El Hayek-Chahrour Neurodevelopmental Disorder (NEDEHC; KDM5A-related neurodevelopmental disorder): Research Report

Prepared: 2026-10-14 · MONDO: MONDO:0970951 · OMIM: #620820 · Gene: KDM5A (12p13.33)

Scope and source basis

Three primary papers from one group, the Chahrour laboratory at UT Southwestern, define what is known about this ultra-rare disorder:

In this report: - Quotes marked [abstract] come from the abstract. - Quotes marked [full text] come from the PMC full text cached in the repository (references_cache/). - No GeneReviews chapter, Orphanet record, natural-history study, clinical guideline or clinical trial was found. - The OLS and PubMed MCP connectors were not authorised in this session. Ontology IDs below are leads to verify with runoak/OLS before binding, not looked-up values.

1. Disease information

Overview. NEDEHC is a Mendelian neurodevelopmental chromatinopathy caused by germline variants in KDM5A. It can be inherited in either of two ways: - Monoallelic: de novo, or inherited dominant. - Biallelic: homozygous or compound heterozygous.

KDM5A encodes lysine-specific demethylase 5A (JARID1A/RBP2), which removes methyl groups from H3K4me2/3. The core clinical picture is: - severe speech impairment, often with no speech at all; - intellectual disability or global developmental delay; - autism spectrum disorder (ASD).

Variable additional features include hypotonia, seizures, feeding difficulties, sleep disturbance, joint hypermobility, facial dysmorphism, cardiac septal defects and structural brain abnormalities.

• OMIM/MedGen defines it as "characterized by absent speech, impaired intellectual development, and autism" (MedGen C5935620).
• PMID:41889174 [abstract]: "All individuals presented with severe speech impairment and intellectual disability, often alongside ASD and other neurodevelopmental features."

Identifiers

Synonyms: El Hayek-Chahrour neurodevelopmental syndrome; neurodevelopmental disorder with absent speech, impaired intellectual development, and autism; NEDEHC; KDM5A-related neurodevelopmental disorder.

Data provenance. All data are aggregated case series assembled through international collaboration (GeneMatcher-style matchmaking, the CAUSES study, and clinical exome and microarray cohorts). No EHR-level data exist.

Gene–disease curation status - Genomics England PanelApp: Intellectual Disability panel Green, "BOTH monoallelic and biallelic, autosomal or pseudoautosomal"; Fetal Anomalies panel Amber; DDG2P Red (biallelic, "autosomal recessive mental retardation") (PanelApp). - PanelApp Australia: lists KDM5A on its ID panel (PanelApp-AUS). - ClinGen: no gene–disease validity classification was found. Check cache/clingen/ and just list-gene-validity before recording a tier.

2. Etiology

Cause. The disorder is purely genetic: pathogenic germline KDM5A variants. No environmental or infectious component has been described.

PMID:41889174 [full text]: "In conclusion, both monoallelic and biallelic KDM5A variants cause a neurodevelopmental disorder characterized by ASD, severe speech abnormalities, developmental delay, and intellectual disability."

Genetic risk factors - Consanguinity: many of the biallelic families come from Iran, Saudi Arabia, Egypt and Kuwait. - A parent carrying a heterozygous variant: several monoallelic variants were inherited from parents described as mildly affected or unaffected, which raises the question of incomplete penetrance (see §9).

Protective factors, modifiers, gene–environment interactions: none reported.

Historical antecedent. One homozygous KDM5A missense family was reported in the Najmabadi et al. 2011 autosomal-recessive intellectual disability screen (Nature; PMID:21937992 — verify the PMID).

PMID:33350388 [full text]: "To date only a single recessive missense variant in KDM5A has been reported to be associated with an undefined developmental disorder (intellectual disability and facial dysmorphisms) in one family (Najmabadi et al."

3. Phenotypes

Counting basis. Frequencies combine the 2020 cohort (n = 9) and the 2026 cohort (n = 24); the denominator is about 33 individuals. The 2026 cohort figures are counted from the published Table 1, split by monoallelic (n = 11–12 evaluable) and biallelic (n = 13) groups. Counts are approximate where the table reports "UK" (unknown) or "N/A".

