El Hayek-Chahrour neurodevelopmental disorder

Mendelian MONDO:0970951 Pathograph 18 Show in embeddings browser Mendelian neurodevelopmental disorder Chromatin disorder

El Hayek-Chahrour neurodevelopmental disorder (NEDEHC, OMIM #620820) is a Mendelian neurodevelopmental chromatinopathy caused by monoallelic or biallelic loss-of-function and domain-disrupting variants in KDM5A, encoding lysine-specific demethylase 5A (JARID1A), an H3K4me3 histone demethylase that removes activating methyl marks from histone H3 lysine 4 (H3K4me3) at gene promoters. It is characterized by global developmental delay, universal speech impairment (with complete absence of speech in ~70% of affected individuals), autism spectrum disorder, intellectual disability, craniofacial dysmorphism (including hypertelorism), microcephaly, hypotonia, feeding difficulties, sleep disturbances, joint hypermobility, seizures, congenital cardiac defects (such as atrial septal defect), and variable structural brain abnormalities such as corpus callosum hypoplasia.

Ask OpenScientist

Ask a research question about El Hayek-Chahrour neurodevelopmental disorder. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

2
Inheritance
6
Pathophys.
16
Phenotypes
2
Gaps
18
Pathograph
1
Genes
3
Medical Actions
1
Models
1
Deep Research
🏷

Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
👪

Inheritance

2
Autosomal Dominant HP:0000006
Monoallelic loss-of-function or missense variants in KDM5A—most commonly de novo heterozygous variants or rarely inherited dominant variants (12/24 individuals in the 2026 cohort and 3/9 in the 2020 discovery cohort)—cause El Hayek-Chahrour neurodevelopmental disorder.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:41889174 SUPPORT Human Clinical
"In conclusion, both monoallelic and biallelic KDM5A variants cause a neurodevelopmental disorder characterized by ASD, severe speech abnormalities, developmental delay, and intellectual disability."
Establishes that monoallelic (autosomal dominant) and biallelic variants in KDM5A cause El Hayek-Chahrour neurodevelopmental disorder.
PMID:41889174 SUPPORT Human Clinical
"In total, we identified de novo variants in seven individuals, inherited variants in 13 individuals, and variants in four individuals for whom the inheritance pattern could not be confirmed (Figure 1C; Tables 1 and S3). There were 12 individuals with biallelic variants and 12 individuals with..."
Documents monoallelic (de novo and dominant inherited) KDM5A variants in half of the 24-patient expansion cohort.
Autosomal Recessive HP:0000007
Biallelic (homozygous or compound heterozygous) multi-exon deletions, frameshift, nonsense, splice-site, and missense variants in KDM5A (6/9 individuals in the 2020 discovery cohort and 12/24 individuals in the 2026 cohort) cause an overlapping neurodevelopmental disorder.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:33350388 SUPPORT Human Clinical
"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..."
Documents autosomal recessive biallelic inheritance in 6 of the 9 individuals in the initial discovery cohort.
PMID:41889174 SUPPORT Human Clinical
"There were 12 individuals with biallelic variants and 12 individuals with monoallelic variants (Figure 1C; Tables 1 and S3)."
Confirms autosomal recessive biallelic KDM5A variants in 12 of 24 individuals in the expanded cohort.
?

Discussions and Knowledge Gaps

2
Why do monoallelic (de novo heterozygous or dominantly inherited) KDM5A variants cause syndromic intellectual disability, absent speech, and autism spectrum disorder in humans, whereas heterozygous Kdm5a+/- mice display normal spatial learning and memory on the Morris water maze?
HUMAN MODEL MISMATCH kdm5a_heterozygous_mouse_vs_monoallelic_human_mismatch
Attached to
animal_models#Kdm5a-/-
In humans, half of the reported cohort (15/33 individuals across PMID:33350388 and PMID:41889174) harbor monoallelic KDM5A variants and present with severe speech impairment, developmental delay, intellectual disability, and ASD indistinguishable in core neurodevelopmental spectrum from biallelic patients. By contrast, in the mouse model characterized by El Hayek et al. (2020, PMID:33350388), heterozygous Kdm5a+/- littermates exhibited normal spatial learning and memory on the Morris water maze, and severe vocalization, sociability, repetitive behavior, cognitive, and dendritic morphogenesis deficits required homozygous Kdm5a-/- inactivation. This dosage sensitivity divergence may reflect species differences in human cortical/hippocampal chromatin regulation by KDM5A or variant-specific dominant/hypomorphic effects of human missense and PLU1-domain alleles.
Show evidence (1 reference)
PMID:33350388 SUPPORT Model Organism
"WT and Kdm5a+/- littermates had normal learning abilities shown by the decrease in latency to locate the hidden platform over a period of 4 days, as well as normal memory by showing preference for the quadrant where the platform was during the probe test (target quadrant). However, Kdm5a-/- mice..."
Demonstrates that heterozygous Kdm5a+/- mice exhibit normal spatial learning and memory on the Morris water maze, whereas homozygous Kdm5a-/- mice display severe learning and memory deficits.
Which specific genomic loci exhibit altered H3K4me2/3 occupancy in KDM5A-deficient patient neural cells or Kdm5a-/- mouse brain tissue?
KNOWLEDGE GAP kdm5a_h3k4me3_brain_chromatin_profiling_gap
Attached to
pathophysiology#Impaired H3K4 Methylation Erasure and Chromatin State Imbalance
Although KDM5A is biochemically established as an H3K4me2/3 histone demethylase and bulk and single-nucleus RNA-seq in patient lymphoblastoid cell lines (PMID:41889174) and Kdm5a-/- mouse hippocampus (PMID:33350388; PMID:37992166) demonstrate pronounced transcriptional dysregulation, direct chromatin profiling (e.g., H3K4me3 ChIP-seq or CUT&RUN) has not yet been reported in patient cells or Kdm5a-/- brain tissue to distinguish direct demethylase target promoters from secondary transcriptional cascades.
⚙

Pathophysiology

6
KDM5A Loss of Function and Reduced H3K4 Demethylase Dosage
Pathogenic monoallelic (de novo or inherited heterozygous) and biallelic (homozygous or compound heterozygous) truncating, splice-site, multi-exon deletion, and missense variants in KDM5A (frequently affecting the PLU1 chromatin-binding motif and the composite JmjN/JmjC catalytic core) cause nonsense-mediated decay, protein destabilization, or loss of enzymatic activity, resulting in reduced KDM5A protein levels and H3K4 demethylase dosage.
KDM5A hgnc:9886 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDM5A (hgnc:9886). hgnc:9886 is a gene from the HUGO Gene Nomenclature Committee.
histone H3K4me/H3K4me2/H3K4me3 demethylase activity GO:0034647 ⇓ LOSS OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves histone H3K4me/H3K4me2/H3K4me3 demethylase activity (GO:0034647), qualified as loss of function. GO:0034647 is a molecular function from the Gene Ontology.
Downstream
Impaired H3K4 Methylation Erasure and Chromatin State Imbalance Reduced KDM5A histone H3K4me3 demethylase dosage or impaired chromatin binding is inferred to disrupt H3K4 methylation erasure and chromatin organization at target promoters.
Show evidence (3 references)
PMID:33350388 SUPPORT In Vitro
"We analyzed the impact of the KDM5A mutations and found that they resulted in decreased protein levels and in one case a truncated protein."
Demonstrates that pathogenic KDM5A variants reduce KDM5A protein levels or produce truncated protein in patient-derived lymphoblastoid cell lines.
PMID:41889174 SUPPORT In Vitro
"Western blot analyses demonstrated reduced KDM5A protein levels in affected individuals from KD-8, KD-19, KD-20, KD-21, and KD-26 (Figure 2C)."
Confirms reduced KDM5A protein levels across patient-derived lymphoblastoid cell lines carrying missense, frameshift, and nonsense variants.
PMID:41889174 SUPPORT Human Clinical
"While the identified variants were distributed across the entire protein, including multiple domains and inter-domain regions, the PLU1 domain was most frequently affected, with seven unique variants identified in eight individuals."
Identifies the PLU1 chromatin-binding domain as the most frequently affected domain in KDM5A.
Impaired H3K4 Methylation Erasure and Chromatin State Imbalance
Deficiency of KDM5A histone H3K4 demethylase activity and PLU1-mediated chromatin binding is biochemically inferred from KDM5A's canonical catalytic function to perturb erasure of H3K4me2/3 marks at target promoters and alter chromatin-mediated gene regulation, although H3K4me2/3 levels have not been directly assayed in patient cells or Kdm5a-/- mouse brain tissue.
protein demethylation GO:0006482 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein demethylation (GO:0006482). GO:0006482 is a biological process from the Gene Ontology. chromatin organization GO:0006325 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated chromatin organization (GO:0006325). GO:0006325 is a biological process from the Gene Ontology.
histone H3K4me/H3K4me2/H3K4me3 demethylase activity GO:0034647 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone H3K4me/H3K4me2/H3K4me3 demethylase activity (GO:0034647). GO:0034647 is a molecular function from the Gene Ontology.
Downstream
Dysregulated Neurodevelopmental and Autism Risk Gene Transcription Impaired H3K4me3 demethylation and PLU1 chromatin-binding motif disruption dysregulate transcriptional programs governing chromatin organization, neuron differentiation, neuron development, neurogenesis, and ASD risk genes.
Show evidence (2 references)
PMID:33350388 SUPPORT BACKGROUND Other
"KDM5A is a histone lysine demethylase that removes methyl groups from lysine 4 of histone H3, resulting in repression of target genes."
Describes the canonical biochemical role of KDM5A in removing methyl groups from histone H3 lysine 4 to repress target genes, from which impaired H3K4me3 demethylation upon KDM5A loss is inferred.
PMID:41889174 SUPPORT In Vitro
"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."
Shows that variants disrupting the PLU1 chromatin-binding motif and JmjC catalytic core perturb chromatin-mediated transcriptional regulation.
Dysregulated Neurodevelopmental and Autism Risk Gene Transcription
Loss of KDM5A function or PLU1/JmjC domain integrity causes widespread transcriptional dysregulation across hippocampal neurons and patient-derived cells, affecting genes involved in neurogenesis, neuron differentiation, cell-cell adhesion, RNA splicing, and known autism spectrum disorder risk genes.
regulation of DNA-templated transcription GO:0006355 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology. nervous system development GO:0007399 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated nervous system development (GO:0007399). GO:0007399 is a biological process from the Gene Ontology.
Ammon's horn UBERON:0001954 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Ammon's horn (UBERON:0001954). UBERON:0001954 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Kdm5a-/- constitutive knockout mouse Mus musculus recapitulates Hippocampal bulk RNA-seq in Kdm5a-/- mice recapitulates dysregulation of 450 genes enriched in neurological processes, RNA splicing, neurogenesis, and ASD risk gene homologs.
Downstream
Altered Hippocampal Neuronal Subtype Identity and Accelerated Maturation Dysregulated neurodevelopmental gene expression disrupts the early hippocampal differentiation switch, accelerates neuronal maturation trajectories, and alters excitatory and inhibitory neuronal subtype proportions.
Hippocampal Neuronal Dendritic Hyper-Arborization Precocious hippocampal neuronal maturation and transcriptional dysregulation of morphogenesis genes drive excessive apical and basal dendritic branching and length in hippocampal excitatory neurons.
Cortical Pyramidal Neuron Dendritic and Spine Hypoplasia Loss of KDM5A-mediated chromatin regulation impairs dendritic morphogenesis and spine maturation in cortical layer II/III pyramidal neurons.
Show evidence (3 references)
PMID:33350388 SUPPORT Model Organism
"Loss of KDM5A resulted in dysregulation of 450 genes (FDR-corrected p≤0.05 and log2 fold change ≥|0.3|) (Figure 5—source data 1), of which 191 genes were upregulated and 259 genes were downregulated"
Demonstrates widespread hippocampal transcriptional dysregulation (450 DEGs) upon loss of Kdm5a in vivo.
PMID:41889174 SUPPORT In Vitro
"DEGs identified in KD-5 and KD-8 were significantly enriched for ASD-associated genes from the SFARI Gene database (p = 0.05 and 0.0015, respectively) (Table S5)."
Demonstrates significant enrichment of SFARI ASD risk genes among differentially expressed genes in patient-derived cell lines with KDM5A JmjC and PLU1 variants.
PMID:41889174 SUPPORT In Vitro
"Gene Ontology analysis was performed for the DEGs in KD-5 and KD-8, the families with the highest number of DEGs, and revealed enrichment in several key biological processes, including signal transduction, cell-cell adhesion, translation, chromatin organization, neuron differentiation, neuron..."
Shows dysregulation of neuron differentiation, neuron development, and neurogenesis transcriptional programs in patient-derived cells.
Altered Hippocampal Neuronal Subtype Identity and Accelerated Maturation
Loss of KDM5A disrupts an early developmental differentiation switch and accelerates hippocampal maturation trajectories, altering the proportions of vulnerable hippocampal excitatory (CA1, CA2, CA3) and inhibitory (Pvalb+, Sst+) neuronal subclusters and disturbing excitation-inhibition balance.
pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology. GABAergic neuron CL:0000617 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves GABAergic neuron (CL:0000617). CL:0000617 is a cell type from the Cell Ontology.
neuron differentiation GO:0030182 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated neuron differentiation (GO:0030182). GO:0030182 is a biological process from the Gene Ontology.
Ammon's horn UBERON:0001954 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Ammon's horn (UBERON:0001954). UBERON:0001954 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Kdm5a-/- constitutive knockout mouse Mus musculus recapitulates Single-nucleus RNA-seq of Kdm5a-/- mouse hippocampi demonstrates altered proportions of excitatory (CA1, CA2, CA3) and inhibitory (Pvalb+, Sst+) neuronal subtypes and accelerated maturation trajectories.
Downstream
Autism Altered development of hippocampal excitatory and inhibitory neuronal subtypes disrupts excitation-inhibition balance underlying autism spectrum disorder.
Intellectual disability Altered hippocampal excitatory and inhibitory neuronal subtype identity and loss of Satb2-positive superficial CA1 neurons impair hippocampal learning and memory circuits, contributing to severe cognitive deficits and intellectual disability.
Show evidence (2 references)
PMID:37992166 SUPPORT Model Organism
"We analyzed the proportions of WT and Kdm5a−/− nuclei for each cluster and identified six distinct clusters that are most vulnerable to the loss of KDM5A: two inhibitory subclusters (Inh1 Pvalb positive and Inh2 Sst positive) and four excitatory subclusters (CA1.1, CA1.4, CA2, and CA3.4)"
Demonstrates altered hippocampal excitatory (CA1, CA2, CA3) and inhibitory (Pvalb+, Sst+) neuronal subtype proportions upon Kdm5a loss.
PMID:37992166 SUPPORT Model Organism
"Pseudotime analysis revealed that loss of KDM5A results in a shift toward a more mature cellular identity and a decrease in later developed hippocampal cells compared to WT. The data are in line with the increase in CA1.1 cells (earlier born) and the decrease in the CA1.4 cells (later born) that..."
Shows a shift toward a more mature cellular identity and altered proportions of deep and superficial CA1 excitatory neurons in the Kdm5a-/- hippocampus.
Hippocampal Neuronal Dendritic Hyper-Arborization
Consistent with precocious hippocampal maturation, hippocampal excitatory neurons in Kdm5a-/- mice exhibit significantly increased dendritic branching complexity (~116% increase) and total dendritic length (~67% increase) across both apical and basal dendrites.
pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology.
dendrite morphogenesis GO:0048813 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased dendrite morphogenesis (GO:0048813). GO:0048813 is a biological process from the Gene Ontology.
Ammon's horn UBERON:0001954 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Ammon's horn (UBERON:0001954). UBERON:0001954 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Kdm5a-/- constitutive knockout mouse Mus musculus recapitulates Golgi-Cox staining and Sholl analysis of Kdm5a-/- mouse hippocampal excitatory neurons reveal increased dendritic branching complexity (~116%) and total dendritic length (~67%).
Downstream
Intellectual disability Abnormal hippocampal dendritic arborization disrupts hippocampal circuit function required for spatial learning and memory, contributing to cognitive dysfunction and intellectual disability.
Global developmental delay Altered developmental timing of hippocampal dendritic morphogenesis impairs proper neurodevelopmental circuitry and brain function.
Show evidence (1 reference)
PMID:37992166 SUPPORT Model Organism
"Sholl analysis revealed a significant increase in dendritic complexity (~116%) of hippocampal neurons from Kdm5a−/− mice (Fig. 5). Furthermore, hippocampal neurons from Kdm5a−/− mice have a significant increase in total dendritic length (~67%), while the mean dendritic length is unchanged..."
Shows excessive dendritic branching complexity (~116% increase) and total dendritic length (~67% increase) in hippocampal neurons lacking Kdm5a.
Cortical Pyramidal Neuron Dendritic and Spine Hypoplasia
In contrast to hippocampal neurons, cortical layer II/III pyramidal neurons in Kdm5a-/- mice exhibit severe reductions in basal dendritic branching complexity (~67% decrease), dendritic length (~50% decrease), and dendritic spine density (~33% decrease), impairing cortical circuitry and wiring.
pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology.
dendrite morphogenesis GO:0048813 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dendrite morphogenesis (GO:0048813). GO:0048813 is a biological process from the Gene Ontology.
cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Kdm5a-/- constitutive knockout mouse Mus musculus recapitulates Golgi-Cox staining of cortical layer II/III pyramidal neurons in Kdm5a-/- mice shows severe reductions in basal dendritic complexity (~67%), length (~50%), and spine density (~33%).
Downstream
Autism Impaired cortical dendritic morphogenesis and reduced spine density disrupt cortical circuit wiring, recapitulating sociability deficits and repetitive behaviors characteristic of autism spectrum disorder.
Intellectual disability Cortical dendritic and spine hypoplasia impairs neuronal circuitry and synaptic connectivity underlying cognitive function.
Absent speech Disrupted cortical neuronal morphogenesis and brain wiring in KDM5A deficiency parallel severe vocalization defects in mice and absent speech in patients.
Delayed speech and language development Impaired cortical neuronal morphogenesis and circuit wiring disrupt vocal communication development.
Show evidence (1 reference)
PMID:33350388 SUPPORT Model Organism
"Sholl analysis revealed a severe reduction (~67%) in dendritic complexity of cortical neurons from Kdm5a-/- mice (Figure 3A and B). Furthermore, cortical neurons from Kdm5a-/- mice had significant reduction in dendritic length (∼50% decrease) and dendritic spine density (∼33% decrease) compared..."
Demonstrates severe reductions in dendritic complexity (~67%), dendritic length (~50%), and spine density (~33%) in cortical layer II/III neurons of Kdm5a-/- mice.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for El Hayek-Chahrour neurodevelopmental disorder Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

