive behaviours with relatively fewer problems in
    social motivation.
  phenotype_term:
    preferred_term: Autism spectrum disorder
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autism spectrum disorder | 7/17 (41%) | 8/31 (26%) | 15/48 (31%)"
    explanation: Combined frequency 15/48.
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similarly, about one third of affected individuals have an autism spectrum
      disorder diagnosis, of which most to date are male.
    explanation: GeneReviews summary including the male predominance.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Male | 22 | 82% (9/11) | 35% (7/20) | 5% (1/19) | 52% (11/21) | 0% (0/21)"
    explanation: Autism in 7/20 males with truncating variants.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Female | 8 | 80% (4/5) | 0% (0/7) | 43% (3/7) | 63% (5/8) | 0% (0/8)"
    explanation: Autism in 0/7 females with truncating variants.
  - reference: PMID:41137515
    reference_title: "Towards Characterizing the Developmental and Behavioral Profiles of ODLURO Syndrome: Shared Features With Wiedemann-Steiner Syndrome and Kabuki Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      study findings highlighted a pattern of most day-to-day difficulties in
      Restricted/Repetitive Behaviors paired with relatively fewer challenges in
      Social Motivation
    explanation: Profile of autism-related behaviours on parent rating.
- name: Anxiety
  category: Behavioral
  frequency: FREQUENT
  description: >-
    Anxiety problems were rated in 33% of a neurobehavioral series (the
    abstract does not state the number of participants); anxiety was also among
    the behavioural concerns in the index cohort.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:41137515
    reference_title: "Towards Characterizing the Developmental and Behavioral Profiles of ODLURO Syndrome: Shared Features With Wiedemann-Steiner Syndrome and Kabuki Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Findings show prominent behavioral features in ODLURO include problems
      with anxiety (33%), attention (67%), and executive function (50%)
      (working memory, cognitive inflexibility)
    explanation: Quantifies anxiety problems in a neurobehavioral series.
- name: Attention problems
  category: Behavioral
  frequency: FREQUENT
  description: >-
    Attention problems were rated in 67% of a neurobehavioral series and in
    more than half of a neuropsychological series of ten; a formal ADHD
    diagnosis was recorded in 3/52 (6%) of the combined loss-of-function
    cohorts.
  phenotype_term:
    preferred_term: Attention problems
    term:
      id: HP:0000736
      label: Short attention span
  evidence:
  - reference: PMID:41137515
    reference_title: "Towards Characterizing the Developmental and Behavioral Profiles of ODLURO Syndrome: Shared Features With Wiedemann-Steiner Syndrome and Kabuki Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Findings show prominent behavioral features in ODLURO include problems
      with anxiety (33%), attention (67%), and executive function (50%)
      (working memory, cognitive inflexibility)
    explanation: Attention problems in two-thirds of a neurobehavioral series.
  - reference: PMID:40616444
    reference_title: "Delineating the Cognitive Profile of ODLURO Syndrome: Emergent Clues on the Endophenotype Across KMT2 Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over half of respondents rated their children in the at-risk to
      clinically significant range for attention problems and hyperactivity.
    explanation: Independent series (n=10) with the same finding.
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ADHD | 1/18 (6%) | 2/34 (6%) | 3/52 (6%)"
    explanation: Formal ADHD diagnoses are much less frequent than rated attention problems.
- name: Motor stereotypies
  category: Behavioral
  frequency: OCCASIONAL
  description: Stereotypical behaviour in 9/52 (17%) of the combined loss-of-function cohorts.
  phenotype_term:
    preferred_term: Stereotypical behaviour
    term:
      id: HP:0000733
      label: Motor stereotypy
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stereotypical behaviour | 6/18 (33%) | 3/34 (9%) | 9/52 (17%)"
    explanation: Combined frequency 9/52.
- name: Self-injurious behavior
  category: Behavioral
  frequency: OCCASIONAL
  description: Self-injury in 3/52 (6%) of the combined loss-of-function cohorts.
  phenotype_term:
    preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Self-injurious behaviour | 2/18 (11%) | 1/34 (3%) | 3/52 (6%)"
    explanation: Combined frequency 3/52.
- name: Aggressive behavior
  category: Behavioral
  frequency: OCCASIONAL
  description: Aggression in 3/52 (6%) of the combined loss-of-function cohorts.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aggressive behaviour | 1/18 (6%) | 2/34 (6%) | 3/52 (6%)"
    explanation: Combined frequency 3/52.
- name: Sleep disturbance
  category: Behavioral
  frequency: FREQUENT
  description: >-
    Frequent awakening and difficulty falling asleep, reported in 8/17 (47%)
    of the second cohort, including children without autism, and in 85% of a
    later neurobehavioral series where it was associated with behaviour
    regulation difficulties.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sleep disturbances | 8/17 (47%) | n/s"
    explanation: Frequency in the second cohort; not systematically recorded in the index cohort.
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The reported sleep disturbances in our cohort consisted of frequent
      awakening and difficulty falling asleep with prolonged sleep latency.
    explanation: Describes the type of sleep disturbance.
  - reference: PMID:41137515
    reference_title: "Towards Characterizing the Developmental and Behavioral Profiles of ODLURO Syndrome: Shared Features With Wiedemann-Steiner Syndrome and Kabuki Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sleep disturbances are common in ODLURO (85%) and associated with behavior
      regulation difficulties, highlighting the importance of early
      screening/intervention.
    explanation: Higher frequency in a dedicated neurobehavioral series.
- name: Hypotonia
  category: Neurological
  frequency: FREQUENT
  description: Muscular hypotonia in 23/45 (51%) of the combined loss-of-function cohorts.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscular hypotonia | 8/18 (44%) | 15/27 (56%) | 23/45 (51%)"
    explanation: Combined frequency 23/45.
- name: Macrocephaly
  category: Growth
  frequency: FREQUENT
  subtype: Loss-of-function
  description: >-
    Macrocephaly (head circumference 2 SD or more above the mean) in 28/51
    (55%) of the combined loss-of-function cohorts, usually postnatal in onset
    and sometimes progressive; a few more have relative macrocephaly. Height and
    weight are usually normal. No individual in the index truncating group had
    microcephaly.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Macrocephaly | 10/18 (56%) | 18/33 (55%) | 28/51 (55%)"
    explanation: Combined frequency 28/51.
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth parameters are typically in the normal range for length/height and
      weight, although about half of affected individuals have macrocephaly or
      relative macrocephaly.
    explanation: GeneReviews summary; somatic growth is otherwise normal.
  - reference: PMID:39709003
    reference_title: "Molecular and clinical Insights into KMT2E-Related O'Donnell-Luria-Rodan syndrome in a novel patient cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By a systematic review of the previously reported series, we also discuss
      previously unappreciated findings, including progressive macrocephaly,
      apraxia, and higher risk of bone fractures.
    explanation: Notes that macrocephaly can be progressive.
- name: Microcephaly
  category: Growth
  subtype: Missense
  description: >-
    Two of three individuals with de novo missense variants and a measured
    head circumference had microcephaly, the opposite of the typical
    loss-of-function presentation.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Missense Total | 4 | 100% (3/3) | 33% (1/3) | 100% (4/4) | 0% (0/3) | 66% (2/3)"
    explanation: Microcephaly in 2/3 and macrocephaly in 0/3 of the missense group.
- name: Epilepsy
  category: Neurological
  frequency: OCCASIONAL
  subtype: Loss-of-function
  description: >-
    Epilepsy in 7/48 (15%) of the combined loss-of-function cohorts (4/26 of
    intragenic truncating variants in the index cohort, 3/4 of its
    microdeletions, 0/18 in the second cohort). In the index truncating group it
    was seen in 3/7 females and 1/19 males. No single seizure type or epilepsy
    syndrome predominates; focal seizures, childhood absence epilepsy and
    febrile seizures have been associated with truncating variants and
    deletions. GeneReviews gives about one third across all variant classes,
    and a systematic review of cases with epilepsy estimated 29%; these
    all-class figures include the missense and large-deletion groups, in which
    epilepsy is more frequent.
  phenotype_term:
    preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy | 0/18 (0%) | 7/30 (23%) | 7/48 (15%)"
    explanation: Combined frequency 7/48 in the loss-of-function cohorts.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the rates of intellectual disability and macrocephaly were
      similar, interestingly, epilepsy was seen in 43% of females but in only 5%
      of males (p = 0.047, Fisher's exact test)
    explanation: Sex difference in epilepsy among truncating-variant carriers.
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About one third of affected individuals develop seizures, with no
      consistent seizure semiology or epilepsy syndrome. However, females may be
      more likely to develop seizures compared to males.
    explanation: GeneReviews all-class estimate and sex difference.
  - reference: PMID:39709003
    reference_title: "Molecular and clinical Insights into KMT2E-Related O'Donnell-Luria-Rodan syndrome in a novel patient cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also highlight different epilepsy phenotype-genotype correlation with
      preferential association of generalized epilepsy and/or developmental and
      epileptic encephalopathy with missense pathogenic variants and focal
      epilepsy, childhood absence epilepsy and/or febrile seizures with
      pathogenic truncating variants and structural rearrangements.
    explanation: Epilepsy types associated with the loss-of-function class.
  - reference: PMID:40048818
    reference_title: "Genotype-phenotype correlation of ODLURO syndrome comorbid epilepsy associated with KMT2E variations: Report on a novel case and systematic literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epilepsy, observed in 29% of affected individuals, has not been thoroughly
      investigated.
    explanation: All-class estimate from a systematic review.
- name: Febrile seizures
  category: Neurological
  frequency: OCCASIONAL
  subtype: Loss-of-function
  description: Recurrent febrile seizures without complications in 2/18 (11%) of the second cohort, none of whom had epilepsy.
  phenotype_term:
    preferred_term: Febrile seizures
    term:
      id: HP:0002373
      label: Febrile seizure (within the age range of 3 months to 6 years)
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Febrile seizures | 2/18 (11%) | n/s"
    explanation: Frequency in the second cohort.
- name: Epileptic encephalopathy
  category: Neurological
  subtype: Missense
  description: >-
    Three of four individuals with de novo missense variants had infantile-onset
    (neonatal to 6 months) epileptic encephalopathy with treatment-resistant
    seizures, including epileptic spasms; EEGs showed burst suppression
    evolving to hypsarrhythmia, or hypsarrhythmia. A de novo splice variant
    causing exon skipping has also been reported with West syndrome (spasms and
    hypsarrhythmia at 6 months), so infantile spasms are not confined to
    missense variants.
  phenotype_term:
    preferred_term: Infantile-onset epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals 34, 35, and 36 all presented with infantile epileptic
      encephalopathy.
    explanation: Three of four missense carriers had infantile epileptic encephalopathy.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The initial EEG in individual 35 showed burst suppression and subsequently
      evolved into hypsarrhythmia. The EEG in individual 36 also showed
      hypsarrhythmia.
    explanation: EEG pattern in the missense group.
  - reference: PMID:40070083
    reference_title: "A Novel KMT2E Splicing Variant as a Cause of O'Donnell-Luria-Rodan Syndrome With West Syndrome: Expansion of the Phenotype and Genotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient presented with spasmodic seizures and developmental delay at 6
      months of age. The video electroencephalogram (EEG) displayed
      hypsarrhythmia.
    explanation: West syndrome with a de novo KMT2E splice variant.
- name: Hypoplasia of the corpus callosum
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    Brain MRI is often normal or non-specific. Corpus callosum hypoplasia in
    7/36 (19%) of imaged individuals in the combined loss-of-function cohorts.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Corpus callosum hypoplasia | 3/14 (21%) | 4/22 (18%) | 7/36 (19%)"
    explanation: Combined frequency 7/36 imaged.
- name: Intracranial cysts
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    Cerebral cysts (pineal, epidermoid, arachnoid, ependymal and others) in
    7/36 (19%) of imaged individuals in the combined loss-of-function cohorts.
  phenotype_term:
    preferred_term: Intracranial cysts
    term:
      id: HP:0010576
      label: Intracranial cystic lesion
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebral cysts | 3/14 (21%) | 4/22 (18%) | 7/36 (19%)"
    explanation: Combined frequency 7/36 imaged.
- name: Ventriculomegaly
  category: Neurological
  frequency: OCCASIONAL
  description: Ventriculomegaly in 5/36 (14%) of imaged individuals in the combined loss-of-function cohorts.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ventriculomegaly | 2/14 (14%) | 3/22 (14%) | 5/36 (14%)"
    explanation: Combined frequency 5/36 imaged.
- name: Delayed CNS myelination
  category: Neurological
  frequency: OCCASIONAL