Supporting quotes (PMID:41889174 [full text]) - "Additional phenotypes included autistic features, developmental delay, intellectual disability, muscle hypotonia, seizures, and cardiac abnormalities" - "Additional shared phenotypes included developmental delay (five individuals), feeding difficulties (five individuals), intellectual disability (four individuals), and sleep disturbances (four individuals)." - "The condition is often accompanied by comorbidities, including intellectual disability, developmental delay, motor impairments, and seizures."

Genotype–phenotype trend (observed in this report, not stated by the authors). Biallelic individuals in Table 1 appear to have more seizures, hypotonia, structural brain MRI abnormalities and non-ambulation. The authors do not formally state this, so record it as an observation rather than a curated claim.

Severity, course and quality of life - Severity: moderate to severe. - Course: static neurodevelopmental. No regression is reported. - Burden: lifelong dependence driven mainly by absent speech and intellectual disability. - No QoL instrument data exist.

4. Genetic and molecular information

Gene. KDM5A (JARID1A, RBP2). Transcript NM_001042603. Protein of 1,690 aa.

Domain map (PMID:41889174 [full text]):

• The catalytic core is JmjN plus JmjC (Fe(II)/2-oxoglutarate dependent).
• PHD1 binds unmodified H3K4 and stimulates catalytic activity.
• PHD3 binds H3K4me2/3.

Variant spectrum - Across both cohorts there are 31 unique, all private variants in 33 individuals from 28 families: missense, nonsense, frameshift, splice-site, and multi-exon deletions of 4 and 10 exons. - 2020 cohort (PMID:33350388) [full text]: "Three individuals carried homozygous deletions removing four exons (in two individuals) or ten exons (in one individual) of KDM5A, three individuals carried homozygous recessive variants (two splice site and one missense), and the remaining three individuals were heterozygous for de novo variants (two missense and one nonsense)" - 2026 cohort (PMID:41889174) [full text]: "There were 12 individuals with biallelic variants and 12 individuals with monoallelic variants". Of these, 7 were de novo, 13 inherited, and 4 of unknown inheritance. - Location in the protein (2026 cohort): JmjC 1, JmjN 1, PHD1 1, PHD3 1, PLU1 7, inter-domain 13. PLU1 is a clear cluster. - Recurrence: PMID:41889174 [full text]: "Importantly, all 31 unique variants identified to date are private, with no recurrent alleles observed across unrelated individuals."

Classification. PMID:41889174 [abstract]: "American College of Medical Genetics and Genomics-guided reclassification supported pathogenicity for the majority of variants, including multiple upgrades from uncertain significance to pathogenic or likely pathogenic."

Functional consequence - Loss of function / reduced dosage. PMID:41889174 [abstract]: "For a subset of variants, we demonstrated reduced KDM5A protein levels in cell lines derived from affected individuals." - Domain disruption without protein loss is also proposed. PMID:41889174 [full text]: "While variants in the JmjC domain can impair its demethylase function, variants in other domains may disrupt non-enzymatic functions, such as chromatin positioning or interactions with regulatory complexes, leading to equally severe phenotypes."

Origin, population frequency and other genomic features - Origin: germline only. No somatic mosaic cases are reported. - Population frequency: variants are absent or ultra-rare in gnomAD, per the cohort filtering criteria. - Modifier genes, epigenetic signatures and chromosomal rearrangements: none described. - Episignature: no DNA-methylation episignature has been reported, unlike KDM5C and other chromatinopathies. This is a gap. - Microdeletions: some biallelic alleles are intragenic CNVs found by read-depth or split-read analysis, so CNV-aware analysis matters (see §10). - Nearby locus: KDM5A sits at the 12p13.33 subtelomere, near the CACNA1C/ERC1 region. No reports of contiguous-gene syndromes involving KDM5A were found.

5. Environmental information

None. No environmental, lifestyle or infectious factors apply.

6. Mechanism and pathophysiology

Ordered causal chain

1. Initiating lesion. Germline KDM5A variants occur in one of two configurations:
2. Monoallelic: de novo or inherited missense or truncating variants.
3. Biallelic: multi-exon deletions, splice, frameshift, nonsense or missense variants.