16
Cardiovascular 1
Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:41889174 SUPPORT Human Clinical
"Additional phenotypes included autistic features, developmental delay, intellectual disability, muscle hypotonia, seizures, and cardiac abnormalities (Figure 1B; Tables 1 and S2)."
Documents cardiac abnormalities as a recurrent clinical feature across the KDM5A cohort.
PMID:33350388 SUPPORT Human Clinical
"The identified anomalies included: global developmental delay, hypotonia, feeding difficulty, gastroesophageal reflux, small accessory loop of the small bowel, anterior segment dysgenesis of the right ocular globe with an eccentric pupil, posterior embryotoxon, and iris hypoplasia, borderline..."
Documents atrial septal defect requiring surgical repair in proband KD-2-3.
PMID:33350388 SUPPORT Human Clinical
"Other findings include atrial septal defect secundum type, abnormal gait, sleep problems, hyperextensible joints, bilateral clinodactyly of the 5th fingers, syndactyly 2/3 toes, high degree exotropia, hyperpigmented skin in the pubic region, and nevoid telangiectasia on the left side of the back."
Documents secundum-type atrial septal defect in proband KD-5-3.
Digestive 1
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41889174 SUPPORT Human Clinical
"All eight individuals presented with profound speech abnormalities, ranging from absent or markedly delayed speech to vocabulary restricted to only a few words. Additional shared phenotypes included developmental delay (five individuals), feeding difficulties (five individuals), intellectual..."
Documents feeding difficulties in 5 of the 8 individuals harboring PLU1-domain variants.
Eye 1
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33350388 SUPPORT Human Clinical
"The third child (KD-2–4), a male, was found at birth to have hypotonia, feeding difficulties, hypertelorism, and a prominent glabellar region."
Documents hypertelorism in proband KD-2-4.
PMID:33350388 SUPPORT Human Clinical
"Her dysmorphic features include frontal bossing, prominent eyes with blue sclera, lax lower eyelids, down slanted palpebral fissures, orbital hypertelorism, maxillary hypoplasia, hypoplastic ala nasi, smooth philtrum, micrognathia, and low set ears."
Documents orbital hypertelorism in proband KD-5-3.
Head and Neck 2
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 (2 references)
PMID:33350388 SUPPORT Human Clinical
"Her dysmorphic features include frontal bossing, prominent eyes with blue sclera, lax lower eyelids, down slanted palpebral fissures, orbital hypertelorism, maxillary hypoplasia, hypoplastic ala nasi, smooth philtrum, micrognathia, and low set ears."
Details craniofacial dysmorphism in proband KD-5-3 with KDM5A deficiency.
PMID:33350388 SUPPORT Human Clinical
"She presented with severe intellectual disability, lack of speech, self-abusive behaviors, microcephaly, and dysmorphic facies, including flat midface, proptosis, low set ears, broad forehead, broad nasal tip, high nasal bridge, and high palate."
Documents dysmorphic facies in proband KD-7-3 with a homozygous KDM5A deletion.
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 (2 references)
PMID:33350388 SUPPORT Human Clinical
"At 4 years of age her weight was 16 kg, her height was 100 cm, and her head circumference was 47 cm indicative of microcephaly."
Documents microcephaly in proband KD-5-3.
PMID:33350388 SUPPORT Human Clinical
"She presented with severe intellectual disability, lack of speech, self-abusive behaviors, microcephaly, and dysmorphic facies, including flat midface, proptosis, low set ears, broad forehead, broad nasal tip, high nasal bridge, and high palate."
Documents microcephaly in proband KD-7-3.
Musculoskeletal 2
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41889174 SUPPORT Human Clinical
"Additional phenotypes included autistic features, developmental delay, intellectual disability, muscle hypotonia, seizures, and cardiac abnormalities (Figure 1B; Tables 1 and S2)."
Documents muscle hypotonia as a recurrent clinical feature of KDM5A-related neurodevelopmental disorder.
Joint hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33350388 SUPPORT Human Clinical
"Other findings include atrial septal defect secundum type, abnormal gait, sleep problems, hyperextensible joints, bilateral clinodactyly of the 5th fingers, syndactyly 2/3 toes, high degree exotropia, hyperpigmented skin in the pubic region, and nevoid telangiectasia on the left side of the back."
Documents hyperextensible joints in proband KD-5-3.
PMID:33350388 SUPPORT Human Clinical
"Other findings include a flow murmur, tight phimosis, moderate pectus excavatum, a mild increase in joint range of motion, and slightly brisk deep tendon reflexes in his lower extremities."
Documents increased joint range of motion in proband KD-1-3.
Nervous System 9
Delayed speech and language development OBLIGATE HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41889174 SUPPORT Human Clinical
"Clinical characteristics of individuals with KDM5A mutations. The most common feature is speech deficits (100%), followed by developmental delay (96%), and ASD, diagnosed in 89% of individuals."
Establishes that 100% of assessed individuals have speech deficits.
Absent speech VERY_FREQUENT HP:0001344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent speech (HP:0001344). HP:0001344 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41889174 SUPPORT Human Clinical
"The patients primarily presented with ASD and speech abnormalities, ranging from complete lack of speech (16/23 patients assessed) to very limited speech of a few words or other speech issues (7/23 patients assessed)."
Documents complete lack of speech in 16 of 23 assessed patients (~70%) in the 2026 cohort.
PMID:33350388 SUPPORT Human Clinical
"All nine individuals with KDM5A mutations presented clinically with ASD and a spectrum of neurodevelopmental phenotypes including complete lack of speech, intellectual disability, and developmental delay"
Documents complete lack of speech as a core feature in the initial 9-patient cohort.
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41889174 SUPPORT Human Clinical
"Clinical characteristics of individuals with KDM5A mutations. The most common feature is speech deficits (100%), followed by developmental delay (96%), and ASD, diagnosed in 89% of individuals."
Documents developmental delay in 96% of assessed individuals.
Autism VERY_FREQUENT HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41889174 SUPPORT Human Clinical
"Clinical characteristics of individuals with KDM5A mutations. The most common feature is speech deficits (100%), followed by developmental delay (96%), and ASD, diagnosed in 89% of individuals."
Documents autism spectrum disorder diagnosis in 89% of assessed patients.
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41889174 SUPPORT Human Clinical
"Through international collaborations, we assembled a cohort of 24 additional individuals from 21 families with rare, protein-altering KDM5A variants. All individuals presented with severe speech impairment and intellectual disability, often alongside ASD and other neurodevelopmental features."
Documents intellectual disability as a core clinical feature in the 2026 expansion cohort (recorded in Table 1 across 25 columns as present in 19 [13/13 in the biallelic block and 6/9 assessed in the monoallelic block], absent in 3, and unassessed in 3).
Hypoplasia of the corpus callosum 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:33350388 SUPPORT Human Clinical
"The identified anomalies included: global developmental delay, hypotonia, feeding difficulty, gastroesophageal reflux, small accessory loop of the small bowel, anterior segment dysgenesis of the right ocular globe with an eccentric pupil, posterior embryotoxon, and iris hypoplasia, borderline..."
Documents a hypoplastic and dysgenic corpus callosum on neuroimaging in proband KD-2-3.
Sleep disturbance 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 (1 reference)
PMID:41889174 SUPPORT Human Clinical
"Additional shared phenotypes included developmental delay (five individuals), feeding difficulties (five individuals), intellectual disability (four individuals), and sleep disturbances (four individuals)."
Documents sleep disturbances in 4 of the 8 individuals harboring PLU1-domain variants.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41889174 SUPPORT Human Clinical
"Additional phenotypes included autistic features, developmental delay, intellectual disability, muscle hypotonia, seizures, and cardiac abnormalities (Figure 1B; Tables 1 and S2)."
Documents seizures as a recurrent clinical feature across the cohort.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33350388 SUPPORT Human Clinical
"Neurological exam showed hypotonia, tremor, ataxia, abnormal gait, kyphoscoliosis, and difficulty feeding and swallowing."
Documents ataxia on neurological examination in proband KD-4-4.
PMID:33350388 SUPPORT Human Clinical
"The proband (KD-6–3) is a 40 year old female of European ancestry. She presented with severe intellectual disability, developmental delay, focal epilepsy, tetraspastic gait, and ataxia."
Confirms ataxia in an adult individual with a heterozygous nonsense KDM5A variant.
🧬