  description: Delayed myelination in 5/36 (14%) of imaged individuals in the combined loss-of-function cohorts.
  phenotype_term:
    preferred_term: Delayed CNS myelination
    term:
      id: HP:0002188
      label: Delayed CNS myelination
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Delayed myelination | 4/14 (29%) | 1/22 (5%) | 5/36 (14%)"
    explanation: Combined frequency 5/36 imaged.
- name: Constipation
  category: Digestive
  frequency: OCCASIONAL
  description: >-
    Constipation is the most frequent gastrointestinal problem, in 13/45 (29%)
    of the combined loss-of-function cohorts (8/18 in the second cohort).
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Constipation | 8/18 (44%) | 5/27 (19%) | 13/45 (29%)"
    explanation: Combined frequency 13/45.
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Constipation is the most frequent gastrointestinal issue, although
      gastroesophageal reflux, vomiting, and/or reduced bowel motility have been
      reported in almost half of affected individuals.
    explanation: GeneReviews ranks constipation as the leading gastrointestinal issue.
- name: Gastrointestinal dysmotility
  category: Digestive
  frequency: FREQUENT
  description: >-
    Functional gastrointestinal problems (reflux, vomiting and/or reduced bowel
    motility) in almost half of affected individuals per GeneReviews. Counted
    separately in the combined loss-of-function cohorts, reflux was reported in
    3/45 (7%) and vomiting in 4/45 (9%).
  phenotype_term:
    preferred_term: Gastrointestinal dysmotility
    term:
      id: HP:0002579
      label: Gastrointestinal dysmotility
  evidence:
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Constipation is the most frequent gastrointestinal issue, although
      gastroesophageal reflux, vomiting, and/or reduced bowel motility have been
      reported in almost half of affected individuals.
    explanation: Almost half have reflux, vomiting or dysmotility.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many of the individuals were reported to have gastrointestinal symptoms,
      including reflux, vomiting, or bowel motility issues; these are issues
      commonly seen in individuals with hypotonia.
    explanation: Index cohort description of functional gastrointestinal symptoms.
- name: Gastroesophageal reflux
  category: Digestive
  frequency: OCCASIONAL
  description: Reflux in 3/45 (7%) of the combined loss-of-function cohorts.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastro-oesophageal reflux | 1/18 (6%) | 2/27 (7%) | 3/45 (7%)"
    explanation: Combined frequency 3/45.
- name: Vomiting
  category: Digestive
  frequency: OCCASIONAL
  description: Vomiting in 4/45 (9%) of the combined loss-of-function cohorts.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vomiting | 3/18 (18%) | 1/27 (4%) | 4/45 (9%)"
    explanation: Combined frequency 4/45 (the published cell reads 3/18 as 18%).
- name: Characteristic facial gestalt
  category: Craniofacial
  description: >-
    A subtle facial gestalt: large or high forehead, dolichocephaly, deep-set
    eyes, downslanting palpebral fissures, periorbital fullness, full or
    prominent cheeks and prominent nasolabial folds. The individual features
    are listed separately with their frequencies.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consistent facial features include dolichocephaly, large foreheads, and
      deep-set eyes, often with down-slanting palpebral fissures, periorbital
      fullness, prominent cheeks, and prominent nasolacrimal folds.
    explanation: Index cohort description of the facial gestalt.
- name: Large forehead
  category: Craniofacial
  frequency: FREQUENT
  description: Large forehead in 10/17 (59%) of the second cohort.
  phenotype_term:
    preferred_term: Large or high forehead
    term:
      id: HP:0000348
      label: High forehead
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Large forehead | 10/17 (59%) | n/q"
    explanation: Frequency in the second cohort.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Comparison of the facial features of eleven of the individuals in our
      cohort suggests some commonalities, including macrocephaly,
      dolichocephaly, high forehead, deep-set eyes, periorbital fullness,
      prominent cheeks, and prominent nasolabial folds (Figures 2 and 4).
    explanation: The index cohort describes the forehead as high.
- name: Full cheeks
  category: Craniofacial
  frequency: FREQUENT
  description: Full cheeks in 9/17 (53%) of the second cohort.
  phenotype_term:
    preferred_term: Full cheeks
    term:
      id: HP:0000293
      label: Full cheeks
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Full cheeks | 9/17 (53%) | n/q"
    explanation: Frequency in the second cohort.
- name: Deeply set eyes
  category: Craniofacial
  frequency: FREQUENT
  description: Deep-set eyes in 7/17 (41%) of the second cohort.
  phenotype_term:
    preferred_term: Deep-set eyes
    term:
      id: HP:0000490
      label: Deeply set eye
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deep-set eyes | 7/17 (41%) | n/q"
    explanation: Frequency in the second cohort.
- name: Epicanthus
  category: Craniofacial
  frequency: FREQUENT
  description: Epicanthal folds in 7/17 (41%) of the second cohort.
  phenotype_term:
    preferred_term: Epicanthal folds
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epicanthal folds | 7/17 (41%) | n/q"
    explanation: Frequency in the second cohort.
- name: Dolichocephaly
  category: Craniofacial
  frequency: OCCASIONAL
  description: Dolichocephaly in 2/17 (12%) of the second cohort; described as a consistent feature of the index cohort's gestalt.
  phenotype_term:
    preferred_term: Dolichocephaly
    term:
      id: HP:0000268
      label: Dolichocephaly
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dolichocephaly | 2/17 (12%) | n/q"
    explanation: Frequency in the second cohort.
- name: Prominent nasolabial fold
  category: Craniofacial
  frequency: OCCASIONAL
  description: Prominent nasolabial folds in 3/17 (18%) of the second cohort.
  phenotype_term:
    preferred_term: Prominent nasolabial folds
    term:
      id: HP:0005272
      label: Prominent nasolabial fold
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prominent nasolabial folds | 3/17 (18%) | n/q"
    explanation: Frequency in the second cohort.
- name: Downslanted palpebral fissures
  category: Craniofacial
  description: Down-slanting palpebral fissures are part of the index cohort's gestalt; no frequency reported.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consistent facial features include dolichocephaly, large foreheads, and
      deep-set eyes, often with down-slanting palpebral fissures, periorbital
      fullness, prominent cheeks, and prominent nasolacrimal folds.
    explanation: Index cohort facial description.
- name: Periorbital fullness
  category: Craniofacial
  description: Periorbital fullness is part of the index cohort's gestalt; no frequency reported.
  phenotype_term:
    preferred_term: Periorbital fullness
    term:
      id: HP:0000629
      label: Periorbital fullness
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consistent facial features include dolichocephaly, large foreheads, and
      deep-set eyes, often with down-slanting palpebral fissures, periorbital
      fullness, prominent cheeks, and prominent nasolacrimal folds.
    explanation: Index cohort facial description.
- name: Small ears
  category: Craniofacial
  frequency: OCCASIONAL
  description: Small ears in 4/17 (24%) of the second cohort.
  phenotype_term:
    preferred_term: Small ears
    term:
      id: HP:0008551
      label: Microtia
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Small ears | 4/17 (24%) | n/q"
    explanation: Frequency in the second cohort.
- name: Clinodactyly
  category: Skeletal
  frequency: OCCASIONAL
  description: Clinodactyly in 4/17 (24%) of the second cohort.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinodactyly | 4/17 (24%) | n/q"
    explanation: Frequency in the second cohort.
- name: Recurrent fractures
  category: Skeletal
  description: >-
    A higher risk of bone fractures was identified in a systematic review of
    published series; frequency and mechanism are not given in the abstract.
  phenotype_term:
    preferred_term: Bone fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:39709003
    reference_title: "Molecular and clinical Insights into KMT2E-Related O'Donnell-Luria-Rodan syndrome in a novel patient cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By a systematic review of the previously reported series, we also discuss
      previously unappreciated findings, including progressive macrocephaly,
      apraxia, and higher risk of bone fractures.
    explanation: Reports increased fracture risk as a newly recognized finding.
genetic:
- name: KMT2E
  notes: >-
    Heterozygous KMT2E variants (NM_182931) cause the disorder; ClinGen
    classifies KMT2E and autosomal dominant complex neurodevelopmental disorder
    (the ODLURO phenotype) as Definitive with a loss-of-function mechanism.
    Reported variant classes are frameshift, nonsense, canonical splice,
    synonymous variants creating cryptic splice sites, complex structural
    variants disrupting the gene, 7q22.2-q22.3 deletions (0.052 to 3.2 Mb) and rare
    de novo missense variants. Frameshifts in the last exon that escape
    nonsense-mediated decay and extend the protein occur and are clinically
    indistinguishable from earlier truncations. The gene is constrained against
    truncating (pLI 1.0) but not missense variation.
  gene_term:
    preferred_term: KMT2E
    term:
      id: hgnc:18541
      label: KMT2E
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: CGGV:assertion_2d0a0603-e446-4bb9-a202-4f8066a60c5a-2022-08-02T180000.000Z
    reference_title: "KMT2E / complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KMT2E | HGNC:18541 | complex neurodevelopmental disorder | MONDO:0100038 | AD | Definitive"
    explanation: ClinGen Definitive gene-disease validity for autosomal dominant disease.
  - reference: CGGV:assertion_2d0a0603-e446-4bb9-a202-4f8066a60c5a-2022-08-02T180000.000Z
    reference_title: "KMT2E / complex neurodevelopmental disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Complex neurodevelopmental disorder in relation to variants in KMT2E was
      originally termed as O'Donnell-Luria-Rodan syndrome (ODLURO)
    explanation: ClinGen equates its lumped disease term with ODLURO.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study includes 31 distinct heterozygous variants in KMT2E (28
      ascertained from Matchmaker Exchange and three previously reported), and
      four individuals with chromosome 7q22.2-22.23 microdeletions encompassing
      KMT2E (one previously reported).
    explanation: Index cohort variant spectrum.
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual 13 carried a seemingly synonymous heterozygous variant c.264A>G
      (the translation impact is predicted as p.(Glu88=) but will subsequently
      be given as p.?) that is predicted to activate a cryptic donor splice
      site.
    explanation: Apparently synonymous variants can act through splicing.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KMT2E is not significantly constrained for missense variation in the
      general population (Z score +1.42, observed/expected ratio of 0.87
      [0.82-0.92 95% CI] for missense variation in gnomAD).
    explanation: Missense constraint is absent, unlike truncating constraint.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Diagnosis is established by a heterozygous pathogenic KMT2E variant in a
    proband with suggestive findings. Intragenic variants are found by exome or
    genome sequencing and deletions by chromosomal microarray. There are no
    consensus clinical diagnostic criteria. Complex structural variants can be
    missed by standard exome and genome pipelines and have been found on
    reanalysis of genome data.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: A heterozygous pathogenic KMT2E variant or a deletion including KMT2E establishes the diagnosis.
  evidence:
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of KMT2E-NDD is established in a proband with suggestive
      findings and a heterozygous pathogenic variant in KMT2E identified by
      molecular genetic testing.
    explanation: GeneReviews diagnostic criterion.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microdeletions were detected by chromosomal microarrays in some
      individuals, whereas all other individuals were found to have variants in
      KMT2E via exome or genome sequencing.
    explanation: Testing modalities by variant class.
  - reference: PMID:37157895
    reference_title: "Genome sequencing identifies KMT2E-disrupting cryptic structural variant in a female with O'Donnell-Luria-Rodan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case expands the mutational spectrum for this syndrome and highlights
      the importance of revisiting unsolved cases using better SV prioritisation
      tools and updated gene panels.
    explanation: A cryptic structural variant was found only on dedicated structural-variant reanalysis.
differential_diagnoses:
- name: Other KMT2-family and H3K4-related chromatinopathies
  description: >-
    Wiedemann-Steiner syndrome (KMT2A) and Kabuki syndrome (KMT2D) share
    developmental delay, intellectual disability, autism features, sleep
    disturbance and gastrointestinal symptoms, and neurobehavioral comparisons
    show overlapping profiles.
  distinguishing_features:
  - Macrocephaly in about half of the loss-of-function group.
  - Molecular confirmation of a KMT2E variant.
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ODLURO phenotypic spectrum has a considerable overlap with these
      disorders, which may suggest an underlying pathomechanistic similarity.
    explanation: Overlap with the other KMT2-family disorders.
  - reference: PMID:41137515
    reference_title: "Towards Characterizing the Developmental and Behavioral Profiles of ODLURO Syndrome: Shared Features With Wiedemann-Steiner Syndrome and Kabuki Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In brief, ODLURO shares similarities in neurobehavioral functioning with
      other disorders of H3K4 modulation of gene expression, warranting further
      systematic research with cross-syndrome comparisons