These lead to → 2. Reduced KDM5A protein or a domain-specific functional defect. Patient lymphoblastoid cell lines (LCLs) show reduced protein for a subset of variants; JmjC, PLU1 and PHD variants are predicted to disrupt catalysis or chromatin binding. This is demonstrated in LCLs and inferred from structural modelling for the rest. It results in → 3. Altered H3K4me2/3 demethylation at KDM5A target promoters and enhancers. This step is inferred: no patient or mouse H3K4me3 ChIP data are cited in these papers. It leads to → 4. Dysregulated transcription. - Patient LCL RNA-seq shows variant-specific expression changes, worst for PLU1, then JmjC, then inter-domain variants. - Mouse Kdm5a⁻/⁻ hippocampus has 450 differentially expressed genes, including ASD genes (Oxtr, Cnr1, Ppp1r1b, Ace) and brain-development genes (Otx2, Sema3b, Cdh3).

This leads to → 5. A defect in the switch that sets neuronal differentiation and cell identity during hippocampal development. Superficial (Satb2⁺) and deep (Col11a1⁺) CA1 identity is mis-specified, and specific excitatory and inhibitory subtypes are affected. This is shown in mouse snRNA-seq. In parallel (branch) → 6. Impaired dendritic morphogenesis. Cortical neurons show about 67% less dendritic complexity, about 50% shorter dendrites and about 33% lower spine density (mouse, Golgi-Cox). This results in → 7. Abnormal circuit formation and synaptic connectivity. This step is inferred. It leads to → 8. Clinical phenotype: - absent speech / communication deficit (mouse USV deficit); - ASD-like behaviour (repetitive grooming, sociability deficit, poor nest building); - intellectual disability (Morris water maze learning and memory deficit); - seizures.

Branch: multisystem features (cardiac septal defects, corpus callosum hypoplasia, joint laxity) presumably reflect KDM5A's ubiquitous expression and its developmental role outside the brain. These are not mechanistically studied.

Key evidence

• Mouse knockout phenotype. PMID:33350388 [abstract]: "Kdm5a-/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Loss of KDM5A also resulted in dysregulation of the hippocampal transcriptome."
• Dendritic measurements. PMID:33350388 [full text]: "cortical neurons from Kdm5a-/- mice had significant reduction in dendritic length (∼50% decrease) and dendritic spine density (∼33% decrease) compared with neurons from WT littermates"
• Hippocampal transcriptome. PMID:33350388 [full text]: "Out of 450 differentially expressed genes, 15 were homologs of known ASD genes, including Ace, Cnr1, Mfrp, Oxtr, and Ppp1r1b, and 33 were homologs of genes essential for brain development"
• Predicted direction of target-gene change. PMID:33350388 [full text]: "By demethylating H3K4me3, an activating histone mark, KDM5A would be expected to repress the expression of its target genes, suggesting that genes upregulated in the hippocampus of the Kdm5a-/- mice are potential direct targets of KDM5A." The paper frames this as an expectation, so it is not demonstrated.
• Cell identity. PMID:37992166 [abstract]: "KDM5A regulates the development of specific subtypes of excitatory and inhibitory neurons. We found that KDM5A is essential for establishing hippocampal cell identity by controlling a differentiation switch early in development."
• Loss of a CA1 population. PMID:37992166 [full text]: "the loss of CA1 superficial neurons marked by the expression of Satb2 in Kdm5a−/− is predicted to be one major factor leading to the severe cognitive deficits observed upon loss of KDM5A"
• Patient transcriptomics. PMID:41889174 [abstract]: "Transcriptomic profiling revealed variant-specific gene expression changes, most pronounced in variants affecting the PLU1 chromatin-binding motif and the Jumonji C domain of the enzymatic core."

Ontology suggestions (verify each)

GO biological processes - histone H3-K4 demethylation (GO:0034720) — the current GO label may be "histone H3K4 demethylation" - regulation of DNA-templated transcription (GO:0006355) - dendrite morphogenesis (GO:0048813) - dendritic spine development (GO:0060996) - neuron differentiation (GO:0030182) - hippocampus development (GO:0021766) - vocalization behavior (GO:0071625) - learning or memory (GO:0007611)

GO molecular function: histone H3K4me/H3K4me2/H3K4me3 demethylase activity (GO:0032453 / GO:0034647 family — verify the current IDs).