Genetic Associations

1
KDM5A (Causal (Monoallelic and Biallelic Loss-of-Function and Missense Variants))
Gene: KDM5A hgnc:9886 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KDM5A (hgnc:9886). hgnc:9886 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:33350388 SUPPORT Human Clinical
"We identified pathogenic KDM5A variants in nine patients with ASD and lack of speech."
Identifies pathogenic KDM5A variants as the cause of this neurodevelopmental disorder in the initial discovery cohort.
PMID:41889174 SUPPORT Human Clinical
"In conclusion, both monoallelic and biallelic KDM5A variants cause a neurodevelopmental disorder characterized by ASD, severe speech abnormalities, developmental delay, and intellectual disability. Functional studies confirm that these KDM5A variants reduce protein levels, disrupt protein..."
Confirms that both monoallelic and biallelic KDM5A variants cause El Hayek-Chahrour neurodevelopmental disorder and reduce KDM5A protein function.
PMID:41889174 SUPPORT Human Clinical
"While the identified variants were distributed across the entire protein, including multiple domains and inter-domain regions, the PLU1 domain was most frequently affected, with seven unique variants identified in eight individuals."
Establishes the PLU1 domain of KDM5A as the most frequently mutated domain in affected individuals.
💊

Medical Actions

3
Anticonvulsant Pharmacotherapy
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. NCIT:C64172
Agent: lamotrigine CHEBI:6367 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses lamotrigine (CHEBI:6367). CHEBI:6367 is a therapeutic agent from Chemical Entities of Biological Interest. oxcarbazepine CHEBI:7824 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses oxcarbazepine (CHEBI:7824). CHEBI:7824 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Antiseizure medications such as lamotrigine and oxcarbazepine (Trileptal) are used to control focal and generalized seizures in affected individuals.
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 (2 references)
PMID:33350388 SUPPORT Human Clinical
"She developed focal seizures at 9 years of age controlled with Lamotrigine."
Documents control of focal seizures with lamotrigine in proband KD-2-3.
PMID:33350388 SUPPORT Human Clinical
"He experienced his first seizure at 14 months of age. The seizures became well-controlled on Trileptal, he has not experienced a seizure since he was 5 years old, and was subsequently weaned off of anticonvulsants at 7 years of age."
Documents effective seizure management with oxcarbazepine (Trileptal) in proband KD-3-3.
Behavioral and Rehabilitative Therapies
Category: Therapeutic Action: Behavioral InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Behavioral Intervention (NCIT:C15184). NCIT:C15184 is a clinical intervention from the NCI Thesaurus. NCIT:C15184
Platform: Behavioral / lifestyle
Multidisciplinary developmental and behavioral interventions—including applied behavior analysis (ABA) therapy and speech, physical, and occupational therapies—are used to support communication, motor milestones, and adaptive functioning.
Target Phenotypes: Autism HP:0000717 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology. 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 (2 references)
PMID:33350388 SUPPORT Human Clinical
"He attends a special school for children with ASD and is receiving applied behavioral analysis (ABA) therapy."
Documents applied behavior analysis (ABA) therapy for autism management in proband KD-1-3.
PMID:33350388 SUPPORT Human Clinical
"He received physical, speech, and occupational therapies for many years."
Documents long-term physical, speech, and occupational therapies in proband KD-3-3.
Gastrostomy Tube Feeding Support
Category: Therapeutic Action: GastrostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gastrostomy (NCIT:C52006). NCIT:C52006 is a clinical intervention from the NCI Thesaurus. NCIT:C52006
Platform: Surgery
Enteral nutrition via gastrostomy tube placement is used in patients with severe infantile feeding difficulties and failure to thrive.
Target Phenotypes: Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33350388 SUPPORT Human Clinical
"Follow-up over time demonstrated limited developmental progress with ongoing dependence on gastrostomy feeding."
Documents gastrostomy feeding support in proband KD-2-3 with severe feeding difficulties and failure to thrive.
PMID:33350388 SUPPORT Human Clinical
"He had a gastrostomy-button placed at 13 months of age and continues to use a gastrostomy tube to supplement table feeds."
Documents gastrostomy tube supplementation for feeding difficulties in proband KD-3-3.
🔬

Diagnosis

3
Whole Exome and Genome Sequencing
Definitive molecular diagnosis is established by identifying monoallelic or biallelic pathogenic variants in KDM5A via clinical whole exome sequencing (WES), whole genome sequencing (WGS), or multigene neurodevelopmental panel sequencing, combined with parental segregation testing.
Whole Exome Sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:41889174 SUPPORT Human Clinical
"KDM5A variants were identified through whole exome sequencing, whole genome sequencing, panel testing, or chromosomal microarray analysis. None of the patients harbored pathogenic variants in other known disease genes, and the identified KDM5A variants segregated with the clinical phenotypes in..."
Documents molecular diagnostic confirmation of KDM5A variants via WES, WGS, and panel sequencing with family segregation.
Chromosomal Microarray Analysis
Chromosomal microarray analysis (CMA) detects multi-exon or focal microdeletions at 12p13.33 encompassing KDM5A (such as homozygous deletions of exons 1–10 or exons 6–9) as well as regions of homozygosity in consanguineous families.
Microarray Analysis NCIT:C18477 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:33350388 SUPPORT Human Clinical
"Through global collaborative efforts, we identified nine individuals from seven families where clinical whole exome sequencing or chromosomal microarray analysis revealed pathogenic variants in KDM5A that segregated with phenotype in these families (Figure 4A and Clinical presentation)."
Establishes chromosomal microarray analysis alongside WES as a primary diagnostic modality for identifying pathogenic KDM5A deletions and variants.
PMID:33350388 SUPPORT Human Clinical
"Chromosomal microarray revealed a 28.92 Mb region of loss of heterozygosity and a 50 kb microdeletion encompassing the KDM5A locus at 12p13.33 (chr12:458,096–507,789)."
Demonstrates detection of a 50 kb homozygous KDM5A microdeletion at 12p13.33 by chromosomal microarray.
Brain Magnetic Resonance Imaging
Brain MRI is used to evaluate structural neuroimaging abnormalities including hypoplastic or dysgenic corpus callosum, periventricular leukomalacia, and mild hippocampal or parietal atrophy.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33350388 SUPPORT Human Clinical
"Brain magnetic resonance imaging (MRI) identified a dysgenic corpus callosum."
Documents the use of brain MRI to identify corpus callosum dysgenesis in affected individuals.
📊

Prevalence

1
Global published cohorts
Cases In Literature Ultra Rare
33 reported individuals from 28 families (31 unique private KDM5A variants): 9 individuals from 7 families in the initial 2020 discovery cohort (PMID:33350388) and 24 additional individuals from 21 families in the 2026 cohort expansion (PMID:41889174).
Show evidence (2 references)
PMID:41889174 SUPPORT Human Clinical
"In this study, through international clinical collaborations, we expanded the genetic landscape of KDM5A-related neurodevelopmental disorders by identifying unique variants in a cohort of 24 individuals with ASD from 21 families. This work builds upon our previous publication, which described..."
Documents the total of 33 reported individuals across 28 families (7 in the 2020 study and 21 in the 2026 study).
PMID:41889174 SUPPORT Human Clinical
"Importantly, all 31 unique variants identified to date are private, with no recurrent alleles observed across unrelated individuals."
Confirms that 31 unique private KDM5A variants have been identified across the 33 reported individuals.
🐁

Animal Models

1
Kdm5a-/- constitutive knockout mouse KNOCKOUT
Constitutive Kdm5a knockout mice exhibit severe impairment in ultrasonic vocalizations, repetitive forepaw wringing and self-grooming behaviors, sociability deficits, severe disabilities in spatial learning and memory on the Morris water maze, reduced basal dendritic complexity and spine density in cortical layer II/III neurons, increased dendritic complexity and length in hippocampal neurons, and altered hippocampal excitatory (CA1, CA2, CA3) and inhibitory (Pvalb+, Sst+) neuronal subtype proportions.
Species
Mus musculus
Genotype
Kdm5a-/-
Background
C57BL/6J
Publication
PMID:33350388
Pathograph links
Dysregulated Neurodevelopmental and Autism Risk Gene Transcription recapitulates Hippocampal bulk RNA-seq in Kdm5a-/- mice recapitulates dysregulation of 450 genes enriched in neurological processes, RNA splicing, neurogenesis, and ASD risk gene homologs.
Show evidence (1 reference)
PMID:33350388 SUPPORT Model Organism
"Loss of KDM5A resulted in dysregulation of 450 genes (FDR-corrected p≤0.05 and log2 fold change ≥|0.3|) (Figure 5—source data 1), of which 191 genes were upregulated and 259 genes were downregulated"
Demonstrates hippocampal transcriptional dysregulation of 450 genes in Kdm5a-/- mice.
Altered Hippocampal Neuronal Subtype Identity and Accelerated Maturation recapitulates Single-nucleus RNA-seq of Kdm5a-/- mouse hippocampi demonstrates altered proportions of excitatory (CA1, CA2, CA3) and inhibitory (Pvalb+, Sst+) neuronal subtypes and accelerated maturation trajectories.
Show evidence (1 reference)
PMID:37992166 SUPPORT Model Organism
"We analyzed the proportions of WT and Kdm5a−/− nuclei for each cluster and identified six distinct clusters that are most vulnerable to the loss of KDM5A: two inhibitory subclusters (Inh1 Pvalb positive and Inh2 Sst positive) and four excitatory subclusters (CA1.1, CA1.4, CA2, and CA3.4)"
Shows altered hippocampal excitatory and inhibitory neuronal subtype proportions in Kdm5a-/- mice.
Hippocampal Neuronal Dendritic Hyper-Arborization recapitulates Golgi-Cox staining and Sholl analysis of Kdm5a-/- mouse hippocampal excitatory neurons reveal increased dendritic branching complexity (~116%) and total dendritic length (~67%).
Show evidence (1 reference)
PMID:37992166 SUPPORT Model Organism
"Sholl analysis revealed a significant increase in dendritic complexity (~116%) of hippocampal neurons from Kdm5a−/− mice (Fig. 5). Furthermore, hippocampal neurons from Kdm5a−/− mice have a significant increase in total dendritic length (~67%), while the mean dendritic length is unchanged..."
Demonstrates hippocampal dendritic hyper-arborization in Kdm5a-/- mice.
Cortical Pyramidal Neuron Dendritic and Spine Hypoplasia recapitulates Golgi-Cox staining of cortical layer II/III pyramidal neurons in Kdm5a-/- mice shows severe reductions in basal dendritic complexity (~67%), length (~50%), and spine density (~33%).
Show evidence (1 reference)
PMID:33350388 SUPPORT Model Organism
"Sholl analysis revealed a severe reduction (~67%) in dendritic complexity of cortical neurons from Kdm5a-/- mice (Figure 3A and B). Furthermore, cortical neurons from Kdm5a-/- mice had significant reduction in dendritic length (∼50% decrease) and dendritic spine density (∼33% decrease) compared..."
Demonstrates cortical dendritic and spine hypoplasia in Kdm5a-/- mice.
Show evidence (3 references)
PMID:33350388 SUPPORT Model Organism
"To validate our discovery, we generated a Kdm5a knockout mouse model (Kdm5a-/-) and confirmed that inactivating Kdm5a disrupts vocalization. In addition, Kdm5a-/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Loss of KDM5A..."
Characterizes the core behavioral, neuroanatomical, and transcriptomic phenotypes of Kdm5a-/- knockout mice.
PMID:33350388 SUPPORT Model Organism
"WT and Kdm5a+/- littermates had normal learning abilities shown by the decrease in latency to locate the hidden platform over a period of 4 days, as well as normal memory by showing preference for the quadrant where the platform was during the probe test (target quadrant). However, Kdm5a-/- mice..."
Demonstrates severe spatial learning and memory deficits in Kdm5a-/- mice on the Morris water maze test.
PMID:37992166 SUPPORT Model Organism
"We analyzed the proportions of WT and Kdm5a−/− nuclei for each cluster and identified six distinct clusters that are most vulnerable to the loss of KDM5A: two inhibitory subclusters (Inh1 Pvalb positive and Inh2 Sst positive) and four excitatory subclusters (CA1.1, CA1.4, CA2, and CA3.4)"
Shows disrupted hippocampal excitatory and inhibitory neuronal subtype proportions in Kdm5a-/- mice.
{ }