    explanation: Neurobehavioral overlap with Wiedemann-Steiner and Kabuki syndromes.
- name: CHD8-related neurodevelopmental disorder
  description: >-
    CHD8 truncating variants also cause mild to moderate intellectual
    disability, autism susceptibility and macrocephaly or overgrowth. One child
    in the second ODLURO cohort carried de novo truncating variants in both
    genes.
  distinguishing_features:
  - Molecular testing distinguishes the two and can identify dual diagnoses.
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonsense variants in CHD8 have been robustly associated with mild to
      moderate ID and ASD susceptibility.
    explanation: Phenotypic overlap noted in the context of a dual diagnosis.
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, a large proportion of patients display overgrowth with
      increased height and/or macrocephaly.
    explanation: CHD8-related disorder shares macrocephaly with ODLURO.
- name: PTEN hamartoma tumor syndrome
  description: >-
    Macrocephaly with developmental delay or autism prompts PTEN testing; PTEN
    was tested and excluded in one ODLURO patient before KMT2E was found, and a
    child in the index cohort had pathogenic variants in both KMT2E and PTEN.
  distinguishing_features:
  - Molecular testing; a PTEN result does not exclude KMT2E and vice versa.
  evidence:
  - reference: PMID:37157895
    reference_title: "Genome sequencing identifies KMT2E-disrupting cryptic structural variant in a female with O'Donnell-Luria-Rodan syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The large OFC at 11 years prompted Sanger sequencing and MLPA analysis of
      PTEN but no pathogenic variants were identified.
    explanation: PTEN was the first diagnostic consideration for macrocephaly in an ODLURO patient.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual 6 also had a de novo pathogenic PTEN (GenBank: NM_000314.6,
      MIM: 601728) c.493G>A (p.Gly165Arg) variant, which can also account for his
      macrocephaly.
    explanation: Dual KMT2E and PTEN diagnosis in the index cohort.
treatments:
- name: Antiseizure medication
  description: >-
    Seizures are treated with standard antiseizure medications chosen by seizure
    type; no drug has been studied specifically in ODLURO. In the index cohort,
    epilepsy with truncating variants was controlled with medication in almost
    all, whereas missense-variant epileptic encephalopathy was treatment
    resistant (a ketogenic diet did not help in one child). In a systematic
    review of cases with epilepsy, about 70% of those with medication records
    needed two or more drugs.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Anticonvulsant therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epilepsy was present in about one-fifth of individuals with truncating
      variants and was responsive to treatment with anti-epileptic medications
      in almost all.
    explanation: Treatment response in the truncating-variant group.
  - reference: PMID:40048818
    reference_title: "Genotype-phenotype correlation of ODLURO syndrome comorbid epilepsy associated with KMT2E variations: Report on a novel case and systematic literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among ten individuals with a record of antiseizure medication,
      approximately 70% required two or more antiseizure medications.
    explanation: Polytherapy was often needed among cases ascertained for epilepsy.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual 34 was started on the ketogenic diet at 14 months of age, but
      this diet did not improve seizure control.
    explanation: Single-case negative experience with the ketogenic diet in the missense group.
- name: Developmental and educational therapies
  description: >-
    Standard early intervention, speech-language, physical and occupational
    therapy and educational support for developmental delay and intellectual
    disability, per GeneReviews management guidance. Not studied specifically
    in ODLURO.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Speech language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Standard treatment for developmental delay / intellectual disability,
      neuropsychiatric issues, seizures, constipation, gastroesophageal
      reflux/dysmotility, vomiting, and sleep disturbance.
    explanation: GeneReviews recommends standard developmental treatment.
- name: Symptomatic management of gastrointestinal and sleep problems
  description: >-
    Standard management of constipation, reflux and dysmotility, vomiting and
    sleep disturbance, per GeneReviews. Not studied specifically in ODLURO.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  - preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Standard treatment for developmental delay / intellectual disability,
      neuropsychiatric issues, seizures, constipation, gastroesophageal
      reflux/dysmotility, vomiting, and sleep disturbance.
    explanation: GeneReviews recommends standard symptomatic treatment.
- name: Surveillance
  description: >-
    At each visit: growth parameters including head circumference, new
    neurologic manifestations and seizure monitoring, developmental progress
    and educational needs, behaviour (anxiety, ADHD, aggression, self-injury),
    and chronic vomiting, constipation and sleep.
  action_category: MONITORING
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At each visit, measure growth parameters (including head circumference);
      assess for new neurologic manifestations and monitor those with seizures
      as clinically indicated; monitor developmental progress and educational
      need; assess for behavioral issues, including anxiety, ADHD, aggression,
      and self-injury; and assess for chronic vomiting, constipation, and
      signs/symptoms of sleep disturbance.
    explanation: GeneReviews surveillance recommendations.
- name: Genetic counseling
  description: >-
    Counseling on autosomal dominant inheritance, the predominance of de novo
    variants, the 50% risk to offspring of an affected individual, testing of
    parents who may be mildly affected, and prenatal or preimplantation testing
    once the familial variant is known.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38648332
    reference_title: "KMT2E-Related Neurodevelopmental Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with KMT2E-NDD has a 50% chance of inheriting
      the pathogenic variant. Once the KMT2E pathogenic variant has been
      identified in an affected family member, prenatal and preimplantation
      genetic testing are possible.
    explanation: GeneReviews counseling content.
animal_models:
- name: Kmt2e heterozygous mouse (amygdala study)
  species: Mouse
  genotype: Kmt2e+/- (constitutive heterozygous)
  description: >-
    Heterozygous mice show social deficit and anxiety-like behaviour, reduced
    relative amygdala glucose metabolism on FDG-PET, and increased numbers and
    soma size of amygdala neurons. Developmental delay, macrocephaly and
    seizures are not reported in the abstract.
  genes:
  - preferred_term: KMT2E
    term:
      id: hgnc:18541
      label: KMT2E
  associated_phenotypes:
  - Social deficit
  - Anxiety-like behaviour
  - Reduced amygdala glucose metabolism
  - Increased amygdala neuron number and soma size
  publication: PMID:36534336
  evidence:
  - reference: PMID:36534336
    reference_title: "KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Behavioral results revealed that KMT2E haploinsufficiency was sufficient
      to produce social deficit, accompanied by anxiety in mice.
    explanation: Behavioural phenotype of the heterozygous mouse.
  modeled_mechanisms:
  - target: Amygdala Neuronal Development Abnormality
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: TISSUE
    limitations: >-
      The amygdala finding has no reported human counterpart, so fidelity to the
      human disorder cannot be assessed.
    evidence:
    - reference: PMID:36534336
      reference_title: "KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The numbers and soma sizes of amygdala neurons in KMT2E+/- mice were
        prominently increased.
      explanation: The model is the source of this node.
- name: Mll5 heterozygous mouse (microglia study)
  species: Mouse
  genotype: Mll5 (Kmt2e) haploinsufficient
  description: >-
    Haploinsufficient mice show impaired microglial phagocytosis through
    TREM2-SGK3-GSK3B signalling, neuronal hyperexcitability and autism-like
    behaviours; lithium chloride rescued the microglial and behavioural
    abnormalities.
  genes:
  - preferred_term: KMT2E
    term:
      id: hgnc:18541
      label: KMT2E
  associated_phenotypes:
  - Impaired microglial phagocytosis
  - Neuronal hyperexcitability
  - Autism-like behaviours
  publication: PMID:41997967
  evidence:
  - reference: PMID:41997967
    reference_title: "Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we demonstrate that Mll5 haploinsufficiency in mice impairs
      microglial phagocytosis, drives neuronal hyperexcitability, and
      recapitulates core ASD-like behaviors.
    explanation: Summary of the model phenotype.
  modeled_mechanisms:
  - target: Impaired Microglial Phagocytosis
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: CELLULAR
    limitations: >-
      Microglial phagocytosis has not been studied in individuals with ODLURO;
      the human comparison in the study used microglia from an individual with
      autism, not with ODLURO.
    evidence:
    - reference: PMID:41997967
      reference_title: "Mll5 haploinsufficiency attenuates microglial phagocytosis through dysregulated TREM2-SGK3-GSK3β signaling and recapitulates ASD-like behaviors in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Furthermore, microglia derived from individual with ASD exhibit parallel
        reductions in MLL5 expression and phagocytic function.
      explanation: The only human correlate comes from autism, not ODLURO.
discussions:
- discussion_id: kmt2e_catalytic_activity
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Does KMT2E have intrinsic histone methyltransferase activity, and does any
    such activity matter for ODLURO?
  attaches_to:
  - pathophysiology#KMT2E Haploinsufficiency
  - pathophysiology#Altered H3K4 Methylation and Transcriptional Regulation
  rationale: >-
    KMT2E is named as a lysine methyltransferase, but the crystal structure of
    its SET domain shows missing key residues and an obstructing loop, and the
    purified domain had no activity on histones or H3 peptides. An earlier study
    reported H3K4 mono- and di-methyltransferase activity dependent on
    O-GlcNAcylation of the SET domain in a myeloid cell line. The entry
    therefore binds the PHD-finger reader function rather than methyltransferase
    activity, and treats any H3K4 methylation change as indirect.
  evidence:
  - reference: PMID:27812132
    reference_title: "The Human Mixed Lineage Leukemia 5 (MLL5), a Sequentially and Structurally Divergent SET Domain-Containing Protein with No Intrinsic Catalytic Activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Accordingly, we show that MLL5 is devoid of any in vitro methyltransferase
      activity on full-length histones and histone H3 peptides.
    explanation: Structural and biochemical evidence against intrinsic activity.
  - reference: PMID:19377461
    reference_title: "GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      GlcNAcylation at Thr 440 in the MLL5 SET domain evokes its H3K4 HKMT
      activity and co-activates RARalpha in target gene promoters.
    explanation: Reports modification-dependent H3K4 methyltransferase activity, contradicting the inactive-SET view.
- discussion_id: kmt2e_neural_chromatin_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What chromatin and transcriptional changes does heterozygous KMT2E loss
    cause in developing human neurons, and is there a KMT2E DNA methylation
    episignature?
  attaches_to:
  - pathophysiology#Altered H3K4 Methylation and Transcriptional Regulation
  rationale: >-
    Evidence for KMT2E's chromatin function comes from myoblasts, myeloid and
    cancer cell lines. No patient-derived neuronal model, brain transcriptome or
    blood episignature for ODLURO was found (the PubMed query "(KMT2E OR MLL5)
    AND (episignature OR DNA methylation signature)" returned no ODLURO study),
    so the link from reduced dosage to the neurodevelopmental phenotype is
    unmeasured and the conformed module's central transcriptional node is not
    declared.
  evidence:
  - reference: PMID:19264965
    reference_title: "MLL5, a trithorax homolog, indirectly regulates H3K4 methylation, represses cyclin A2 expression, and promotes myogenic differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We have examined the epigenetic mechanisms operating in conditional
      quiescence by analyzing the function of a predicted chromatin regulator
      mixed lineage leukemia 5 (MLL5) in a culture model of reversible arrest.
    explanation: The chromatin evidence used here comes from a myoblast culture model, not neural tissue.
- discussion_id: kmt2e_sex_biased_expressivity
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is the male excess among reported individuals, and the higher epilepsy and
    lower autism rates in females, biological or an ascertainment effect?
  attaches_to:
  - phenotypes#Epilepsy
  - phenotypes#Autism
  rationale: >-
    Across published loss-of-function cases 41 were male and 15 female, a
    significant excess. The authors raise reduced penetrance or milder
    expressivity in females as possible explanations but have not tested them.
  evidence:
  - reference: PMID:34321323
    reference_title: "O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this sex distribution of 41 males to 15 females with putative
      loss-of-function variants (excluding 7 patients carrying missense variants
      with a suspected gain-of-function
    explanation: Quantifies the male excess.
  - reference: PMID:31079897
    reference_title: "Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is possible that decreased penetrance or variable expressivity of the
      condition in females means that fewer female individuals with de novo
      protein-truncating variants come to diagnostic attention.
    explanation: The index authors' proposed, untested explanation.
📚