Cell types (CL) - excitatory neuron / glutamatergic neuron (CL:0000679) - GABAergic interneuron (CL:0000617) - hippocampal CA1 pyramidal neuron (CL:4023111 or similar — verify) - cerebral cortex neuron (CL:0010012)

Other mechanistic categories: no immune, metabolic or tissue-damage mechanisms are described. The disorder is a developmental chromatin-regulation defect.

Molecular profiling. RNA-seq exists from patient LCLs (PMID:41889174) and mouse hippocampus (bulk and snRNA-seq). Check GEO for the accessions with just discover-datasets; the accessions were not verified here. No proteomics, metabolomics or human single-cell data were found.

7. Anatomical structures

Brain imaging findings are bilateral and diffuse.

8. Temporal development

9. Inheritance and population

Inheritance - Autosomal dominant (HP:0000006): 15 of 33 individuals. - Autosomal recessive (HP:0000007): 18 of 33 individuals. - PanelApp lists "BOTH monoallelic and biallelic".

Penetrance and expressivity - Several monoallelic variants were inherited from a parent. Penetrance may be incomplete, or the transmitting parents may have mild phenotypes. Parental phenotypes are only partly described. - Expressivity is variable.

Other inheritance features - No anticipation. - No reported germline or somatic mosaicism. - No founder alleles, because every variant is private.

Consanguinity. Prominent in the biallelic families, which come mainly from Iran, the Arabian Peninsula, Egypt and Kuwait. Monoallelic cases come mainly from Europe and the USA.

Prevalence. Unknown; ultra-rare. Exactly 33 published individuals from 28 families (PMID:41889174 [full text]: "significantly increasing the number of known cases to a total of 33"). For a dismech entry this is measure_type: CASES_IN_LITERATURE with prevalence_class: ULTRA_RARE — and should not use the deprecated percentage field.

Demographics. Both sexes are affected. There are too few cases to establish a sex ratio.

10. Diagnostics

Genetic testing (primary) - First-tier test: exome or genome sequencing. - Use CNV-aware calling. Intragenic homozygous deletions of 4 or 10 exons were found by read depth and split reads. PMID:33350388 [full text]: "A combination of read depth calling and split-read analysis identified a homozygous deletion encompassing four exons of KDM5A, spanning 10 kb". - Chromosomal microarray can detect the larger deletions. - KDM5A is on the Genomics England ID panel (green).

Functional and adjunctive tests (research use only) - Western blot of patient LCLs shows reduced KDM5A protein. - Patient-cell RNA-seq. - No validated biomarker or episignature exists.

Clinical work-up - Brain MRI (corpus callosum, ventricles, white matter). - EEG if seizures occur. - Echocardiography, given the septal defects. - Formal ASD assessment (ADOS-2). - Developmental and IQ testing. - Audiology and ophthalmology.

Differential diagnosis - Other H3K4-methylation chromatinopathies: - KDM5C (X-linked Claes-Jensen ID); - KDM5B (AR ID); - KMT2A (Wiedemann-Steiner syndrome); - KMT2D (Kabuki syndrome); - SETD1A, KMT2E. - Other syndromes with absent speech and ASD: - MECP2 (Rett syndrome); - Angelman syndrome (UBE3A); - CHD8, ARID1B, SETD5, FOXP1. - Molecular testing is required to tell these apart.

Screening. No newborn screening. Cascade testing of parents and siblings, and prenatal or preimplantation testing, are feasible once the familial variants are known.

11. Outcome and prognosis

• Mortality and life expectancy: no mortality data. The oldest reported individual is 29.
• Morbidity:
• absent or minimal speech;
• intellectual disability;
• non-ambulation in a subset of biallelic individuals;
• seizures;
• behavioural and psychiatric comorbidity (self-injury, ADHD, mood disorders);
• congenital heart disease, some of which resolved and one case with pulmonary hypertension.
• Prognostic factors: none established. The biallelic genotype and PLU1/JmjC variants are hypothesised to be more severe, based on LCL transcriptomic data.

12. Treatment

Disease-modifying treatments: none. No trials appear on ClinicalTrials.gov or WHO ICTRP. Management is supportive and multidisciplinary.

Research directions (speculative; no data in this disease) - KDM5 inhibitors are oncology tools and would go the wrong way for a loss-of-function disorder. - Approaches that restore dosage (gene therapy, CRISPRa) have not been tested.