Source YAML

click to show 
name: El Hayek-Chahrour neurodevelopmental disorder
creation_date: '2026-10-14T10:30:00Z'
description: >-
  El Hayek-Chahrour neurodevelopmental disorder (NEDEHC, OMIM #620820) is a Mendelian
  neurodevelopmental chromatinopathy caused by monoallelic or biallelic loss-of-function
  and domain-disrupting variants in KDM5A, encoding lysine-specific demethylase 5A
  (JARID1A), an H3K4me3 histone demethylase that removes activating methyl marks from
  histone H3 lysine 4 (H3K4me3) at gene promoters. It is characterized by global
  developmental delay, universal speech impairment (with complete absence of speech
  in ~70% of affected individuals), autism spectrum disorder, intellectual disability,
  craniofacial dysmorphism (including hypertelorism), microcephaly, hypotonia, feeding
  difficulties, sleep disturbances, joint hypermobility, seizures, congenital cardiac
  defects (such as atrial septal defect), and variable structural brain abnormalities
  such as corpus callosum hypoplasia.
synonyms:
- NEDEHC
- neurodevelopmental disorder, El Hayek-Chahrour type
- KDM5A-related neurodevelopmental disorder
category: Mendelian
parents:
- Mendelian neurodevelopmental disorder
- Chromatin disorder
disease_term:
  preferred_term: El Hayek-Chahrour neurodevelopmental disorder
  term:
    id: MONDO:0970951
    label: El Hayek-Chahrour neurodevelopmental disorder
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Monoallelic loss-of-function or missense variants in KDM5A—most commonly de novo
    heterozygous variants or rarely inherited dominant variants (12/24 individuals in
    the 2026 cohort and 3/9 in the 2020 discovery cohort)—cause El Hayek-Chahrour
    neurodevelopmental disorder.
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, both monoallelic and biallelic KDM5A variants cause a neurodevelopmental disorder characterized by ASD, severe speech abnormalities, developmental delay, and intellectual disability."
    explanation: >-
      Establishes that monoallelic (autosomal dominant) and biallelic variants in
      KDM5A cause El Hayek-Chahrour neurodevelopmental disorder.
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, we identified de novo variants in seven individuals, inherited variants in 13 individuals, and variants in four individuals for whom the inheritance pattern could not be confirmed (Figure 1C; Tables 1 and S3). There were 12 individuals with biallelic variants and 12 individuals with monoallelic variants (Figure 1C; Tables 1 and S3)."
    explanation: >-
      Documents monoallelic (de novo and dominant inherited) KDM5A variants in half
      of the 24-patient expansion cohort.
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic (homozygous or compound heterozygous) multi-exon deletions, frameshift,
    nonsense, splice-site, and missense variants in KDM5A (6/9 individuals in the 2020
    discovery cohort and 12/24 individuals in the 2026 cohort) cause an overlapping
    neurodevelopmental disorder.
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)"
    explanation: >-
      Documents autosomal recessive biallelic inheritance in 6 of the 9 individuals
      in the initial discovery cohort.
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were 12 individuals with biallelic variants and 12 individuals with monoallelic variants (Figure 1C; Tables 1 and S3)."
    explanation: >-
      Confirms autosomal recessive biallelic KDM5A variants in 12 of 24 individuals
      in the expanded cohort.
prevalence:
- population: Global published cohorts
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    33 reported individuals from 28 families (31 unique private KDM5A variants):
    9 individuals from 7 families in the initial 2020 discovery cohort (PMID:33350388)
    and 24 additional individuals from 21 families in the 2026 cohort expansion
    (PMID:41889174).
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, through international clinical collaborations, we expanded the genetic landscape of KDM5A-related neurodevelopmental disorders by identifying unique variants in a cohort of 24 individuals with ASD from 21 families. This work builds upon our previous publication, which described nine individuals with ASD,28 significantly increasing the number of known cases to a total of 33."
    explanation: >-
      Documents the total of 33 reported individuals across 28 families (7 in the
      2020 study and 21 in the 2026 study).
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, all 31 unique variants identified to date are private, with no recurrent alleles observed across unrelated individuals."
    explanation: >-
      Confirms that 31 unique private KDM5A variants have been identified across the
      33 reported individuals.
pathophysiology:
- name: KDM5A Loss of Function and Reduced H3K4 Demethylase Dosage
  description: >-
    Pathogenic monoallelic (de novo or inherited heterozygous) and biallelic (homozygous
    or compound heterozygous) truncating, splice-site, multi-exon deletion, and
    missense variants in KDM5A (frequently affecting the PLU1 chromatin-binding motif
    and the composite JmjN/JmjC catalytic core) cause nonsense-mediated decay, protein
    destabilization, or loss of enzymatic activity, resulting in reduced KDM5A protein
    levels and H3K4 demethylase dosage.
  genes:
  - preferred_term: KDM5A
    term:
      id: hgnc:9886
      label: KDM5A
  molecular_functions:
  - preferred_term: histone H3K4me/H3K4me2/H3K4me3 demethylase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0034647
      label: histone H3K4me/H3K4me2/H3K4me3 demethylase activity
  conforms_to: epigenetic_machinery_neurodevelopmental_dysregulation#Epigenetic Machinery Component Haploinsufficiency
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We analyzed the impact of the KDM5A mutations and found that they resulted in decreased protein levels and in one case a truncated protein."
    explanation: >-
      Demonstrates that pathogenic KDM5A variants reduce KDM5A protein levels or
      produce truncated protein in patient-derived lymphoblastoid cell lines.
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Western blot analyses demonstrated reduced KDM5A protein levels in affected individuals from KD-8, KD-19, KD-20, KD-21, and KD-26 (Figure 2C)."
    explanation: >-
      Confirms reduced KDM5A protein levels across patient-derived lymphoblastoid
      cell lines carrying missense, frameshift, and nonsense variants.
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While the identified variants were distributed across the entire protein, including multiple domains and inter-domain regions, the PLU1 domain was most frequently affected, with seven unique variants identified in eight individuals."
    explanation: >-
      Identifies the PLU1 chromatin-binding domain as the most frequently affected
      domain in KDM5A.
  downstream:
  - target: Impaired H3K4 Methylation Erasure and Chromatin State Imbalance
    causal_link_type: DIRECT
    description: >-
      Reduced KDM5A histone H3K4me3 demethylase dosage or impaired chromatin binding
      is inferred to disrupt H3K4 methylation erasure and chromatin organization at
      target promoters.
    evidence:
    - reference: PMID:41889174
      reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "We previously identified KDM5A, which encodes a chromatin regulator in the KDM5 family of histone H3 lysine 4 (H3K4) demethylases,5,27 as an ASD gene28 (MIM: 620820). KDM5A represses transcription by demethylating the H3K4me3 mark typically found at promoters of actively transcribed genes."
      explanation: >-
        Establishes that KDM5A is an H3K4 demethylase that represses transcription
        by erasing H3K4me3 marks at active promoters.
- name: Impaired H3K4 Methylation Erasure and Chromatin State Imbalance
  description: >-
    Deficiency of KDM5A histone H3K4 demethylase activity and PLU1-mediated chromatin
    binding is biochemically inferred from KDM5A's canonical catalytic function to
    perturb erasure of H3K4me2/3 marks at target promoters and alter chromatin-mediated
    gene regulation, although H3K4me2/3 levels have not been directly assayed in
    patient cells or Kdm5a-/- mouse brain tissue.
  molecular_functions:
  - preferred_term: histone H3K4me/H3K4me2/H3K4me3 demethylase activity
    modifier: DECREASED
    term:
      id: GO:0034647
      label: histone H3K4me/H3K4me2/H3K4me3 demethylase activity
  biological_processes:
  - preferred_term: protein demethylation
    modifier: DECREASED
    term:
      id: GO:0006482
      label: protein demethylation
  - preferred_term: chromatin organization
    modifier: DYSREGULATED
    term:
      id: GO:0006325
      label: chromatin organization
  conforms_to: epigenetic_machinery_neurodevelopmental_dysregulation#Permissive-Repressive Chromatin State Imbalance
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "KDM5A is a histone lysine demethylase that removes methyl groups from lysine 4 of histone H3, resulting in repression of target genes."
    explanation: >-
      Describes the canonical biochemical role of KDM5A in removing methyl groups
      from histone H3 lysine 4 to repress target genes, from which impaired H3K4me3
      demethylation upon KDM5A loss is inferred.
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >-
      Shows that variants disrupting the PLU1 chromatin-binding motif and JmjC
      catalytic core perturb chromatin-mediated transcriptional regulation.
  downstream:
  - target: Dysregulated Neurodevelopmental and Autism Risk Gene Transcription
    causal_link_type: DIRECT
    description: >-
      Impaired H3K4me3 demethylation and PLU1 chromatin-binding motif disruption
      dysregulate transcriptional programs governing chromatin organization, neuron
      differentiation, neuron development, neurogenesis, and ASD risk genes.
    evidence:
    - reference: PMID:41889174
      reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Gene Ontology analysis was performed for the DEGs in KD-5 and KD-8, the families with the highest number of DEGs, and revealed enrichment in several key biological processes, including signal transduction, cell-cell adhesion, translation, chromatin organization, neuron differentiation, neuron development, and neurogenesis"
      explanation: >-
        Links KDM5A JmjC (KD-5) and PLU1 (KD-8) domain variants to dysregulation of
        chromatin organization, neuron differentiation, neuron development, and
        neurogenesis pathways.
- name: Dysregulated Neurodevelopmental and Autism Risk Gene Transcription
  description: >-
    Loss of KDM5A function or PLU1/JmjC domain integrity causes widespread
    transcriptional dysregulation across hippocampal neurons and patient-derived cells,
    affecting genes involved in neurogenesis, neuron differentiation, cell-cell
    adhesion, RNA splicing, and known autism spectrum disorder risk genes.
  locations:
  - preferred_term: Ammon's horn
    term:
      id: UBERON:0001954
      label: Ammon's horn
  biological_processes:
  - preferred_term: regulation of DNA-templated transcription
    modifier: DYSREGULATED
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
  - preferred_term: nervous system development
    modifier: DYSREGULATED
    term:
      id: GO:0007399
      label: nervous system development
  conforms_to: epigenetic_machinery_neurodevelopmental_dysregulation#Dysregulated Neurodevelopmental Transcriptional Program
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of KDM5A resulted in dysregulation of 450 genes (FDR-corrected p≤0.05 and log2 fold change ≥|0.3|) (Figure 5—source data 1), of which 191 genes were upregulated and 259 genes were downregulated"
    explanation: >-
      Demonstrates widespread hippocampal transcriptional dysregulation (450 DEGs)
      upon loss of Kdm5a in vivo.
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "DEGs identified in KD-5 and KD-8 were significantly enriched for ASD-associated genes from the SFARI Gene database (p = 0.05 and 0.0015, respectively) (Table S5)."
    explanation: >-
      Demonstrates significant enrichment of SFARI ASD risk genes among differentially
      expressed genes in patient-derived cell lines with KDM5A JmjC and PLU1 variants.
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Gene Ontology analysis was performed for the DEGs in KD-5 and KD-8, the families with the highest number of DEGs, and revealed enrichment in several key biological processes, including signal transduction, cell-cell adhesion, translation, chromatin organization, neuron differentiation, neuron development, and neurogenesis"
    explanation: >-
      Shows dysregulation of neuron differentiation, neuron development, and
      neurogenesis transcriptional programs in patient-derived cells.
  downstream:
  - target: Altered Hippocampal Neuronal Subtype Identity and Accelerated Maturation
    causal_link_type: DIRECT
    description: >-
      Dysregulated neurodevelopmental gene expression disrupts the early hippocampal
      differentiation switch, accelerates neuronal maturation trajectories, and alters
      excitatory and inhibitory neuronal subtype proportions.
    evidence:
    - reference: PMID:37992166
      reference_title: "Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Using single-nucleus RNA sequencing, we show that the ASD gene, lysine demethylase 5A (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."
      explanation: >-
        Connects KDM5A-mediated transcriptional regulation to the establishment of
        hippocampal excitatory and inhibitory neuronal subtype identity.
    - reference: PMID:37992166
      reference_title: "Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The shift of Kdm5a−/− cells and their accumulation at the end of the developmental trajectories suggests an accelerated development and a more mature cellular identity in the Kdm5a−/− hippocampus."
      explanation: >-
        Shows that loss of KDM5A accelerates neuronal developmental trajectories in
        the hippocampus.
  - target: Hippocampal Neuronal Dendritic Hyper-Arborization
    causal_link_type: DIRECT
    description: >-
      Precocious hippocampal neuronal maturation and transcriptional dysregulation of
      morphogenesis genes drive excessive apical and basal dendritic branching and
      length in hippocampal excitatory neurons.
    evidence:
    - reference: PMID:37992166