References & Deep Research

References

1
PMID:38648332
KMT2E-Related Neurodevelopmental Disorder.
No top-level findings curated for this source.

Deep Research

1

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 (1)

Create: ODonnell-Luria-Rodan_Syndrome · 2026-09-23T20:20:44Z · View source

New entry for O'Donnell-Luria-Rodan syndrome (MONDO:0032793; KMT2E). One deep-research report was run: falcon was requested and returned HTTP 402, so the claude_code fallback produced research/ODonnell-Luria-Rodan_Syndrome-deep-research-claude_code.md (fell_back: true). Its generation-time term validation failed on an OLS timeout, so reference and term validation sections were added afterwards with validate-research-reference (11/11 references resolved, 1/1 quote found, 0 off topic) and validate-research-terms (0 unresolved; 2 obsolete GO terms; 3 label mismatches that are table-parsing artifacts). preflight-dr returned PASS. Report content was used only as leads; every claim is sourced to a fetched primary or structured source. Report identifiers not used in the entry: PMID:28188343 (review), PMID:40225946 (ASO treatability review), DOI:10.3390/genes15040430 (synonymous-variant case); their caches are kept because the report's validation cites them. Structured sources: ClinGen gene-disease validity CGGV assertion (KMT2E / complex neurodevelopmental disorder, Definitive, AD) built with the structured-source CLI from the ClinGen CSV downloaded 2026-09-23, whose checksum no longer matches the 2026-08-13 manifest pin (upstream release drift); the manifest was not repinned, so the cache file's source line reports the pinned snapshot date. ClinGen dosage (CGDS) was not built for the same reason. No Orphanet product-1 record exists for the syndrome. Lump/split: single MONDO/OMIM concept kept as one entry with two allelic has_subtypes (Loss-of-function; Missense), because the missense group's severe DEE/microcephaly phenotype diverges but its mechanism is an untested hypothesis. KMT2E catalytic activity treated as a CONTROVERSY (PMID:27812132 no activity vs PMID:19377461 GlcNAcylation-dependent activity); the PHD-finger H3K4me3 reader function is what is bound. Conforms to epigenetic_machinery_neurodevelopmental_dysregulation at the haploinsufficiency and chromatin-state nodes only; the central transcriptional node is not declared because no neural chromatin or transcriptome data exist (KNOWLEDGE_GAP). Validation: just validate, validate-terms, count-verified-snippets (136/136), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-environmental-evidence, check-coarse-phenotypes, check-reference-titles, check-genereviews --online (TAGGED), list-gene-term-mismatches, pytest tests/test_data.py -k ODonnell (2 passed), validate-disorders (passed).

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O'Donnell-Luria-Rodan Syndrome (KMT2E-Related Neurodevelopmental Disorder): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 17 citations 2026-09-23T19:55:06.156630

O'Donnell-Luria-Rodan Syndrome (KMT2E-Related Neurodevelopmental Disorder): Comprehensive Research Report

1. Disease Information

Overview. O'Donnell-Luria-Rodan syndrome (ODLURO; also termed KMT2E-related neurodevelopmental disorder, KMT2E-NDD) is an autosomal dominant neurodevelopmental disorder caused by heterozygous pathogenic/likely pathogenic variants in KMT2E (lysine methyltransferase 2E, also known historically as MLL5) or by contiguous microdeletions of 7q22.2-q22.3 that encompass the gene. It is characterized principally by global developmental delay, speech delay, variably impaired intellectual development (typically mild-to-moderate), hypotonia, macrocephaly, a subtle but recognizable facial gestalt, functional gastrointestinal symptoms, sleep disturbance, and — in a substantial minority — autism spectrum disorder (ASD) and/or epilepsy (O'Donnell-Luria et al., AJHG 2019, PMID:31079897; Velmans et al., J Med Genet 2021, PMID:34321323; Pais, Rodan, O'Donnell-Luria, GeneReviews 2024, PMID:38648332).

The disorder was first delineated in 2019 by Anne O'Donnell-Luria and Lance Rodan (Boston Children's Hospital / Harvard Medical School / Broad Institute), using data assembled largely through Matchmaker Exchange, in a report of 38 individuals from 36 families (PMID:31079897). Earlier exome-sequencing studies (2012–2016) had already flagged KMT2E loss-of-function variants as an ASD risk-gene signal without recognizing a distinct syndrome (see Etiology/Genetic section). As of the most recent literature (2024–2025 cohort and case-series publications), well over 100 individuals have been reported worldwide.

Key identifiers: | Resource | Identifier | |---|---| | OMIM (phenotype) | #618512 — O'DONNELL-LURIA-RODAN SYNDROME; ODLURO | | OMIM (gene) | 608444 — KMT2E | | MONDO | MONDO:0032793 | | MedGen | C5193138 | | HGNC (gene) | HGNC:18541 (KMT2E) | | Gene location | 7q22.2–q22.3 | | Reference transcript | NM_182931.2/.3 | | GeneReviews | NBK602945 (PMID:38648332) | | ClinGen gene-disease validity | "Definitive," gene KMT2E* → "Complex neurodevelopmental disorder" MONDO:0100038, autosomal dominant, Intellectual Disability and Autism GCEP, 08/02/2022 | | ClinGen dosage sensitivity | Haploinsufficiency score 3 ("Sufficient Evidence"); Triplosensitivity score 0 ("No Evidence"), scored specifically against the ODLURO phenotype, 12/29/2021 |

I did not find a dedicated Orphanet (ORPHA) code in the sources searched; OMIM/MONDO/MedGen appear to be the primary cross-references currently indexed. This should be treated as an open item rather than a confirmed absence — worth a direct Orphanet lookup at curation time.

Synonyms: ODLURO syndrome; KMT2E-related neurodevelopmental disorder (KMT2E-NDD); MLL5-related disorder (older literature uses the MLL5 gene alias).

