KDM1A-Related Neurodevelopmental Disorder

Mendelian MONDO:0014751 Pathograph 16 Show in embeddings browser hereditary disease multiple congenital anomalies/dysmorphic syndrome-intellectual disability

KDM1A-related neurodevelopmental disorder (CPRF; OMIM #616728; MONDO:0014751) is an ultra-rare autosomal dominant multiple congenital anomalies/dysmorphic syndrome caused by de novo heterozygous missense variants in KDM1A, which encodes lysine-specific histone demethylase 1 (LSD1). Affected individuals share global developmental delay, hypotonia, and a recognisable facial gestalt comprising a prominent forehead, arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips and widely spaced teeth. Cleft palate is a defining feature of the originally delineated phenotype but is not obligate; the Orphanet description of the entity additionally reports a high, narrow palate. The facial gestalt is itself variable — the fourth published proband had unspecific facial features and no palate abnormality. The condition was delineated in 2015-2016 from three unrelated children ascertained through family-driven social networking, and the published cohort remains very small — on the order of four detailed probands — so the full phenotypic spectrum is still being defined.

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1
Mappings
1
Inheritance
5
Pathophys.
12
Phenotypes
2
Gaps
16
Pathograph
1
Genes
3
Variants
4
Medical Actions
3
Differentials
2
Models
1
Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
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Mappings

MONDO
MONDO:0014751 palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome
skos:exactMatch MONDO
Primary MONDO identifier for this entity. MONDO:0014751 xrefs OMIM:616728 and Orphanet:477993 and carries the RO:0004003 gene relation to HGNC:29079 (KDM1A), which is the identity anchor used for the named-entity-confusion preflight on this purely descriptive disease label.
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Inheritance

1
Autosomal dominant, de novo HP:0000006
All reported probands carry heterozygous KDM1A missense variants that arose de novo; no vertical transmission has been reported and parents are unaffected. Expressivity is variable — palatal involvement, the feature that names the MONDO/Orphanet entity, was absent in the fourth published proband.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (2 references)
PMID:26656649 SUPPORT Human Clinical
"All three variants in KDM1A were missense variants predicted to be deleterious (minimum Polyphen-2 HumVar score of 0.962), result in amino acid substitutions of highly conserved amino acid residues (minimum GERP score was 5.72) in KDM1A, and have high CADD scores suggestive of dominant mutations..."
The three index probands each carried a de novo heterozygous missense variant with CADD scores in the range expected for dominant disease alleles, establishing autosomal dominant, de novo inheritance.
PMID:40530541 SUPPORT Human Clinical
"this first reported individual without palate abnormalities highlights the variable expressivity of this feature in the KDM1A-related phenotype."
Directly documents variable expressivity of the palatal phenotype within this autosomal dominant disorder.
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Discussions and Knowledge Gaps