      reference_title: "Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In addition, assessing the neuronal arborization of hippocampal neurons showed a remarkable increase in dendritic complexity and branching in the Kdm5a−/− compared to WT, in line with the pseudotime results showing a more mature identity upon loss of KDM5A."
      explanation: >-
        Shows that loss of KDM5A increases dendritic complexity and branching in
        hippocampal neurons in line with accelerated maturation.
  - target: Cortical Pyramidal Neuron Dendritic and Spine Hypoplasia
    causal_link_type: DIRECT
    description: >-
      Loss of KDM5A-mediated chromatin regulation impairs dendritic morphogenesis and
      spine maturation in cortical layer II/III pyramidal neurons.
    evidence:
    - reference: PMID:33350388
      reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To assess the role of KDM5A in neuronal development, we measured dendritic complexity, length, and spine density in vivo by Golgi-Cox staining of brains from Kdm5a-/- and WT littermates. Sholl analysis revealed a severe reduction (~67%) in dendritic complexity of cortical neurons from Kdm5a-/- mice (Figure 3A and B). Furthermore, 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 (Figure 3C and D)."
      explanation: >-
        Demonstrates that loss of Kdm5a causes severe reductions in cortical neuron
        dendritic complexity, length, and spine density.
- name: Altered Hippocampal Neuronal Subtype Identity and Accelerated Maturation
  description: >-
    Loss of KDM5A disrupts an early developmental differentiation switch and
    accelerates hippocampal maturation trajectories, altering the proportions of
    vulnerable hippocampal excitatory (CA1, CA2, CA3) and inhibitory (Pvalb+, Sst+)
    neuronal subclusters and disturbing excitation-inhibition balance.
  locations:
  - preferred_term: Ammon's horn
    term:
      id: UBERON:0001954
      label: Ammon's horn
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  biological_processes:
  - preferred_term: neuron differentiation
    modifier: DYSREGULATED
    term:
      id: GO:0030182
      label: neuron differentiation
  conforms_to: epigenetic_machinery_neurodevelopmental_dysregulation#Impaired Neuronal Maturation, Plasticity, and Postnatal Neurogenesis
  evidence:
  - reference: PMID:37992166
    reference_title: "Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We analyzed the proportions of WT and Kdm5a−/− nuclei for each cluster and identified six distinct clusters that are most vulnerable to the loss of KDM5A: two inhibitory subclusters (Inh1 Pvalb positive and Inh2 Sst positive) and four excitatory subclusters (CA1.1, CA1.4, CA2, and CA3.4)"
    explanation: >-
      Demonstrates altered hippocampal excitatory (CA1, CA2, CA3) and inhibitory
      (Pvalb+, Sst+) neuronal subtype proportions upon Kdm5a loss.
  - reference: PMID:37992166
    reference_title: "Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Pseudotime analysis revealed that loss of KDM5A results in a shift toward a more mature cellular identity and a decrease in later developed hippocampal cells compared to WT. The data are in line with the increase in CA1.1 cells (earlier born) and the decrease in the CA1.4 cells (later born) that we identified as deep and superficial cells of the CA1, respectively, indicating a role for KDM5A in regulating neuronal development and differentiation in the hippocampus."
    explanation: >-
      Shows a shift toward a more mature cellular identity and altered proportions of
      deep and superficial CA1 excitatory neurons in the Kdm5a-/- hippocampus.
  downstream:
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered development of hippocampal excitatory and inhibitory neuronal subtypes
      disrupts excitation-inhibition balance underlying autism spectrum disorder.
    evidence:
    - reference: PMID:37992166
      reference_title: "Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Last, changes in cell proportions of excitatory and inhibitory neurons can result in a dysregulation of the excitatory-inhibitory balance, a neurodevelopmental disease mechanism frequently observed in ASD (68)."
      explanation: >-
        Links changes in excitatory and inhibitory neuronal proportions and
        excitation-inhibition imbalance to ASD.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered hippocampal excitatory and inhibitory neuronal subtype identity and
      loss of Satb2-positive superficial CA1 neurons impair hippocampal learning and
      memory circuits, contributing to severe cognitive deficits and intellectual
      disability.
    evidence:
    - reference: PMID:37992166
      reference_title: "Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Given all the aforementioned data, 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 (30). This finding uncovers a key role for KDM5A in regulating the superficial CA1 neurons and in mediating learning and memory."
      explanation: >-
        Links loss of superficial CA1 neurons upon KDM5A loss to severe cognitive
        deficits and impaired learning and memory.
- name: Hippocampal Neuronal Dendritic Hyper-Arborization
  description: >-
    Consistent with precocious hippocampal maturation, hippocampal excitatory neurons
    in Kdm5a-/- mice exhibit significantly increased dendritic branching complexity
    (~116% increase) and total dendritic length (~67% increase) across both apical
    and basal dendrites.
  locations:
  - preferred_term: Ammon's horn
    term:
      id: UBERON:0001954
      label: Ammon's horn
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: dendrite morphogenesis
    modifier: INCREASED
    term:
      id: GO:0048813
      label: dendrite morphogenesis
  evidence:
  - reference: PMID:37992166
    reference_title: "Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sholl analysis revealed a significant increase in dendritic complexity (~116%) of hippocampal neurons from Kdm5a−/− mice (Fig. 5). Furthermore, hippocampal neurons from Kdm5a−/− mice have a significant increase in total dendritic length (~67%), while the mean dendritic length is unchanged compared with neurons from WT littermates"
    explanation: >-
      Shows excessive dendritic branching complexity (~116% increase) and total
      dendritic length (~67% increase) in hippocampal neurons lacking Kdm5a.
  downstream:
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal hippocampal dendritic arborization disrupts hippocampal circuit
      function required for spatial learning and memory, contributing to cognitive
      dysfunction and intellectual disability.
    evidence:
    - reference: PMID:33350388
      reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To validate our discovery, we generated a Kdm5a knockout mouse model (Kdm5a-/-) and confirmed that inactivating Kdm5a disrupts vocalization. In addition, Kdm5a-/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis."
      explanation: >-
        Links Kdm5a loss and abnormal dendritic morphogenesis to severe cognitive
        dysfunction in vivo.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Altered developmental timing of hippocampal dendritic morphogenesis impairs
      proper neurodevelopmental circuitry and brain function.
    evidence:
    - reference: PMID:37992166
      reference_title: "Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Abnormal dendritic maturation has been a recurrent phenotype observed in ASD (59), and changes in either direction—more (60, 61) or less branching (62, 63)—are observed in ASD and can alter proper circuitry and brain function."
      explanation: >-
        Connects abnormal dendritic maturation and hyper-branching to altered proper
        circuitry and brain function.
- name: Cortical Pyramidal Neuron Dendritic and Spine Hypoplasia
  description: >-
    In contrast to hippocampal neurons, cortical layer II/III pyramidal neurons in
    Kdm5a-/- mice exhibit severe reductions in basal dendritic branching complexity
    (~67% decrease), dendritic length (~50% decrease), and dendritic spine density
    (~33% decrease), impairing cortical circuitry and wiring.
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: dendrite morphogenesis
    modifier: DECREASED
    term:
      id: GO:0048813
      label: dendrite morphogenesis
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sholl analysis revealed a severe reduction (~67%) in dendritic complexity of cortical neurons from Kdm5a-/- mice (Figure 3A and B). Furthermore, 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"
    explanation: >-
      Demonstrates severe reductions in dendritic complexity (~67%), dendritic length
      (~50%), and spine density (~33%) in cortical layer II/III neurons of Kdm5a-/- mice.
  downstream:
  - target: Autism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired cortical dendritic morphogenesis and reduced spine density disrupt
      cortical circuit wiring, recapitulating sociability deficits and repetitive
      behaviors characteristic of autism spectrum disorder.
    evidence:
    - reference: PMID:33350388
      reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In addition, loss of KDM5A resulted in severe neuronal morphogenesis abnormalities, which included a decrease in dendritic complexity, length, and spine density. These findings reveal an essential role for KDM5A in dendritic morphogenesis and maturation, processes essential for the establishment of neuronal circuitry and wiring of the brain (Dong et al., 2015). Collectively, the neurobehavioral phenotypes observed in the Kdm5a-/- mice uncover the function of KDM5A in the brain and recapitulate phenotypes observed in patients with KDM5A mutations, including deficits in sociability, cognitive function, and repetitive behaviors."
      explanation: >-
        Connects reduced cortical dendritic complexity, length, and spine density in
        Kdm5a-/- mice to disrupted brain wiring and ASD-related sociability and
        repetitive behavioral phenotypes.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cortical dendritic and spine hypoplasia impairs neuronal circuitry and synaptic
      connectivity underlying cognitive function.
    evidence:
    - reference: PMID:33350388
      reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In addition, loss of KDM5A resulted in severe neuronal morphogenesis abnormalities, which included a decrease in dendritic complexity, length, and spine density. These findings reveal an essential role for KDM5A in dendritic morphogenesis and maturation, processes essential for the establishment of neuronal circuitry and wiring of the brain (Dong et al., 2015). Collectively, the neurobehavioral phenotypes observed in the Kdm5a-/- mice uncover the function of KDM5A in the brain and recapitulate phenotypes observed in patients with KDM5A mutations, including deficits in sociability, cognitive function, and repetitive behaviors."
      explanation: >-
        Links defective cortical dendritic morphogenesis and spine density to
        impaired cognitive function in KDM5A deficiency.
  - target: Absent speech
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted cortical neuronal morphogenesis and brain wiring in KDM5A deficiency
      parallel severe vocalization defects in mice and absent speech in patients.
    evidence:
    - reference: PMID:33350388
      reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To validate our discovery, we generated a Kdm5a knockout mouse model (Kdm5a-/-) and confirmed that inactivating Kdm5a disrupts vocalization. In addition, Kdm5a-/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis."
      explanation: >-
        Demonstrates that Kdm5a loss causes abnormal dendritic morphogenesis alongside
        severe vocalization disruption modeling human speech absence.
  - target: Delayed speech and language development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired cortical neuronal morphogenesis and circuit wiring disrupt vocal
      communication development.
    evidence:
    - reference: PMID:33350388
      reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We found that Kdm5a-/- mice had reduced peak frequency of emitted USVs, which replicates the Selbst phenotype, and a severe reduction in the number of USVs (~84% decrease) compared with control littermates (Figure 2C and Figure 2—figure supplement 2A)."
      explanation: >-
        Shows severe vocalization impairment (~84% reduction in ultrasonic
        vocalizations) upon Kdm5a loss.
phenotypes:
- category: Neurologic
  name: Delayed speech and language development
  frequency: OBLIGATE
  diagnostic: true
  description: >-
    Speech and language impairment is the universal hallmark of El Hayek-Chahrour
    neurodevelopmental disorder, present in 100% of assessed individuals, ranging
    from complete absence of speech to severe delay with vocabulary limited to a few
    words.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics of individuals with KDM5A mutations. The most common feature is speech deficits (100%), followed by developmental delay (96%), and ASD, diagnosed in 89% of individuals."
    explanation: >-
      Establishes that 100% of assessed individuals have speech deficits.
- category: Neurologic
  name: Absent speech
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Complete absence of speech is observed in the majority of affected individuals
    (16/23 assessed patients in the 2026 cohort and 8/9 in the 2020 discovery cohort).
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients primarily presented with ASD and speech abnormalities, ranging from complete lack of speech (16/23 patients assessed) to very limited speech of a few words or other speech issues (7/23 patients assessed)."
    explanation: >-
      Documents complete lack of speech in 16 of 23 assessed patients (~70%) in the
      2026 cohort.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All nine individuals with KDM5A mutations presented clinically with ASD and a spectrum of neurodevelopmental phenotypes including complete lack of speech, intellectual disability, and developmental delay"
    explanation: >-
      Documents complete lack of speech as a core feature in the initial 9-patient
      cohort.
- category: Neurologic
  name: Global developmental delay
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Global developmental delay affecting motor, cognitive, and language milestones
    is present in 96% of assessed individuals.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics of individuals with KDM5A mutations. The most common feature is speech deficits (100%), followed by developmental delay (96%), and ASD, diagnosed in 89% of individuals."