Evidentiary basis. All information below is derived from aggregated case-series/cohort publications (disease-level, retrospective ascertainment through clinical genetics services, ClinGen matchmaking, and research sequencing cohorts such as Deciphering Developmental Disorders/DDD and Simons Searchlight), not from a single large prospective natural-history study or individual-level EHR data. This matters for interpreting the frequency figures below — they are cohort proportions from case series of variable ascertainment, not population-based incidence/prevalence.

2. Etiology

Disease causal factor: monogenic, autosomal dominant. ODLURO is caused by heterozygous loss-of-function (predominantly) or missense (less common, more severe) variants in KMT2E, or by 7q22.2-q22.3 microdeletions removing KMT2E (and in larger deletions, neighboring genes). The disorder is not known to have environmental, infectious, or multifactorial causal contributions — it is a single-gene, largely de novo Mendelian disorder.

Genetic risk factors: - Causal variant class: In the founding cohort (n=38), 30/38 (79%) carried protein-truncating variants (24 indels/frameshift, 4 nonsense, 2 splice-site), 4/38 (11%) carried missense variants, and 4/38 (11%) carried 7q22.2-q22.23 microdeletions (0.052–3.2 Mb) (PMID:31079897). In the second cohort (Velmans et al., n=18), variant types were 7 frameshift, 4 nonsense, 4 splice-site (including one activating a cryptic donor site), and 2 partial microdeletions (711 kb, 61 kb); 14/15 sequence variants were novel (PMID:34321323). - Inheritance: Overwhelmingly de novo. In the 2019 cohort, 26/38 were confirmed de novo, 1 maternally inherited, 4 of unknown inheritance (parents unavailable), and one family had three affected male siblings with unknown paternal mosaicism status (PMID:31079897). In the 2021 cohort, 13/18 were de novo, 2 were paternally inherited in familial cases (siblings; one unrelated inherited case), with one instance of negative maternal testing and unavailable paternal testing (PMID:34321323). - gnomAD constraint: KMT2E is highly intolerant of protein-truncating variation — pLI = 1.0, observed/expected ratio for PTVs = 0.01 (i.e., ~99% fewer PTVs observed in gnomAD than expected under neutral mutation), consistent with strong purifying selection against haploinsufficiency. The gene is not significantly constrained against missense variation (Z-score +1.42, missense o/e = 0.87), consistent with the rarity of pathogenic missense alleles and suggesting most missense substitutions are tolerated (PMID:31079897). Only ~5 apparent PTVs were found among >140,000 gnomAD individuals, mostly outside neurologic-disease cohorts. - Modifier genes: No established modifier loci. One case in the second cohort carried a comorbid pathogenic CHD8 variant plus a MYH8 variant, producing a blended phenotype — illustrating that dual-diagnosis can complicate genotype-phenotype interpretation in individual cases but is not evidence of a systematic modifier (PMID:34321323). - Sex: Marked male predominance across cohorts (73% male in the 2019 cohort; 78% male in the 2021 cohort), with a statistically significant sex-specific phenotype split: females showed higher epilepsy rates (43% vs 5% in males, p=0.047 in the founding cohort) while males trended toward higher autism rates (35% vs 0% in females, p=0.14) (PMID:31079897). The basis for the sex skew (ascertainment bias vs biological effect) is not established in the literature reviewed.

Environmental/lifestyle risk factors: None reported or plausible given the near-exclusively de novo monogenic mechanism; no gene-environment interaction data identified in the literature searched.

Protective factors: None identified; no protective variants or modifier alleles reported.

3. Phenotypes

Frequencies below are drawn primarily from the two largest published cohorts — O'Donnell-Luria et al. 2019 (n=38, PMID:31079897) and Velmans et al. 2021 (n=18, PMID:34321323) — with the 2019 truncating-variant subgroup (n=~27–30) and the 2021 cohort reported separately because ascertainment and instruments differed. A pooled table (Velmans et al.) combined both cohorts for several features.

Neurodevelopmental / cognitive

Phenotype 2019 cohort (truncating) 2021 cohort Combined (where reported) Suggested HP term
Global developmental delay Near-universal Near-universal — HP:0001263
Speech delay 75% (21/28) 94% (17/18) 83% (38/46) HP:0000750
Motor delay 67% (18/27) 72% (13/18) 69% (31/45) HP:0001270 / HP:0001263
Intellectual disability (any) 85% (17/20) / 81% (13/16 with IQ data) 50% (6/12) 72% (23/32) HP:0001249 (mild: HP:0001256)
Mean IQ (n=7, truncating subgroup) 74 (range 62–98) — — —
Autism spectrum disorder 26% (8/31) 41% (7/17) 31% (15/48) HP:0000717
Behavioral abnormalities (stereotypies, skin-picking, self-injury, aggression, anxiety) 11/29 individuals present — HP:0000733 (self-injurious behavior), HP:0000722 (aggressive behavior), HP:0000726 (anxiety)
Sleep disturbance not systematically reported 47% (8/17), incl. 30% without ASD — HP:0002360
Executive-function difficulty described qualitatively — — —

Onset is uniformly congenital/infantile — developmental delay is present from infancy in essentially all reported individuals. Mean age of independent walking and first words was 20 months (range 12–48) in the founding truncating-variant subgroup; individuals with microdeletions or missense variants had later milestones (walking 15–42 months; first words mean 34.5 months, range 18–48 for microdeletions). Almost all individuals who reach childhood achieve independent ambulation; most are verbal, though articulation problems are common (7/14 verbal individuals with articulation difficulty in the 2019 cohort).

Neurological

Phenotype Frequency Suggested HP term
Macrocephaly (≥2 SD) 55% (16–18/29–33, both cohorts consistent at ~55–56%) HP:0000256
Hypotonia 41–56% (varies by cohort: 41% 2019, 44–56% 2021) HP:0001252
Epilepsy/seizures 15–23% in truncating-variant carriers (2019: 15%, 4/26, plus 1 additional single seizure); 0% in the 2021 cohort (0/18) but 11% febrile seizures; a 2025 systematic review across the pooled literature estimates ~29% incidence HP:0001250
Epilepsy in missense-variant carriers 4/4 (100%), often infantile epileptic encephalopathy, frequently drug-resistant HP:0032792 / HP:0011097 (infantile spasms context)
Epilepsy in microdeletion carriers 3/4 (75%) HP:0001250

Where epilepsy occurs, seizure types reported include generalized tonic-clonic, tonic, atonic, myoclonic seizures, and infantile spasms, with EEG showing burst suppression, hypsarrhythmia, or background disorganization in the missense subgroup. A 2025 genotype-phenotype/systematic-review paper on ODLURO-associated epilepsy (PMID:40048818) found that of individuals on record with antiseizure medication (n=10), ~70% required ≥2 agents, and at least 5 individuals had drug-resistant epilepsy — indicating epilepsy, when present, is often clinically significant rather than a mild/self-limited feature, and treatment response is heterogeneous (contrasting with the more optimistic "responsive to treatment in almost all" characterization from the original 2019 series, which was itself based on the truncating-variant subgroup only).

Craniofacial / dysmorphic (subtle facial gestalt)

Composite Face2Gene analysis (2019 cohort, n=11) and independent description (2021 cohort) converge on: dolichocephaly, tall/large/prominent forehead, deep-set eyes, downslanting palpebral fissures, periorbital fullness, prominent/full cheeks, and prominent nasolabial folds. 2021-cohort-specific frequencies: large forehead 59% (10/17), full cheeks 53% (9/17), epicanthal folds 41% (7/17), deep-set eyes 41% (7/17). Suggested HP terms: dolichocephaly (HP:0000268), frontal bossing/prominent forehead (HP:0011220 or HP:0002007), deep-set eye (HP:0000490), downslanting palpebral fissures (HP:0000494), periorbital fullness (HP:0000629), full cheeks (HP:0000293), prominent nasolabial folds (no precise HP term identified — flag for lookup).

Gastrointestinal

Reflux, vomiting, and bowel-motility problems (constipation) are common though inconsistently quantified in the 2019 series; the 2021 cohort specifically reports constipation in 44% (8/18) vs 19% (5/27) in the original cohort — combined 29% (13/45). Suggested HP terms: gastroesophageal reflux (HP:0002020), constipation (HP:0002019), vomiting (HP:0002013), feeding difficulties in infancy (HP:0011968).

Other/rare features

Cardiac septal defects, neonatal jaundice, kyphosis, tapering fingers, cryptorchidism, hyperflexible joints — each reported in only isolated individuals, not core features.

Neuroimaging

Brain MRI is frequently normal or shows nonspecific findings. Pooled abnormalities across cohorts/reviews: corpus callosum hypoplasia/thinning/agenesis, cerebral/ventricular cysts, ventriculomegaly, delayed myelination, reduced cerebral or cerebellar volume, white-matter signal changes, basal ganglia hyperintensity, heterotopia, Chiari I malformation, and (in the epilepsy-focused 2025 review, pooling across a larger literature set) brain atrophy (3 cases), congenital cerebral malformation (3 cases), corpus callosum hypoplasia (5 cases), cysts (4 cases), normal (2 cases), delayed myelination (1 case). This is imaging-pattern description across published case reports rather than a systematically ascertained cohort, so denominators vary by report.

Quality of life

No disease-specific QoL instrument data (EQ-5D, SF-36, PROMIS) were identified in the literature searched; this is likely an evidence gap rather than a negative finding — flag as not yet studied.

Sensory

Hearing and ophthalmologic examinations were reported as normal in all tested individuals in the founding cohort; no consistent sensory phenotype.

4. Genetic / Molecular Information

Causal gene: KMT2E (HGNC:18541; OMIM *608444), chromosome 7q22.2-q22.3, encoding lysine methyltransferase 2E / MLL5 (histone-lysine N-methyltransferase 2E), a member of the KMT2 (mixed-lineage leukemia, MLL) gene family. Reference transcript NM_182931.2/.3; the encoded protein is 1,858 amino acids.

