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

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

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

• O'Donnell-Luria A, et al. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy. Am J Hum Genet. 2019;104(6):1210-1222. PMID:31079897 / PMC full text
• Velmans C, O'Donnell-Luria A, et al. O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum. J Med Genet. 2021;59(7):697-705. PMID:34321323 / PMC full text
• Pais LS, Rodan LH, O'Donnell-Luria A. KMT2E-Related Neurodevelopmental Disorder. GeneReviews. 2024. PMID:38648332
• O'DONNELL-LURIA-RODAN SYNDROME; ODLURO — OMIM #618512
• KMT2E gene — OMIM *608444
• O'Donnell-Luria-Rodan syndrome — MONDO:0032793 (Monarch Initiative)
• KMT2E gene-disease validity and dosage sensitivity curation — ClinGen
• Li et al. KMT2E Haploinsufficiency Manifests Autism-Like Behaviors and Amygdala Neuronal Development Dysfunction in Mice. Mol Neurobiol. 2023. PMID:36534336
• Genotype-phenotype correlation of ODLURO syndrome comorbid epilepsy associated with KMT2E variations: report on a novel case and systematic literature review. Epilepsy Behav. 2025. PMID:40048818
• Molecular and clinical Insights into KMT2E-Related O'Donnell-Luria-Rodan syndrome in a novel patient cohort. PMID:39709003
• Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments
• Phenotypic Description of A Patient with ODLURO Syndrome and Functional Characterization of a Synonymous Variant c.186G>A in KMT2E. Genes. 2024;15(4):430
• Weirauch/Vora et al. MLL5 (KMT2E): structure, function, and clinical relevance. Cell Mol Life Sci. 2017. PMID:28188343
• O'Donnell-Luria–Rodan syndrome — Wikipedia (tertiary summary, cross-checked against primary sources above where possible)
• Kmt2e^tm1Apa^ allele — Mouse Genome Informatics, MGI:3835772

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

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

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.