    explanation: >-
      Documents developmental delay in 96% of assessed individuals.
- category: Behavioral
  name: Autism
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Autism spectrum disorder is diagnosed in 89% of assessed individuals, often
    accompanied by motor stereotypies, self-injurious behavior, aggression, or
    attention deficits.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical characteristics of individuals with KDM5A mutations. The most common feature is speech deficits (100%), followed by developmental delay (96%), and ASD, diagnosed in 89% of individuals."
    explanation: >-
      Documents autism spectrum disorder diagnosis in 89% of assessed patients.
- category: Neurologic
  name: Intellectual disability
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Reported in all 9 individuals of the 2020 cohort (PMID:33350388); the 2026
    expansion study abstract describes intellectual disability across the cohort,
    while its Table 1 (12 monoallelic columns and 13 biallelic columns, which
    places KD-9-3 in the biallelic block) records it across 25 columns as
    present in 19 (13/13 biallelic and 6/9 assessed monoallelic), absent in 3
    monoallelic individuals (KD-19-2, KD-19-3, KD-20-3), unknown in 2 (KD-11-3,
    KD-27-3), and not applicable in 1 fetal demise (KD-10-3) (PMID:41889174).
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through international collaborations, we assembled a cohort of 24 additional individuals from 21 families with rare, protein-altering KDM5A variants. All individuals presented with severe speech impairment and intellectual disability, often alongside ASD and other neurodevelopmental features."
    explanation: >-
      Documents intellectual disability as a core clinical feature in the 2026
      expansion cohort (recorded in Table 1 across 25 columns as present in 19
      [13/13 in the biallelic block and 6/9 assessed in the monoallelic block],
      absent in 3, and unassessed in 3).
- category: Craniofacial
  name: Abnormal facial shape
  description: >-
    Craniofacial dysmorphic features are observed across multiple monoallelic and
    biallelic patients (6/9 individuals in Table 1 of the 2020 cohort and multiple
    individuals in the 2026 cohort), including frontal bossing, downslanted palpebral
    fissures, prominent glabellar region, flat midface, and micrognathia.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her dysmorphic features include frontal bossing, prominent eyes with blue sclera, lax lower eyelids, down slanted palpebral fissures, orbital hypertelorism, maxillary hypoplasia, hypoplastic ala nasi, smooth philtrum, micrognathia, and low set ears."
    explanation: >-
      Details craniofacial dysmorphism in proband KD-5-3 with KDM5A deficiency.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She presented with severe intellectual disability, lack of speech, self-abusive behaviors, microcephaly, and dysmorphic facies, including flat midface, proptosis, low set ears, broad forehead, broad nasal tip, high nasal bridge, and high palate."
    explanation: >-
      Documents dysmorphic facies in proband KD-7-3 with a homozygous KDM5A deletion.
- category: Craniofacial
  name: Hypertelorism
  description: >-
    Hypertelorism is reported in multiple affected individuals in the 2020 cohort
    (including siblings KD-2-3 and KD-2-4 and proband KD-5-3).
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The third child (KD-2–4), a male, was found at birth to have hypotonia, feeding difficulties, hypertelorism, and a prominent glabellar region."
    explanation: >-
      Documents hypertelorism in proband KD-2-4.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her dysmorphic features include frontal bossing, prominent eyes with blue sclera, lax lower eyelids, down slanted palpebral fissures, orbital hypertelorism, maxillary hypoplasia, hypoplastic ala nasi, smooth philtrum, micrognathia, and low set ears."
    explanation: >-
      Documents orbital hypertelorism in proband KD-5-3.
- category: Neurologic
  name: Microcephaly
  description: >-
    Microcephaly (head circumference <2nd to <5th percentile) is documented in
    multiple affected individuals in the 2020 cohort (including KD-2-3, KD-4-4,
    KD-5-3, KD-6-3, and KD-7-3).
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 4 years of age her weight was 16 kg, her height was 100 cm, and her head circumference was 47 cm indicative of microcephaly."
    explanation: >-
      Documents microcephaly in proband KD-5-3.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She presented with severe intellectual disability, lack of speech, self-abusive behaviors, microcephaly, and dysmorphic facies, including flat midface, proptosis, low set ears, broad forehead, broad nasal tip, high nasal bridge, and high palate."
    explanation: >-
      Documents microcephaly in proband KD-7-3.
- category: Cardiovascular
  name: Atrial septal defect
  description: >-
    Congenital cardiac abnormalities, most commonly atrial septal defect (sometimes
    co-occurring with ventricular septal defect, pulmonary hypertension, or aortic
    arch anomalies), occur in a subset of individuals across both the 2020 and 2026
    cohorts.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional phenotypes included autistic features, developmental delay, intellectual disability, muscle hypotonia, seizures, and cardiac abnormalities (Figure 1B; Tables 1 and S2)."
    explanation: >-
      Documents cardiac abnormalities as a recurrent clinical feature across the
      KDM5A cohort.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identified anomalies included: global developmental delay, hypotonia, feeding difficulty, gastroesophageal reflux, small accessory loop of the small bowel, anterior segment dysgenesis of the right ocular globe with an eccentric pupil, posterior embryotoxon, and iris hypoplasia, borderline microcephaly, atrial septal defect, hypoplastic and dysgenic corpus callosum, and unusual morphological features including hypertelorism and a prominent glabellar region."
    explanation: >-
      Documents atrial septal defect requiring surgical repair in proband KD-2-3.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other findings include atrial septal defect secundum type, abnormal gait, sleep problems, hyperextensible joints, bilateral clinodactyly of the 5th fingers, syndactyly 2/3 toes, high degree exotropia, hyperpigmented skin in the pubic region, and nevoid telangiectasia on the left side of the back."
    explanation: >-
      Documents secundum-type atrial septal defect in proband KD-5-3.
- category: Neurologic
  name: Hypotonia
  description: >-
    Muscle hypotonia is present from infancy across multiple monoallelic and
    biallelic KDM5A patients.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional phenotypes included autistic features, developmental delay, intellectual disability, muscle hypotonia, seizures, and cardiac abnormalities (Figure 1B; Tables 1 and S2)."
    explanation: >-
      Documents muscle hypotonia as a recurrent clinical feature of KDM5A-related
      neurodevelopmental disorder.
- category: Gastrointestinal
  name: Feeding difficulties
  description: >-
    Feeding and swallowing difficulties occur in infancy and childhood (including
    5/8 individuals with PLU1-domain variants in the 2026 cohort and 6/9 individuals
    in the 2020 cohort) and may lead to failure to thrive or gastrostomy dependence.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All eight individuals presented with profound speech abnormalities, ranging from absent or markedly delayed speech to vocabulary restricted to only a few words. Additional shared phenotypes included developmental delay (five individuals), feeding difficulties (five individuals), intellectual disability (four individuals), and sleep disturbances (four individuals)."
    explanation: >-
      Documents feeding difficulties in 5 of the 8 individuals harboring PLU1-domain
      variants.
- category: Musculoskeletal
  name: Joint hypermobility
  description: >-
    Hyperextensible joints and increased joint range of motion are observed in a
    subset of affected individuals.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other findings include atrial septal defect secundum type, abnormal gait, sleep problems, hyperextensible joints, bilateral clinodactyly of the 5th fingers, syndactyly 2/3 toes, high degree exotropia, hyperpigmented skin in the pubic region, and nevoid telangiectasia on the left side of the back."
    explanation: >-
      Documents hyperextensible joints in proband KD-5-3.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other findings include a flow murmur, tight phimosis, moderate pectus excavatum, a mild increase in joint range of motion, and slightly brisk deep tendon reflexes in his lower extremities."
    explanation: >-
      Documents increased joint range of motion in proband KD-1-3.
- category: Neurologic
  name: Hypoplasia of the corpus callosum
  description: >-
    Structural brain MRI abnormalities in a subset of individuals include a thin,
    hypoplastic, or dysgenic corpus callosum, sometimes accompanied by mild
    hippocampal or parietal atrophy.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identified anomalies included: global developmental delay, hypotonia, feeding difficulty, gastroesophageal reflux, small accessory loop of the small bowel, anterior segment dysgenesis of the right ocular globe with an eccentric pupil, posterior embryotoxon, and iris hypoplasia, borderline microcephaly, atrial septal defect, hypoplastic and dysgenic corpus callosum, and unusual morphological features including hypertelorism and a prominent glabellar region."
    explanation: >-
      Documents a hypoplastic and dysgenic corpus callosum on neuroimaging in
      proband KD-2-3.
- category: Neurologic
  name: Sleep disturbance
  description: >-
    Sleep disturbances are observed across multiple affected individuals (including
    4/8 individuals with PLU1-domain variants in the 2026 cohort).
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional shared phenotypes included developmental delay (five individuals), feeding difficulties (five individuals), intellectual disability (four individuals), and sleep disturbances (four individuals)."
    explanation: >-
      Documents sleep disturbances in 4 of the 8 individuals harboring PLU1-domain
      variants.
- category: Neurologic
  name: Seizure
  description: >-
    Seizures (including focal epilepsy, febrile seizures, and generalized tonic-clonic
    seizures) occur in 4/9 individuals in the 2020 cohort and in 9/24 assessed
    individuals in Table 1 of the 2026 cohort (7/13 in the biallelic block and
    2/11 assessed [KD-8-3, KD-11-3] in the monoallelic block, with 1 fetal demise
    not applicable).
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional phenotypes included autistic features, developmental delay, intellectual disability, muscle hypotonia, seizures, and cardiac abnormalities (Figure 1B; Tables 1 and S2)."
    explanation: >-
      Documents seizures as a recurrent clinical feature across the cohort.
- category: Neurologic
  name: Ataxia
  description: >-
    Ataxia and abnormal gait are observed in a subset of affected individuals.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological exam showed hypotonia, tremor, ataxia, abnormal gait, kyphoscoliosis, and difficulty feeding and swallowing."
    explanation: >-
      Documents ataxia on neurological examination in proband KD-4-4.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband (KD-6–3) is a 40 year old female of European ancestry. She presented with severe intellectual disability, developmental delay, focal epilepsy, tetraspastic gait, and ataxia."
    explanation: >-
      Confirms ataxia in an adult individual with a heterozygous nonsense KDM5A variant.
genetic:
- name: KDM5A
  association: Causal (Monoallelic and Biallelic Loss-of-Function and Missense Variants)
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: KDM5A
    term:
      id: hgnc:9886
      label: KDM5A
  features: >-
    Includes de novo or inherited monoallelic and biallelic (homozygous or compound
    heterozygous) multi-exon deletions, nonsense, frameshift, splice-site, and
    missense variants across 33 reported individuals (31 unique private alleles).
    The PLU1 chromatin-binding motif is the most frequently affected domain (7 unique
    variants in 8 individuals), alongside variants in the JmjN/JmjC enzymatic core,
    PHD1, PHD3, and inter-domain regions.
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified pathogenic KDM5A variants in nine patients with ASD and lack of speech."
    explanation: >-
      Identifies pathogenic KDM5A variants as the cause of this neurodevelopmental
      disorder in the initial discovery cohort.
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, both monoallelic and biallelic KDM5A variants cause a neurodevelopmental disorder characterized by ASD, severe speech abnormalities, developmental delay, and intellectual disability. Functional studies confirm that these KDM5A variants reduce protein levels, disrupt protein structure, and significantly alter the transcriptome."
    explanation: >-
      Confirms that both monoallelic and biallelic KDM5A variants cause El
      Hayek-Chahrour neurodevelopmental disorder and reduce KDM5A protein function.
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While the identified variants were distributed across the entire protein, including multiple domains and inter-domain regions, the PLU1 domain was most frequently affected, with seven unique variants identified in eight individuals."
    explanation: >-
      Establishes the PLU1 domain of KDM5A as the most frequently mutated domain in
      affected individuals.
diagnosis:
- name: Whole Exome and Genome Sequencing
  description: >-
    Definitive molecular diagnosis is established by identifying monoallelic or
    biallelic pathogenic variants in KDM5A via clinical whole exome sequencing (WES),
    whole genome sequencing (WGS), or multigene neurodevelopmental panel sequencing,
    combined with parental segregation testing.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:41889174