Protein domain architecture (PMID:31079897): - N-terminal PHD (plant homeodomain) zinc finger: residues ~120–165 - Central SET domain: residues ~282–445 — structurally homologous to the catalytic domain of active KMT2-family methyltransferases, but predicted (and experimentally suggested) to be catalytically inactive ("pseudo-methyltransferase") — KMT2E likely lacks intrinsic histone methyltransferase activity toward histone substrates despite SET-domain homology - Disordered C-terminus for most of the remaining protein length, with helical/strand secondary structure predicted by HMMER/PHYRE2/InterProScan modeling

Pathogenic variant spectrum: - Protein-truncating variants (predominant class): frameshift/indel (most common), nonsense, canonical and cryptic splice-site variants. Most are predicted substrates for nonsense-mediated decay (NMD); a subset of terminal-exon frameshifts (escaping NMD) were predicted in silico to create an aberrant C-terminal "homeodomain-like" fold with increased stability relative to the disordered wild-type C-terminus — a possible structural correlate for why terminal-exon truncations do not obviously differ clinically from NMD-triggering truncations (no clear genotype-phenotype split was found between NMD-predicted and NMD-escaping variants in the 2021 cohort). - Missense variants (rare, more severe phenotype): four reported in the founding cohort — c.418G>A (p.Val140Ile, PHD domain), c.850T>C (p.Tyr284His, SET domain, predicted to abolish a phosphorylation site), c.2720A>T (p.Asp907Val, non-domain region), c.4126C>T (p.Pro1376Ser, non-domain region, predicted to create a novel phosphorylation site). All four missense carriers had epilepsy, often infantile epileptic encephalopathy, more severe developmental delay, and (2/4) microcephaly rather than the typical macrocephaly — a phenotypically distinct, more severe subgroup, possibly reflecting a dominant-negative or gain-of-function mechanism rather than simple haploinsufficiency (mechanism not experimentally confirmed; stated as a hypothesis by the original authors, PMID:31079897). - Microdeletions: 7q22.2-q22.3 deletions ranging 0.052–3.2 Mb; the smallest reported deletion (52 kb) affects KMT2E alone and produces a phenotype similar to truncating point variants, supporting haploinsufficiency as the operative mechanism for the deletion/truncating-variant class. Larger deletions additionally encompass SRPK2, RINT1, LHFPL3 and are associated with more severe developmental delay (mean first words 34.5 months) — attributable at least in part to contiguous-gene effects. - Synonymous variant with cryptic splicing effect: A 2024 case report/functional study (Genes, doi:10.3390/genes15040430) describes a synonymous KMT2E variant, c.186G>A, in a patient with the ODLURO phenotype, with functional characterization supporting a splicing-disruptive mechanism (consistent with the broader observation that some apparently "silent" variants act pathogenically through cryptic splice-site creation/disruption) — I was not able to fully retrieve the primary functional assay methodology (e.g., minigene vs RNA-based confirmation) due to an access restriction on the publisher site; this should be independently verified against the primary text before citing assay-level detail.

Variant classification (ACMG/AMP): Individual variants are curated in ClinVar under the condition "O'Donnell-Luria-Rodan syndrome" (e.g., ClinVar entries for NM_182931.3(KMT2E):c.730-6_730-2del and c.3486C>G p.Tyr1162Ter). Systematic ACMG-classification statistics (e.g., % pathogenic vs likely pathogenic vs VUS across all reported variants) were not retrieved in this search pass.

Population allele frequency: Given near-complete de novo occurrence and strong purifying selection (pLI 1.0, PTV o/e 0.01), pathogenic KMT2E variants are essentially private/ultra-rare and not meaningfully represented in population databases (gnomAD, 1000 Genomes) — consistent with a severe, reproductively-limiting dominant disorder maintained almost entirely by recurrent de novo mutation rather than transmission.

Somatic vs germline: Germline (constitutional) in all reported ODLURO cases; KMT2E has separately been implicated in myeloid neoplasia (myelodysplastic syndrome) contexts as a hematopoietic regulator, but that is a distinct, non-overlapping somatic/hematologic disease association and should not be conflated with the germline neurodevelopmental phenotype (see design-decision guidance on keeping germline syndromes separate from associated somatic phenomena).

Epigenetic information: No disease-specific DNA methylation/EWAS episignature study was identified in this search (unlike, e.g., Kabuki syndrome's KMT2D episignature) — this appears to be an evidence gap rather than a confirmed negative; worth a targeted follow-up search (EpiSign/GeneDx episignature literature) before asserting absence.

Chromosomal abnormalities: 7q22.2-q22.3 microdeletions as above; no translocations, inversions, or other structural rearrangements specifically reported.

5. Environmental Information

No environmental, toxic, infectious, dietary, or lifestyle causal or risk factors are described for ODLURO in the literature reviewed — consistent with its status as an essentially fully-penetrant, de novo monogenic disorder. No CTD, TOXNET, or epidemiological gene-environment interaction data were located. This section is not populated for the underlying disease mechanism, though standard advanced-paternal-age considerations that apply generically to de novo dominant disorders may be relevant (not specifically quantified for ODLURO in the sources reviewed).

6. Mechanism / Pathophysiology

Causal chain (numbered, with confidence/inference flags)

  1. A de novo (rarely inherited) heterozygous protein-truncating variant, damaging missense variant, or a microdeletion arises in KMT2E on 7q22.2-q22.3. (Demonstrated — genetic ascertainment across cohorts, PMID:31079897, 34321323.)
  2. For truncating variants and microdeletions, this leads to reduced dosage of functional MLL5/KMT2E protein from the affected allele — either via nonsense-mediated decay of the truncated transcript or via physical loss of one gene copy — resulting in haploinsufficiency, i.e., insufficient total MLL5 protein from the single remaining wild-type allele to sustain normal function. (Inferred from convergent phenotype between truncating-variant and microdeletion carriers, plus the pLI=1.0/PTV o/e=0.01 constraint signature and ClinGen's independent "Sufficient Evidence for Haploinsufficiency" (score 3) dosage curation — a well-supported but formally indirect line of evidence, since no direct protein-quantification study in patient tissue was identified.)
  3. For the rare missense variants (PHD- and SET-domain-affecting, plus two variants outside annotated domains), the mechanism may instead involve a dominant-negative or altered-function effect rather than simple haploinsufficiency, given that these carriers show a phenotypically distinct and more severe presentation (infantile epileptic encephalopathy, microcephaly) than truncating-variant/deletion carriers. (Explicitly flagged as hypothesis-level, not proven, by the original authors, PMID:31079897 — this is an unresolved mechanistic question, not an established fact.)
  4. MLL5/KMT2E, despite SET-domain homology to catalytically active KMT2-family histone methyltransferases, appears to lack intrinsic histone methyltransferase activity ("pseudo-methyltransferase"). Instead, MLL5 binds H3K4me3-marked promoter chromatin via mechanisms involving its PHD finger and functions as a transcriptional/chromatin co-regulator rather than as the enzyme that writes the H3K4me3 mark itself. (Established biochemical characterization in the broader KMT2E/MLL5 structure-function literature — Springer 2017 review PMID:28188343 — generalized to, but not specifically re-derived in, the ODLURO cohort papers.)
  5. MLL5 forms a complex with host cell factor C1 (HCFC1) and O-GlcNAc transferase (OGT), which is recruited to E2F1-responsive gene promoters, driving transcriptional activation at the G1/S cell-cycle transition and contributing to genomic-stability maintenance through the G2/M transition and mitotic spindle integrity. (Established cell-biology literature on MLL5 function, largely from non-neuronal/hematopoietic systems — extrapolated to neurodevelopmental context by the disease-cohort authors rather than directly demonstrated in human neurons.)
  6. Reduced or altered MLL5 activity is proposed to disrupt normal transcriptional programs during nervous system development, particularly given evidence that KMT2E is highly expressed in fetal brain. (Plausible inference bridging cell-biology data to neurodevelopmental phenotype; not directly demonstrated via patient-neuron transcriptomics — no iPSC-neuron or patient-fibroblast RNA-seq study was identified in the cohort literature reviewed.)
  7. In a Kmt2e+/− mouse model, this haploinsufficiency produces amygdala-selective neurodevelopmental abnormality: decreased relative amygdala glycometabolism on ¹⁸F-FDG-PET imaging, together with increased numbers and soma size of amygdala neurons, leading to social-behavior deficits and anxiety-like behavior — an ASD-relevant behavioral phenotype in the animal model paralleling the human autism association. (Direct experimental animal-model evidence, PMID:36534336 — the clearest mechanistic link in the literature reviewed between Kmt2e dosage and a specific brain region/behavioral output; note this is a mouse model, and translational fidelity to the specific human clinical phenotype has not been independently assessed — flagged as a HUMAN_MODEL_MISMATCH-type consideration for KB curation rather than a demonstrated human mechanism.)
  8. Separately, in hematopoietic/non-neuronal systems, Kmt2e-deficient mouse models show growth restriction, increased mortality, impaired hematopoiesis, and elevated DNA damage/reactive oxygen species (ROS) — reversible with N-acetylcysteine antioxidant supplementation in that model system. (PMID:31079897, citing earlier hematopoiesis-focused Kmt2e mouse literature — this pathway has not been shown to operate in neurons or to explain the neurodevelopmental phenotype; the original ODLURO authors raise it only as a speculative rationale for a possible future antioxidant-biomarker/therapeutic angle, explicitly requiring clinical validation, not as an established human disease mechanism.)
  9. The composite of impaired neurodevelopmental gene transcription (from #6) and amygdala-specific structural/metabolic changes (from #7) culminates in the clinical syndrome: global developmental delay, intellectual disability, macrocephaly, hypotonia, autism-spectrum features, and (in a subset, more severely with missense variants) epilepsy/epileptic encephalopathy.

Molecular pathways

Chromatin regulation / H3K4 methylation pathway (KMT2/COMPASS-family, though KMT2E itself is enzymatically atypical); E2F1 cell-cycle transcriptional pathway (G1/S checkpoint); HCFC1–OGT transcriptional co-regulator complex. Suggested GO terms: histone H3-K4 methylation (GO:0051568), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of cell cycle G1/S phase transition (GO:2000045), DNA damage response (GO:0006974).

Cellular processes

Cell-cycle progression (G1/S and G2/M transitions), maintenance of genomic/chromosomal stability, mitotic spindle integrity, neuronal differentiation/development (inferred), amygdala neuron proliferation/soma growth (mouse model — direction of effect was increased neuron number/soma size in the haploinsufficient state, notably not simple loss of neurons).

Protein dysfunction

Loss of one functional MLL5 allele (haploinsufficiency) for truncating/deletion variants; possible altered-function/dominant-negative effect for domain-disrupting missense variants (unconfirmed mechanism).

Tissue/cell involvement

Cerebral cortex and amygdala are the principal implicated CNS structures (mouse model + human neuroimaging correlate of corpus callosum/white matter/ventricular findings). Suggested CL term: neuron (CL:0000540); no KMT2E-specific neuronal subtype marker was identified. Suggested UBERON terms: amygdala (UBERON:0001876), corpus callosum (UBERON:0002336), cerebral cortex (UBERON:0000956), cerebellum (UBERON:0002037).

Molecular profiling / advanced technologies

No transcriptomic (RNA-seq/GEO), proteomic, metabolomic, single-cell, or spatial-transcriptomic dataset specific to ODLURO patient tissue was identified in this search. The ¹⁸F-FDG-PET amygdala-glycometabolism data from the mouse model (PMID:36534336) is the only "molecular imaging"-type dataset located. This is a notable evidence gap relative to other KMT2-family disorders (e.g., Kabuki syndrome/KMT2D has an established peripheral-blood DNA-methylation episignature; no equivalent was found for KMT2E).