13. Prevention

• Primary: not applicable.
• Genetic counselling:
• Recurrence risk is 25% for biallelic families.
• Risk is up to 50% when an affected or carrier parent transmits a monoallelic variant.
• Risk is low (germline-mosaicism level) for de novo cases.
• Reproductive options: prenatal diagnosis or PGT-M for known familial variants.
• Tertiary prevention:
• seizure surveillance;
• cardiac screening by echocardiography at diagnosis;
• early intensive communication intervention.

14. Other species and natural disease

• No naturally occurring animal disease was found; OMIA was not checked in detail.
• Orthologs:
• mouse Kdm5a (MGI:2136268 — verify), NCBITaxon:10090;
• Drosophila has a single KDM5 ortholog (Kdm5/lid), which is implicated in intellectual-disability-related behaviour in flies through the KDM5C literature.
• KDM5 family function in H3K4 demethylation is conserved from yeast (Jhd2) to humans.

15. Model organisms

Kdm5a Selbst ENU allele (p.C322*), C57BL/6J mouse

• Phenotypes: recessive reduction in USV peak frequency and impaired nest building.
• Fidelity: found by unbiased forward genetics, with strong linkage (p = 2.9×10⁻⁵ for USV; p = 7.0×10⁻⁵ for nesting).

Kdm5a⁻/⁻ targeted knockout mouse (PMID:33350388; PMID:37992166)

What it recapitulates - vocalization deficit, as a proxy for absent speech; - repetitive grooming; - sociability deficit; - Morris water maze learning and memory deficit; - reduced dendritic complexity and spine density; - hippocampal transcriptome dysregulation; - mis-specified CA1 superficial and deep identity (snRNA-seq).

Limitations - Heterozygous mice learn normally. PMID:33350388 [full text]: "WT and Kdm5a+/- littermates had normal learning abilities". So the model does not reproduce the human monoallelic disease. This is a HUMAN_MODEL_MISMATCH candidate in dismech terms. - USV is a proxy for speech, not speech itself. - No seizure, cardiac, corpus callosum or joint phenotypes were reported. - Missense alleles have not been modelled.

Suggested dismech link encoding: RECAPITULATES / PARTIALLY_RECAPITULATES to the ASD-behaviour and dendritic nodes; model_scale: ORGANISM; evidence_source: MODEL_ORGANISM.

Cellular models

• Patient-derived LCLs (PMID:41889174): reduced KDM5A protein and variant-specific transcriptomes. Encode these as IN_VITRO evidence.
• No iPSC-derived neurons or organoids have been reported. This is a gap.

Knowledge gaps (candidates for KNOWLEDGE_GAP discussions)

1. Haploinsufficiency mismatch. Heterozygous Kdm5a mice show no cognitive phenotype, yet humans with monoallelic variants are affected. Is the human disease caused by dominant-negative effects, a species-specific dosage threshold, or incomplete penetrance?
2. Direct chromatin readout. No H3K4me3 ChIP-seq or CUT&Tag exists in patient cells or mutant neurons.
3. Episignature. No DNA-methylation episignature is available as a diagnostic aid.
4. Natural history. There are no longitudinal data, adult outcomes or seizure semiology.
5. Extra-neural features. The mechanism behind the cardiac and connective-tissue features is unexplored.

Sources

• El Hayek L et al. (2020) KDM5A mutations identified in autism spectrum disorder using forward genetics. eLife 9:e56883. PMID:33350388. https://doi.org/10.7554/eLife.56883
• El Hayek L et al. (2023) Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity. Sci Adv. PMID:37992166. https://doi.org/10.1126/sciadv.adi0074
• El Hayek L, Gogate A, et al., Chahrour MH (2026) Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder. HGG Adv. PMID:41889174. Maastricht CRIS record
• MedGen C5935620 / OMIM 620820 mirror
• KEGG DISEASE H02803
• Genomics England PanelApp – KDM5A
• PanelApp Australia – KDM5A
• ERN-ITHACA syndrome page (listed in search results; not reviewed)
• Najmabadi H et al. (2011) Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. PMID:21937992 (verify; cited secondhand through PMID:33350388)
• Excluded as off-target: Sotoudeh Anvari et al. 2024, Iran J Pediatr, which describes a KDM5C case and not KDM5A (brieflands).