    reference_title: "Monoallelic and biallelic KDM5A variants identified in patients with autism spectrum disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "KDM5A variants were identified through whole exome sequencing, whole genome sequencing, panel testing, or chromosomal microarray analysis. None of the patients harbored pathogenic variants in other known disease genes, and the identified KDM5A variants segregated with the clinical phenotypes in the families."
    explanation: >-
      Documents molecular diagnostic confirmation of KDM5A variants via WES, WGS,
      and panel sequencing with family segregation.
- name: Chromosomal Microarray Analysis
  description: >-
    Chromosomal microarray analysis (CMA) detects multi-exon or focal microdeletions
    at 12p13.33 encompassing KDM5A (such as homozygous deletions of exons 1–10 or
    exons 6–9) as well as regions of homozygosity in consanguineous families.
  diagnosis_term:
    preferred_term: Microarray Analysis
    term:
      id: NCIT:C18477
      label: Microarray Analysis
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through global collaborative efforts, we identified nine individuals from seven families where clinical whole exome sequencing or chromosomal microarray analysis revealed pathogenic variants in KDM5A that segregated with phenotype in these families (Figure 4A and Clinical presentation)."
    explanation: >-
      Establishes chromosomal microarray analysis alongside WES as a primary diagnostic
      modality for identifying pathogenic KDM5A deletions and variants.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chromosomal microarray revealed a 28.92 Mb region of loss of heterozygosity and a 50 kb microdeletion encompassing the KDM5A locus at 12p13.33 (chr12:458,096–507,789)."
    explanation: >-
      Demonstrates detection of a 50 kb homozygous KDM5A microdeletion at 12p13.33
      by chromosomal microarray.
- name: Brain Magnetic Resonance Imaging
  description: >-
    Brain MRI is used to evaluate structural neuroimaging abnormalities including
    hypoplastic or dysgenic corpus callosum, periventricular leukomalacia, and mild
    hippocampal or parietal atrophy.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain magnetic resonance imaging (MRI) identified a dysgenic corpus callosum."
    explanation: >-
      Documents the use of brain MRI to identify corpus callosum dysgenesis in affected
      individuals.
treatments:
- name: Anticonvulsant Pharmacotherapy
  description: >-
    Antiseizure medications such as lamotrigine and oxcarbazepine (Trileptal) are
    used to control focal and generalized seizures in affected individuals.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
    therapeutic_agent:
    - preferred_term: lamotrigine
      term:
        id: CHEBI:6367
        label: lamotrigine
    - preferred_term: oxcarbazepine
      term:
        id: CHEBI:7824
        label: oxcarbazepine
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She developed focal seizures at 9 years of age controlled with Lamotrigine."
    explanation: >-
      Documents control of focal seizures with lamotrigine in proband KD-2-3.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He experienced his first seizure at 14 months of age. The seizures became well-controlled on Trileptal, he has not experienced a seizure since he was 5 years old, and was subsequently weaned off of anticonvulsants at 7 years of age."
    explanation: >-
      Documents effective seizure management with oxcarbazepine (Trileptal) in
      proband KD-3-3.
- name: Behavioral and Rehabilitative Therapies
  description: >-
    Multidisciplinary developmental and behavioral interventions—including applied
    behavior analysis (ABA) therapy and speech, physical, and occupational therapies—are
    used to support communication, motor milestones, and adaptive functioning.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Behavioral Intervention
    term:
      id: NCIT:C15184
      label: Behavioral Intervention
  target_phenotypes:
  - preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  - 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:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He attends a special school for children with ASD and is receiving applied behavioral analysis (ABA) therapy."
    explanation: >-
      Documents applied behavior analysis (ABA) therapy for autism management in
      proband KD-1-3.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He received physical, speech, and occupational therapies for many years."
    explanation: >-
      Documents long-term physical, speech, and occupational therapies in proband
      KD-3-3.
- name: Gastrostomy Tube Feeding Support
  description: >-
    Enteral nutrition via gastrostomy tube placement is used in patients with severe
    infantile feeding difficulties and failure to thrive.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Follow-up over time demonstrated limited developmental progress with ongoing dependence on gastrostomy feeding."
    explanation: >-
      Documents gastrostomy feeding support in proband KD-2-3 with severe feeding
      difficulties and failure to thrive.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had a gastrostomy-button placed at 13 months of age and continues to use a gastrostomy tube to supplement table feeds."
    explanation: >-
      Documents gastrostomy tube supplementation for feeding difficulties in proband
      KD-3-3.
animal_models:
- name: Kdm5a-/- constitutive knockout mouse
  species: Mus musculus
  genotype: Kdm5a-/-
  background: C57BL/6J
  category: KNOCKOUT
  publication: PMID:33350388
  description: >-
    Constitutive Kdm5a knockout mice exhibit severe impairment in ultrasonic
    vocalizations, repetitive forepaw wringing and self-grooming behaviors,
    sociability deficits, severe disabilities in spatial learning and memory on the
    Morris water maze, reduced basal dendritic complexity and spine density in
    cortical layer II/III neurons, increased dendritic complexity and length in
    hippocampal neurons, and altered hippocampal excitatory (CA1, CA2, CA3) and
    inhibitory (Pvalb+, Sst+) neuronal subtype proportions.
  modeled_mechanisms:
  - target: Dysregulated Neurodevelopmental and Autism Risk Gene Transcription
    relationship: RECAPITULATES
    description: >-
      Hippocampal bulk RNA-seq in Kdm5a-/- mice recapitulates dysregulation of 450
      genes enriched in neurological processes, RNA splicing, neurogenesis, and ASD
      risk gene homologs.
    evidence:
    - reference: PMID:33350388
      reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Loss of KDM5A resulted in dysregulation of 450 genes (FDR-corrected p≤0.05 and log2 fold change ≥|0.3|) (Figure 5—source data 1), of which 191 genes were upregulated and 259 genes were downregulated"
      explanation: >-
        Demonstrates hippocampal transcriptional dysregulation of 450 genes in
        Kdm5a-/- mice.
  - target: Altered Hippocampal Neuronal Subtype Identity and Accelerated Maturation
    relationship: RECAPITULATES
    description: >-
      Single-nucleus RNA-seq of Kdm5a-/- mouse hippocampi demonstrates altered
      proportions of excitatory (CA1, CA2, CA3) and inhibitory (Pvalb+, Sst+)
      neuronal subtypes and accelerated maturation trajectories.
    evidence:
    - reference: PMID:37992166
      reference_title: "Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We analyzed the proportions of WT and Kdm5a−/− nuclei for each cluster and identified six distinct clusters that are most vulnerable to the loss of KDM5A: two inhibitory subclusters (Inh1 Pvalb positive and Inh2 Sst positive) and four excitatory subclusters (CA1.1, CA1.4, CA2, and CA3.4)"
      explanation: >-
        Shows altered hippocampal excitatory and inhibitory neuronal subtype
        proportions in Kdm5a-/- mice.
  - target: Hippocampal Neuronal Dendritic Hyper-Arborization
    relationship: RECAPITULATES
    description: >-
      Golgi-Cox staining and Sholl analysis of Kdm5a-/- mouse hippocampal excitatory
      neurons reveal increased dendritic branching complexity (~116%) and total
      dendritic length (~67%).
    evidence:
    - reference: PMID:37992166
      reference_title: "Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Sholl analysis revealed a significant increase in dendritic complexity (~116%) of hippocampal neurons from Kdm5a−/− mice (Fig. 5). Furthermore, hippocampal neurons from Kdm5a−/− mice have a significant increase in total dendritic length (~67%), while the mean dendritic length is unchanged compared with neurons from WT littermates"
      explanation: >-
        Demonstrates hippocampal dendritic hyper-arborization in Kdm5a-/- mice.
  - target: Cortical Pyramidal Neuron Dendritic and Spine Hypoplasia
    relationship: RECAPITULATES
    description: >-
      Golgi-Cox staining of cortical layer II/III pyramidal neurons in Kdm5a-/- mice
      shows severe reductions in basal dendritic complexity (~67%), length (~50%),
      and spine density (~33%).
    evidence:
    - reference: PMID:33350388
      reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Sholl analysis revealed a severe reduction (~67%) in dendritic complexity of cortical neurons from Kdm5a-/- mice (Figure 3A and B). Furthermore, 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"
      explanation: >-
        Demonstrates cortical dendritic and spine hypoplasia in Kdm5a-/- mice.
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "To validate our discovery, we generated a Kdm5a knockout mouse model (Kdm5a-/-) and confirmed that inactivating Kdm5a disrupts vocalization. In addition, Kdm5a-/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Loss of KDM5A also resulted in dysregulation of the hippocampal transcriptome."
    explanation: >-
      Characterizes the core behavioral, neuroanatomical, and transcriptomic
      phenotypes of Kdm5a-/- knockout mice.
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "WT and Kdm5a+/- littermates had normal learning abilities shown by the decrease in latency to locate the hidden platform over a period of 4 days, as well as normal memory by showing preference for the quadrant where the platform was during the probe test (target quadrant). However, Kdm5a-/- mice displayed severe disabilities in both learning and memory."
    explanation: >-
      Demonstrates severe spatial learning and memory deficits in Kdm5a-/- mice on
      the Morris water maze test.
  - reference: PMID:37992166
    reference_title: "Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We analyzed the proportions of WT and Kdm5a−/− nuclei for each cluster and identified six distinct clusters that are most vulnerable to the loss of KDM5A: two inhibitory subclusters (Inh1 Pvalb positive and Inh2 Sst positive) and four excitatory subclusters (CA1.1, CA1.4, CA2, and CA3.4)"
    explanation: >-
      Shows disrupted hippocampal excitatory and inhibitory neuronal subtype
      proportions in Kdm5a-/- mice.
discussions:
- discussion_id: kdm5a_heterozygous_mouse_vs_monoallelic_human_mismatch
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Why do monoallelic (de novo heterozygous or dominantly inherited) KDM5A
    variants cause syndromic intellectual disability, absent speech, and autism
    spectrum disorder in humans, whereas heterozygous Kdm5a+/- mice display
    normal spatial learning and memory on the Morris water maze?
  attaches_to:
  - animal_models#Kdm5a-/-
  rationale: >-
    In humans, half of the reported cohort (15/33 individuals across PMID:33350388
    and PMID:41889174) harbor monoallelic KDM5A variants and present with severe
    speech impairment, developmental delay, intellectual disability, and ASD
    indistinguishable in core neurodevelopmental spectrum from biallelic patients.
    By contrast, in the mouse model characterized by El Hayek et al. (2020,
    PMID:33350388), heterozygous Kdm5a+/- littermates exhibited normal spatial
    learning and memory on the Morris water maze, and severe vocalization,
    sociability, repetitive behavior, cognitive, and dendritic morphogenesis
    deficits required homozygous Kdm5a-/- inactivation. This dosage sensitivity
    divergence may reflect species differences in human cortical/hippocampal
    chromatin regulation by KDM5A or variant-specific dominant/hypomorphic effects
    of human missense and PLU1-domain alleles.
  evidence:
  - reference: PMID:33350388
    reference_title: "KDM5A mutations identified in autism spectrum disorder using forward genetics."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "WT and Kdm5a+/- littermates had normal learning abilities shown by the decrease in latency to locate the hidden platform over a period of 4 days, as well as normal memory by showing preference for the quadrant where the platform was during the probe test (target quadrant). However, Kdm5a-/- mice displayed severe disabilities in both learning and memory."
    explanation: >-
      Demonstrates that heterozygous Kdm5a+/- mice exhibit normal spatial learning
      and memory on the Morris water maze, whereas homozygous Kdm5a-/- mice display
      severe learning and memory deficits.
- discussion_id: kdm5a_h3k4me3_brain_chromatin_profiling_gap
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which specific genomic loci exhibit altered H3K4me2/3 occupancy in
    KDM5A-deficient patient neural cells or Kdm5a-/- mouse brain tissue?
  attaches_to:
  - pathophysiology#Impaired H3K4 Methylation Erasure and Chromatin State Imbalance
  rationale: >-
    Although KDM5A is biochemically established as an H3K4me2/3 histone
    demethylase and bulk and single-nucleus RNA-seq in patient lymphoblastoid
    cell lines (PMID:41889174) and Kdm5a-/- mouse hippocampus (PMID:33350388;
    PMID:37992166) demonstrate pronounced transcriptional dysregulation, direct
    chromatin profiling (e.g., H3K4me3 ChIP-seq or CUT&RUN) has not yet been
    reported in patient cells or Kdm5a-/- brain tissue to distinguish direct
    demethylase target promoters from secondary transcriptional cascades.
notes: >-
  El Hayek-Chahrour neurodevelopmental disorder (MONDO:0970951, OMIM #620820)
  exhibits both autosomal dominant (monoallelic) and autosomal recessive
  (biallelic) inheritance across 33 reported individuals from 28 families (31
  unique private variants). Low-count findings mentioned in single or isolated
  cases in the deep-research report (such as isolated ventricular septal defect
  distinct from the curated atrial septal defect phenotype, isolated
  ventriculomegaly, and ADHD in 1/9 of the 2020 cohort) were omitted to focus on
  recurrent cohort phenotypes. Pathophysiology nodes conform to the
  epigenetic_machinery_neurodevelopmental_dysregulation module.
📚