7. Anatomical Structures Affected

Organ level: - Primary: central nervous system (brain — cerebral cortex, corpus callosum, amygdala, cerebellum, ventricular system, white matter) - Secondary: gastrointestinal tract (functional — reflux, motility/constipation); skeletal system (rare — kyphosis, tapering fingers); cardiovascular (rare — septal defects); genitourinary (rare — cryptorchidism) - Body systems: nervous system (primary), digestive system, musculoskeletal system, and rarely cardiovascular and genitourinary systems

Tissue/cell level: Cerebral cortical neurons and amygdala neurons are the specific cell population implicated by the mouse model (increased neuron number and soma size in Kmt2e+/− amygdala). No human neuropathology/biopsy data exist (as expected for a neurodevelopmental, non-degenerative, non-biopsied disorder).

Subcellular level: Nucleus/chromatin — MLL5 is a chromatin-associated transcriptional regulator acting at H3K4me3-marked promoter regions. Suggested GO Cellular Component term: nucleus (GO:0005634), nuclear chromatin (GO:0000790).

Localization: Bilateral, non-lateralized — the amygdala finding in the mouse model was described as a whole-structure/bilateral metabolic change; no laterality pattern reported in human neuroimaging.

8. Temporal Development

Onset: Congenital/infantile-onset — developmental delay is evident from infancy in essentially all affected individuals; there is no adult-onset or late-onset presentation described. Onset pattern is insidious/developmental (progressive delay relative to peers becoming apparent through infancy and early childhood) rather than acute.

Progression: The disorder is best characterized as a static-to-mildly-progressive neurodevelopmental disorder rather than a degenerative one — affected individuals continue to gain skills (most achieve independent walking and verbal speech, albeit delayed) rather than losing previously acquired abilities, with the exception of rare reported speech regression in a subset. No formal staging system exists. Disease course is chronic/lifelong; there is no described remission of the core neurodevelopmental phenotype. Epilepsy, when present, follows its own variable course (from treatment-responsive to drug-resistant, per the 2025 systematic review, PMID:40048818) and can be episodic/relapsing rather than following the same static trajectory as the developmental phenotype.

Critical periods: Fetal/early postnatal brain development is implicated as the critical vulnerability window, based on high fetal-brain expression of KMT2E and the cell-cycle/chromatin regulatory role of MLL5 during neurogenesis; there is no established therapeutic window distinct from standard early-intervention timing for developmental disorders generally.

9. Inheritance and Population

Epidemiology: No formal population-based prevalence or incidence estimate (cases per 100,000) was identified in the literature searched — appropriate given ODLURO's status as a recently delineated (2019), likely under-ascertained condition. Cohort growth (38 individuals in 2019 → >60 within 2 years → >120 individuals reported by 2025 per a Wikipedia-sourced tertiary summary, not independently verified against a primary source) has led multiple authors (notably Velmans et al., PMID:34321323) to argue that ODLURO is "an unexpectedly high relative frequency…among the more common single-gene aetiologies of neurodevelopmental delay and ASD," with an explicit recommendation that KMT2E be included in routine developmental-delay/ID/ASD gene panels — but this remains a qualitative impression from clinical-ascertainment cohorts, not a quantified population prevalence/incidence figure, and should be curated as prevalence_class: NOT_YET_DOCUMENTED or similar pending a real denominator-based estimate.

Inheritance pattern: Autosomal dominant, with the overwhelming majority of cases arising de novo (see Etiology, above). Two multiplex families are documented: three affected male siblings (paternal mosaicism status unresolved, 2019 cohort) and a sibling pair with paternal transmission (2021 cohort), plus one additional unrelated paternally-inherited case.

Penetrance: Reported as apparently high/complete for the core neurodevelopmental phenotype among identified carriers, though formal penetrance estimation (e.g., via large unselected population cohorts) has not been performed — as is typical for a recently described, clinically-ascertained dominant disorder.

Expressivity: Markedly variable — this is one of the syndrome's defining features. Severity ranges from mild developmental/speech delay with normal-range cognition to moderate intellectual disability with autism and drug-resistant infantile epileptic encephalopathy, correlating in part with variant class (truncating/deletion = generally milder; missense = more severe, per the 2019 cohort) though the 2025 genotype-phenotype/epilepsy review notes that even individuals sharing the identical KMT2E variant can show divergent phenotypes, indicating expressivity is not fully explained by variant type alone.

Genetic anticipation: Not applicable/not reported — ODLURO is not a repeat-expansion disorder.

Germline mosaicism: Not formally quantified but clinically relevant, given the multiplex sibling families described above with presumed unaffected or mosaic parents; standard recurrence-risk counseling for germline mosaicism (empiric low-single-digit-percent recurrence risk, as for other de novo dominant NDDs) would apply, though ODLURO-specific recurrence-risk data were not located.

Founder effects: None reported — variants are private/family-specific, consistent with the essentially de novo mutational mechanism.

Consanguinity: Not a relevant risk factor for this autosomal dominant, de novo-predominant disorder.

Carrier frequency: Not applicable in the traditional (autosomal recessive) sense; population allele frequency of pathogenic variants is essentially zero given strong purifying selection (see Etiology).

Population demographics: - Sex ratio: Strong male excess across both major cohorts (73–78% male) — see Etiology section for statistical detail and caveats about ascertainment vs. biological explanation. - Ethnic/geographic distribution: Both major cohorts were explicitly multinational (assembled via Matchmaker Exchange and international collaboration), and no specific ethnic or geographic enrichment/founder population has been reported. No population-specific variant clustering identified. - Age distribution: Cohorts span early childhood through adolescence (2021 cohort ages 1–16 years); no adult-ascertained cohort or aging-population data were identified, which likely reflects the recency of syndrome delineation (2019) rather than a true absence of adult-affected individuals.

10. Diagnostics

Genetic testing (primary diagnostic modality): - First-tier per GeneReviews (PMID:38648332) and Wikipedia tertiary summary corroborating it: chromosomal microarray (SNP array or oligonucleotide-based CGH) to detect 7q22.2-q22.3 microdeletions. - If microarray non-diagnostic: an intellectual-disability/multigene NDD panel that includes KMT2E, or comprehensive genomic testing (exome or genome sequencing). Exome sequencing is currently the most commonly employed comprehensive approach in the literature; genome sequencing is noted as additionally capable of detecting noncoding/regulatory and splicing variants and structural variants missed by exome sequencing (e.g., the cryptic-splice-site and synonymous-splicing-disruptive variants described above would specifically benefit from RNA-level or genome-level analysis). - Variant interpretation: De novo status confirmation via parental (trio) testing is central to establishing pathogenicity, particularly for VUS-level findings, given the disorder's predominantly de novo mechanism.

No disease-specific biochemical, enzymatic, or biomarker laboratory test exists — ODLURO is not a metabolic disorder, and no circulating biomarker (protein, metabolite) has been validated. The single speculative candidate mentioned in the literature (urine F2-isoprostane and blood glutathione as oxidative-stress markers, extrapolated from the hematopoietic mouse-model ROS finding) is explicitly framed by the original authors as unvalidated and requiring clinical study — it is not a diagnostic test in current use.

Neuroimaging: Brain MRI is a standard part of the diagnostic/clinical workup once a genetic diagnosis is suspected or confirmed, useful for characterizing (though not specific/diagnostic for) the condition — findings as detailed in Section 3 (often normal; when abnormal, most commonly corpus callosum hypoplasia, cysts, delayed myelination, ventriculomegaly).

Electrophysiology: EEG is indicated when seizures are suspected clinically, given the significant minority with epilepsy (especially relevant to exclude/characterize infantile epileptic encephalopathy in missense-variant carriers).

Clinical diagnostic criteria: No formal consensus clinical diagnostic criteria exist (no equivalent of, e.g., Kabuki syndrome's clinical scoring system was identified). Diagnosis is made on the basis of a qualifying pathogenic/likely pathogenic KMT2E variant (or qualifying microdeletion) in an individual with a consistent clinical picture.

Differential diagnosis: GeneReviews and secondary sources note phenotypic overlap with other genetic syndromes causing developmental delay/intellectual disability with subtle dysmorphism, specifically naming Kabuki syndrome and Wiedemann-Steiner syndrome as conditions with overlapping clinical findings (per the Wikipedia tertiary summary, sourced to the GeneReviews chapter, though I was not able to directly access the GeneReviews differential-diagnosis table text due to access restrictions — this specific claim should be re-verified against the primary GeneReviews source, PMID:38648332, before being asserted as DIRECT evidence in a KB entry). No specific overlap with Cornelia de Lange syndrome was substantiated in the sources retrieved (a search targeting that comparison returned no supporting content).

Screening: No population newborn-screening or carrier-screening program applies (not a metabolic/recessive disorder amenable to such screening). Standard prenatal counseling applies once a familial variant is known (e.g., for the rare inherited/multiplex-sibling scenario), including consideration of parental testing for germline mosaicism.

11. Outcome / Prognosis

Survival/mortality: No mortality data or life-expectancy figures specific to ODLURO were identified — the disorder is not described in the literature as life-limiting, and no deaths have been reported in the cohorts reviewed. This should be treated as an evidence gap (no data located) rather than a confirmed "normal life expectancy" claim, since no dedicated natural-history/longitudinal-survival study was found.

Morbidity/function: Nearly all affected individuals who reach childhood achieve independent ambulation and (with speech delay) verbal communication, indicating a generally favorable functional trajectory relative to more severe neurodevelopmental syndromes, though intellectual disability (typically mild-to-moderate, pooled cohort rate 72%) and, in a subset, drug-resistant epilepsy represent the principal sources of long-term morbidity. Executive-function difficulties (flexible thinking, working memory) are described qualitatively as prevalent but not quantified.

Quality of life: No validated QoL instrument data located (see Section 3) — an evidence gap.

Complications: Feeding difficulties sometimes progressing to need for gastrostomy tube placement (per GeneReviews/secondary-source management guidance); drug-resistant epilepsy in the missense-variant/more-severe subgroup (up to ~70% of medicated individuals in the 2025 review requiring ≥2 antiseizure medications, ≥5 individuals drug-resistant).

Recovery potential: Developmental gains continue over time in the majority (no degenerative course); speech regression is described as a rare exception rather than the norm.

Prognostic factors: Variant class is the clearest prognostic correlate identified — missense variants (particularly SET/PHD-domain) are associated with more severe developmental delay, microcephaly (rather than the typical macrocephaly), and treatment-resistant infantile epileptic encephalopathy; truncating variants and the smallest microdeletions are associated with a milder, though still variable, phenotype. However, the 2025 genotype-phenotype epilepsy review explicitly notes that "a clear genotype-phenotype correlation remains elusive even among individuals with the same KMT2E variation" (PMID:40048818) — so variant class should be treated as a probabilistic/partial prognostic signal, not a deterministic one.