References & Deep Research

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 (2)

Record notes

El Hayek-Chahrour neurodevelopmental disorder (MONDO:0970951, OMIM #620820) exhibits both autosomal dominant (monoallelic) and autosomal recessive (biallelic) inheritance across 33 reported individuals from 28 families (31 unique private variants). Low-count findings mentioned in single or isolated cases in the deep-research report (such as isolated ventricular septal defect distinct from the curated atrial septal defect phenotype, isolated ventriculomegaly, and ADHD in 1/9 of the 2020 cohort) were omitted to focus on recurrent cohort phenotypes. Pathophysiology nodes conform to the epigenetic_machinery_neurodevelopmental_dysregulation module.

Address PR · 2026-10-14T10:32:27Z · View source

Addressed ai4c-reviewer feedback on PR #14121 and reconciled the entry against the deep-research report: added reference_title to all evidence items; split bundled neuronal/dendritic pathophysiology node into three tissue-specific atomic nodes (Altered Hippocampal Neuronal Subtype Identity and Accelerated Maturation, Hippocampal Neuronal Dendritic Hyper-Arborization, Cortical Pyramidal Neuron Dendritic and Spine Hypoplasia) with specific GO H3K4 demethylase bindings (GO:0034647, GO:0006482), removed redundant GO:0032453, clarified that altered H3K4me2/3 erasure is biochemically inferred rather than directly assayed in brain tissue, and removed the 6 unsupported phenotype causal edges (Hypoplasia of the corpus callosum, Microcephaly, Hypotonia, Feeding difficulties, Sleep disturbance, Seizure); connected Kdm5a-/- mouse model via modeled_mechanisms; added discussions for the heterozygous Kdm5a+/- mouse vs monoallelic human dosage mismatch (HUMAN_MODEL_MISMATCH, with Morris water maze evidence from PMID:33350388) and unassayed brain H3K4me2/3 levels (KNOWLEDGE_GAP); reconciled Intellectual disability (19/22 assessed present across 25 Table 1 columns [13/13 in the biallelic block including KD-9-3, 6/9 assessed in the monoallelic block], 3 absent, 3 unassessed) and Seizure (9/24 assessed across Table 1: 7/13 biallelic and 2/11 assessed monoallelic) cohort counts with Table 1 of PMID:41889174; replaced deprecated prevalence percentage with measure_type: CASES_IN_LITERATURE and prevalence_class: ULTRA_RARE; added MONDO synonyms (NEDEHC, neurodevelopmental disorder, El Hayek-Chahrour type, KDM5A-related neurodevelopmental disorder); added diagnosis (WES/WGS, CMA, Brain MRI) and treatments (anticonvulsant pharmacotherapy with lamotrigine [CHEBI:6367] and oxcarbazepine [CHEBI:7824], behavioral/rehabilitative therapies, gastrostomy feeding support); added Hypertelorism (HP:0000316), Microcephaly (HP:0000252), and Atrial septal defect (HP:0001631); and noted that single-case/low-count leads from the deep-research report (isolated ventricular septal defect, ventriculomegaly, and ADHD in 1/9 of the 2020 cohort) were intentionally left out.

Claude Code ▸
El Hayek-Chahrour Neurodevelopmental Disorder (NEDEHC; KDM5A-related neurodevelopmental disorder): Research Report
claude-haiku-4-5-20251001, claude-opus-5-5 9 citations 2026-10-14T15:52:53.086238

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:

PMID Citation Type What it contributes
33350388 El Hayek L et al., eLife 2020;9:e56883, doi:10.7554/eLife.56883 Mouse forward genetics plus a human cohort (n = 9) Discovers the gene and defines the disorder. Characterises the Kdm5a knockout mouse.
41889174 El Hayek L, Gogate A, … Chahrour MH, HGG Advances 2026 Human cohort (n = 24) plus in vitro and computational work Widens the variant and phenotype spectrum. Adds LCL protein levels, RNA-seq, structural modelling and ACMG reclassification.
37992166 El Hayek L et al., Sci Adv 2023, doi:10.1126/sciadv.adi0074 Mouse snRNA-seq Shows how hippocampal cell identity is disrupted.

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

System ID Notes
OMIM 620820 Phenotype entry; gene MIM 180202 (KDM5A).
MONDO MONDO:0970951 "El Hayek-Chahrour neurodevelopmental disorder"
MedGen C5935620
KEGG DISEASE H02803 Listed as a subtype of "Neurodevelopmental disorder with histone modification defect", alongside KMT2E, KDM6B, SETD1A, KAT5, DOT1L and other genes (KEGG H02803).
Orphanet None found
ICD-10/ICD-11 No specific code Code under F84.0 (autism), F72/F79 (intellectual disability) or the ICD-11 6A00 / LD90 family.
MeSH No specific heading Nearest: Autism Spectrum Disorder; Intellectual Disability.
HGNC hgnc:9886 (KDM5A) Write it in lowercase hgnc: in dismech. Verify before binding.

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".

Phenotype Type / onset Approx. frequency Suggested HPO (verify) Notes
Absent or severely impaired speech Sign; infancy/childhood ~100% impaired; ~70% absent HP:0001344 Absent speech; HP:0002463 Language impairment / HP:0000750 Delayed speech and language development The defining feature. All 9 in 2020 lacked speech.
Intellectual disability Childhood ~90–100% HP:0001249 Intellectual disability Universal in the biallelic group.
Global developmental delay Infancy ~90–100% HP:0001263
Autism spectrum disorder Childhood Majority (~75–85%) HP:0000729 Autistic behavior; HP:0000717 Autism Repetitive behaviour, hand flapping, echolalia
Muscle hypotonia Infancy ~50% overall; higher in biallelic (~10/13) HP:0001252
Seizures Childhood ~30%; more often biallelic (~7/13) HP:0001250
Feeding difficulties Infancy ~50% HP:0011968 Includes selective eating
Sleep disturbance Childhood ~40% HP:0002360
Joint hypermobility / hyperextensible joints — ~40% HP:0001382
Facial dysmorphism Congenital ~50% HP:0001999 MedGen lists frontal bossing, micrognathia and low-set ears
Thin / hypoplastic corpus callosum Congenital ~5 biallelic individuals HP:0002079 Hypoplasia of the corpus callosum
Ventriculomegaly (mild) — Several HP:0002119
Cerebral atrophy / reduced white matter / periventricular leukomalacia — Several biallelic HP:0002059; HP:0006970
Dandy-Walker spectrum with hydrocephalus Congenital 1 HP:0001305 Monoallelic
Congenital heart defects (ASD, VSD, complex CHD, coarctation, pulmonary stenosis) Congenital ~6–8 individuals HP:0001631 ASD; HP:0001629 VSD; HP:0001627
Inability to walk / motor impairment Childhood ~3 biallelic HP:0002540 Inability to walk; HP:0001270 Motor delay
ADHD / hyperactivity / attention deficit Childhood Several HP:0007018; HP:0000752
Self-injurious behaviour, aggression, anxiety, mood disorders Childhood/adult Several HP:0100716; HP:0000718; HP:0000739
Constipation — Several HP:0002019
Visual issues (cortical visual impairment, hyperopia) and hearing loss — Few HP:0100704; HP:0000365
Recurrent upper respiratory infections — Few HP:0002788
Microcephaly / macrocephaly Congenital Few, discordant HP:0000252 / HP:0000256 One case of progressive fetal macrocephaly; MedGen lists microcephaly
Toe syndactyly, clinodactyly, hallux valgus Congenital Few HP:0001770; HP:0030084; HP:0001822

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]):

Domain Residues
JmjN 18–59
ARID 85–170
PHD1 295–343
JmjC 470–586
Zn 676–728
PLU1 741–1,072
PHD2 1,163–1,215
PHD3 1,608–1,659
  • 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

Level Structures Suggested ontology terms
Primary organ Brain UBERON:0000955
Brain regions Hippocampus, especially CA1 (mouse); cerebral cortex; corpus callosum; lateral ventricles; cerebral white matter UBERON:0001954 hippocampus (Ammon's horn); UBERON:0003881 CA1 field; UBERON:0000956; UBERON:0002336; UBERON:0002285; UBERON:0002437
Secondary systems Heart (interatrial and interventricular septa); joints / connective tissue; gastrointestinal tract (feeding, constipation) UBERON:0000948
Subcellular Nucleus / chromatin GO:0005634; GO:0000785

Brain imaging findings are bilateral and diffuse.

8. Temporal development

Aspect Finding
Onset Congenital or infantile. Delayed milestones, hypotonia and feeding problems appear in infancy. Absent speech and ASD become apparent in the toddler years. One individual had progressive macrocephaly and polyhydramnios in late pregnancy.
Course Static or non-progressive, and lifelong. Ages at last evaluation ranged from 1 y 3 m to 29 y. Some adults have psychiatric comorbidity (bipolar disorder, depression, panic attacks).
Stages and remission None defined.
Critical period The mouse data place KDM5A's action in early hippocampal development ("a differentiation switch early in development"). This suggests an early prenatal or postnatal window, which bears on any future therapy.

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.

Intervention Suggested NCIT terms (verify) therapeutic_modality
Speech-language therapy and augmentative and alternative communication (AAC) Speech Language Therapy (NCIT:C159273) BEHAVIORAL
Applied behaviour analysis / behavioural therapy for ASD Behavioral counseling NCIT:C181743 or a behavioural-therapy term BEHAVIORAL
Physical and occupational therapy for hypotonia and motor delay Physical Therapy (NCIT:C15302); Occupational Therapy (NCIT:C121351) BEHAVIORAL
Antiseizure medication Pharmacotherapy (NCIT:C15986) with an agent class —
Feeding and nutritional support Dietary Intervention / Nutritional Support —
Cardiac surgical repair of septal defects where indicated Surgical Procedure (NCIT:C15329) SURGERY
Sleep management, e.g. melatonin Pharmacotherapy (NCIT:C15986); agent melatonin, CHEBI:16796 (verify) —
Genetic counselling Genetic Counseling (NCIT:C15240) —

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).