12. Treatment

There is no disease-modifying or curative therapy for ODLURO. Management is entirely supportive/symptomatic, per GeneReviews (PMID:38648332) and corroborating secondary sources:

Developmental/supportive care: - Early intervention services, special education - Physical therapy (motor skills) — NCIT:C15302 - Occupational therapy (daily functioning) — NCIT:C121351 (Occupational Therapy) or NCIT:C15746-type intervention term - Speech-language therapy — NCIT:C159273 - Periodic monitoring of head circumference and developmental milestones - Gastrostomy tube placement for persistent/severe feeding difficulty — NCIT:C116617-type procedure term (verify exact NCIT code at curation time)

Seizure management (for the subset with epilepsy): - EEG and brain MRI evaluation when seizures are suspected - Individualized antiseizure medication selection based on seizure type/severity — NCIT:C15986 (Pharmacotherapy), with no single first-line agent established specifically for ODLURO; the 2025 review's finding that ~70% of medicated individuals required polytherapy underscores that this is often a difficult-to-control epilepsy requiring individualized, multidisciplinary epileptology input rather than a standard algorithm. - Ketogenic diet was tried in at least one reported missense-variant case with infantile epileptic encephalopathy but was reported as ineffective in that instance (PMID:31079897) — a single-case negative result, not generalizable evidence of futility.

Multidisciplinary/psychosocial care: Medical genetics, developmental pediatrics, neurology, genetic counseling (risk assessment, family planning, prenatal testing discussion for known-variant families), and — for more severely affected individuals — palliative care/social work support.

Experimental/investigational — antisense oligonucleotide (ASO) strategies (preclinical/conceptual stage only): A 2024–2025 treatability-landscape review specifically addressing KMT2-family disorders (PMID for the PMC11925151 article not independently confirmed in this pass — verify before citing) outlines several conceptual, not yet preclinically validated, ASO-based strategies premised on the haploinsufficiency mechanism (goal: increase wild-type protein output from the remaining allele or correct/skip a specific mutant transcript): 1. Variant-specific exon skipping (e.g., targeting exon 15 to restore reading frame for a specific frameshift variant, c.1646_1650del/p.Ile549fs) — patient-specific, N-of-1-style approach. 2. Targeting a "poison exon" in intron 21 whose inclusion is non-productive, to increase canonical-transcript output — proposed as a more generalizable approach applicable across multiple patients (rather than variant-specific). 3. Modulating an identified upstream open reading frame (uORF) in the KMT2E 5′ UTR via steric-blocking ASOs, to relieve uORF-mediated translational repression of the main protein-coding ORF and thereby increase wild-type protein levels. 4. Targeting the naturally occurring antisense transcript KMT2E-AS1, though this requires further functional characterization before it can be considered an actionable target.

The review explicitly states that no preclinical data or ASO treatments are currently under development for KMT2E-associated disorders — these are proposed strategies grounded in the general ASO-therapeutics toolkit and the confirmed haploinsufficiency mechanism, not validated interventions. This should be curated as a PROPOSED/conceptual therapeutic-strategy discussion, not an active clinical or even preclinical program.

No clinical trials (NCT-registered) specific to ODLURO/KMT2E were identified in this search pass.

No gene therapy, cell therapy, targeted small-molecule, or immunotherapy approach has been reported for this condition.

13. Prevention

No primary, secondary, or tertiary prevention strategy exists for ODLURO beyond standard reproductive/genetic counseling, since the disorder is predominantly caused by de novo mutation (not currently preventable) rather than inherited from a carrier population amenable to carrier screening. For the minority of familial (inherited or mosaic-parent) cases, genetic counseling covering recurrence risk (including empiric germline-mosaicism risk), prenatal diagnosis, and preimplantation genetic testing options for known-familial variants is the applicable "prevention" modality — standard practice for autosomal dominant NDDs generally, not ODLURO-specific guidance. No population-level screening program (newborn or carrier) applies, and no immunization, environmental, or public-health intervention is relevant given the monogenic, non-environmental disease mechanism.

14. Other Species / Natural Disease

No naturally occurring ODLURO-like disease has been reported in non-human species (companion animals, wildlife) in the literature searched — I found no OMIA (Online Mendelian Inheritance in Animals) entry or veterinary case series for KMT2E/Kmt2e orthologs. This should be treated as "not identified in this search," not a confirmed absence.

Orthologous gene: Mouse Kmt2e (MGI symbol; allele Kmt2e^tm1Apa^, MGI:3835772, used in the hematopoiesis/ROS studies cited in Section 6/12) is the principal model-organism ortholog used experimentally. No zebrafish, Drosophila, or C. elegans ortholog-based disease model was identified in this search.

Comparative biology: The KMT2/MLL gene family (KMT2A–KMT2F) is broadly conserved across vertebrates and is functionally implicated in a cluster of related human neurodevelopmental disorders (Wiedemann-Steiner syndrome/KMT2A, Kabuki syndrome/KMT2D), reflecting evolutionary conservation of chromatin-regulatory mechanisms in neurodevelopment — but KMT2E is functionally distinct within the family (pseudo-methyltransferase, non-catalytic chromatin reader/co-regulator) rather than a directly redundant paralog, so mechanistic conclusions from KMT2A/KMT2D disorders should not be assumed to transfer directly to KMT2E/ODLURO.

Zoonotic/transmission potential: Not applicable — a non-communicable monogenic disorder.

15. Model Organisms

Mouse — germline heterozygous knockout (Kmt2e+/−): - Model type: Genetic (constitutive heterozygous knockout), mammalian, whole-organism. - Phenotype recapitulation: Kmt2e+/− mice show social-interaction deficits and anxiety-like behavior on standardized behavioral assays, together with decreased relative amygdala glycometabolism on whole-brain ¹⁸F-FDG-PET imaging and increased numbers and soma size of amygdala neurons, relative to wild-type littermates (PMID:36534336). This is presented by the authors as supporting a causative role for KMT2E haploinsufficiency in ASD-relevant behavior, with amygdala neurodevelopmental abnormality proposed as a major underlying mechanism. - Model limitations: This model recapitulates an ASD-relevant behavioral/imaging phenotype but has not been reported to reproduce the broader human ODLURO syndrome (developmental delay/intellectual-disability-equivalent measures, epilepsy, macrocephaly, dysmorphic features, or GI symptoms) — translational fidelity for those additional core human features is unestablished. The direction of the amygdala neuron finding (increased number/soma size, rather than a loss-of-neurons/atrophy pattern) is a specific and somewhat counterintuitive structural correlate worth flagging precisely rather than generalizing to "neurodegeneration." - Research applications: Used to probe ASD-relevant circuit-level (amygdala) and behavioral consequences of Kmt2e dosage reduction; a plausible platform for future preclinical testing of the ASO strategies outlined in Section 12, though no such testing has yet been reported.

Mouse — hematopoiesis-focused Kmt2e-deficient models (both homozygous and heterozygous): - Phenotype: Growth restriction, increased mortality, impaired hematopoiesis, elevated DNA damage and reactive oxygen species (ROS), reversible with N-acetylcysteine (CHEBI:28939) supplementation (cited in PMID:31079897, referencing earlier hematopoiesis-focused literature). - Limitations: No neurological/behavioral phenotype was reported in these earlier hematopoiesis-focused models — i.e., this line of evidence establishes a non-neuronal Kmt2e loss-of-function phenotype (relevant to KMT2E's separately described role in myeloid biology) but does not itself demonstrate a brain phenotype; it is cited by the ODLURO discovery paper only as indirect/speculative support for a possible oxidative-stress axis, not as a validated model of the neurodevelopmental disorder.

Cellular/in vitro models: No patient-derived iPSC, fibroblast, or organoid model specific to ODLURO/KMT2E was identified in this search — a further evidence gap relative to better-resourced neurodevelopmental-disorder genes.

Resources: MGI (Mouse Genome Informatics) hosts the Kmt2e^tm1Apa^ allele record (MGI:3835772); no ZFIN, FlyBase, WormBase, or IMSR-cataloged model was located.

Summary of Notable Evidence Gaps (flagged for curator follow-up rather than asserted as fact)

  1. No confirmed Orphanet (ORPHA) identifier was located — needs direct Orphanet lookup.
  2. No population-based prevalence/incidence figure exists; only qualitative "more common than previously appreciated" cohort-growth framing (prevalence_class: NOT_YET_DOCUMENTED is the honest curation state).
  3. No validated biomarker, EWAS/episignature, or patient-derived cellular/omics dataset was located for KMT2E — contrasts with sibling KMT2-family disorders.
  4. Differential-diagnosis overlap with Kabuki and Wiedemann-Steiner syndromes was sourced only via a tertiary (Wikipedia) summary attributed to GeneReviews; the primary GeneReviews differential-diagnosis text (PMID:38648332) could not be directly accessed in this session (CAPTCHA-blocked) and should be independently re-verified before quoting.
  5. The synonymous-variant splicing functional study (Genes 2024, doi:10.3390/genes15040430) could not be fully retrieved (publisher access blocked) — assay-level detail should be confirmed from the primary text.
  6. Missense-variant dominant-negative/gain-of-function mechanism is explicitly hypothesis-level in the primary literature, not proven — should not be curated as a DIRECT mechanistic claim.
  7. Mouse amygdala model is ASD-behavior/circuit-specific and does not model the full human syndrome — a HUMAN_MODEL_MISMATCH-flavored caveat, not a general-purpose disease model.
  8. Two PMC/PMID numbers for secondary papers (the ASO-treatability review, and the 2024 novel-cohort ScienceDirect paper) were identified via search-result triangulation but full-text access was blocked in this session (403/CAPTCHA); their PMIDs and exact quotable content should be re-confirmed via just fetch-reference at curation time rather than trusted from this report's paraphrase alone.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 11
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 11
On topic 10
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 48
Resolved 44
Unresolved (possible confabulation) 0
Obsolete 2
Unverifiable 2
Terms whose name was checked 5
Terms named correctly 2
Terms named as a different term 3

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:

  • MONDO:0032793 (4 mentions) - the report calls it "if available", "MONDO", "Monarch Initiative"; MONDO calls it O'Donnell-Luria-Rodan syndrome
  • HP:0000256 (1 mention) - the report calls it "55% (16–18/29–33, both cohorts consistent at ~55–56%)"; HP calls it Macrocephaly
  • HP:0001252 (1 mention) - the report calls it "41–56% (varies by cohort: 41% 2019, 44–56% 2021)"; HP calls it Hypotonia

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:0051568 (obsolete histone H3-K4 methylation) (1 mention)
  • GO:0000790 (GO_0000790) (1 mention) - replaced by GO:0000785

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0032793 - called "if available", "MONDO", "Monarch Initiative"

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: MGI.