2
Do the disease-associated KDM1A missense variants act through loss of function, gain of function, or a dominant-negative effect on the LSD1-CoREST complex?
KNOWLEDGE GAP OPEN kdm1a_loss_versus_gain_of_function
Attached to
pathophysiology#Impaired LSD1 Catalytic Activity and Protein Stability
Every reported allele is missense and clusters in the amine oxidase domain, and biochemistry shows only partial catalytic impairment plus reduced protein half-life — a hypomorphic profile. But mice heterozygous for a Kdm1a deletion are reported to be normal, which argues that simple haploinsufficiency is not sufficient to produce the phenotype. The absence of any reported truncating or whole-gene-deletion allele in this phenotype is consistent with a non-loss-of-function mechanism, but could equally reflect ascertainment in an ultra-rare cohort. Because LSD1 acts both catalytically and as a scaffold, a mutant protein that is stably incorporated into CoREST but catalytically crippled could poison the complex — a dominant-negative model that has not been tested. The distinction matters therapeutically: pharmacological LSD1 inhibition, which is beneficial in mouse models of Kabuki syndrome, would be expected to worsen a loss-of-function KDM1A disorder.
Proposed experiments
Truncating-allele cohort screen
kdm1a_truncating_allele_cohort_screen
Screen large developmental-disorder sequencing cohorts for truncating KDM1A alleles and phenotype any carriers.
Supporting outcome
  • Recovery of truncating carriers with the CPRF phenotype would support a simple loss-of-function/haploinsufficiency mechanism.
Refuting outcome
  • Truncating carriers who are unaffected, or complete absence of truncating alleles despite adequate power, would argue against haploinsufficiency and favour a dominant-negative or altered-specificity mechanism.
Patient-allele knock-in versus null allele comparison
kdm1a_knockin_versus_null_comparison
Generate mouse or human iPSC models carrying p.Glu403Lys, p.Asp580Gly or p.Tyr785His in the heterozygous state and compare craniofacial and neurodevelopmental phenotypes and transcriptomes with isogenic heterozygous-null controls.
Supporting outcome
  • A missense knock-in phenotype more severe than the heterozygous null would support a dominant-negative or gain-of-function mechanism.
Refuting outcome
  • Phenotypic equivalence between missense knock-in and heterozygous null would support simple loss of function.
CoREST incorporation and target-locus chromatin profiling
kdm1a_corest_incorporation_profiling
Determine whether mutant LSD1 is still incorporated into the CoREST complex, and measure H3K4me1/2 and target-gene expression at LSD1-CoREST loci in patient-derived neurons.
Supporting outcome
  • Retained complex incorporation with locally increased H3K4me1/2 and target derepression would support complex poisoning by a dominant-negative mechanism.
Refuting outcome
  • Failure of mutant LSD1 to be incorporated into CoREST would favour simple reduction of functional complex.
Show evidence (2 references)
PMID:26656649 SUPPORT Human Clinical
"Nevertheless, it remains to be seen if the phenotypes we report to be caused by variants in KDM1A are due to loss or gain of function."
The delineating study explicitly leaves the direction of effect unresolved.
PMID:27094131 SUPPORT In Vitro
"This depicts a perturbed interplay of catalytic and non-catalytic processes at the origin of the pathology."
PARTIAL — biochemistry shows combined catalytic and non-catalytic perturbation but does not resolve loss versus gain versus dominant-negative at the level of the intact complex in vivo.
Given that mice heterozygous for a Kdm1a deletion are reported to be apparently normal and fertile while homozygous knockout is embryonic-lethal, does any available model reproduce the human heterozygous missense-variant syndrome — and in particular its craniofacial arm?
HUMAN MODEL MISMATCH OPEN kdm1a_heterozygous_mouse_model_mismatch
Attached to
pathophysiology#Impaired LSD1 Catalytic Activity and Protein Stability pathophysiology#Dysregulated Neurodevelopmental and Craniofacial Gene Programs
The mouse Kdm1a allelic series brackets the human condition without reproducing it. The homozygous null dies in early embryogenesis, so it cannot be used to study postnatal neurodevelopment or craniofacial patterning. The heterozygous null is reported as phenotypically normal, so it does not reproduce the human dysmorphism, hypotonia or developmental delay. Human disease sits between these: a stably expressed but catalytically impaired protein at one of two alleles. The two strongest modern datasets share this limitation — the adult forebrain conditional knockout models complete somatic loss in mature neurons, and the zebrafish line is a knockout. Most importantly, the craniofacial and palatal arm of the phenotype, which supplies the disorder's name, has never been modelled with a KDM1A patient allele at all; the supporting evidence comes from knockdown of the partner gene PHF21A. This is a model-fidelity question, not an absence of data.
Proposed experiments
Heterozygous patient-allele knock-in mouse
kdm1a_heterozygous_knockin_mouse
Build heterozygous knock-in mice carrying the human missense substitutions and phenotype palate, craniofacial skeleton, muscle tone and behaviour against both wild-type and heterozygous-null littermates.
Supporting outcome
  • Reproduction of palatal, craniofacial and neurodevelopmental phenotypes would validate the mouse as a model of the human disorder.
Refuting outcome
  • A normal heterozygous knock-in mouse would indicate that the mouse cannot model this disorder and would redirect effort to human cellular models.
Patient-derived iPSC neurons and cranial neural crest cells
kdm1a_ipsc_neural_crest_model
Differentiate patient-derived iPSCs into cortical neurons and cranial neural crest cells and test whether the human alleles perturb LSD1-CoREST target-gene repression in the relevant human cell types, against isogenic corrected controls.
Supporting outcome
  • Allele-dependent derepression of LSD1-CoREST targets in human neural crest would establish the craniofacial arm of the mechanism in human cells.
Refuting outcome
  • Absence of any transcriptional consequence in patient neural crest would argue that the craniofacial phenotype arises by a different route.
Show evidence (2 references)
PMID:26656649 SUPPORT Model Organism
"mice heterozygous for a Kdm1a deletion are apparently normal and fertile"
The heterozygous null mouse does not recapitulate the human heterozygous phenotype, establishing the model-fidelity mismatch.
PMID:26656649 SUPPORT Model Organism
"Homozygous knockout of Kdm1a in mice is lethal during early embryogenesis"
The homozygous null is embryonic-lethal, so it cannot model the postnatal human phenotype either; the two available mouse genotypes bracket rather than reproduce the human condition.
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Pathophysiology

5
De Novo Missense Variants in the LSD1 Amine Oxidase Domain
All three index disease alleles alter highly conserved residues inside the FAD-dependent amine oxidase domain of LSD1/KDM1A. This domain comprises the FAD-binding and substrate-binding subdomains, and the substrate-binding subdomain forms the active-site cavity through which LSD1 demethylates mono- and dimethylated histone H3 lysine 4. Clustering of independently ascertained de novo variants in a single functional domain is itself evidence that the lesion is domain-specific rather than a matter of gene dosage.
KDM1A hgnc:29079 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDM1A (hgnc:29079). hgnc:29079 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired LSD1 Catalytic Activity and Protein Stability Active-site substitutions partially inactivate the demethylase and destabilise the protein.
Impaired LSD1 Engagement of Developmental Transcription Factors The same substitutions differentially disrupt the protein-protein interfaces through which LSD1 is recruited by transcription factors.
Show evidence (2 references)
PMID:26656649 SUPPORT Human Clinical
"all three mutations alter residues in the amine-oxidase domain (Figure 2B), which is composed of FAD-binding and substrate-binding functional subdomains"
Establishes that the disease-associated variants cluster in the catalytic amine oxidase domain of LSD1.
PMID:26656649 SUPPORT In Vitro
"The active site cavity of KDM1A is formed by the substrate-binding subdomain"
Links the affected substrate-binding subdomain to the active-site cavity; the source continues that this cavity "is required for KDM1A to demethylate H3K4me1/2 and repress transcription". Tagged IN_VITRO because this is a structural/biochemical assertion in the discussion rather than a clinical observation.
Impaired LSD1 Catalytic Activity and Protein Stability
In vitro and cellular assays of the three index variants show partial — not complete — impairment of H3K4 demethylase activity, together with a reduction in the cellular half-life of the mutant protein. The hypomorphic rather than null character of the biochemical defect is consistent with the survival of affected individuals, given that complete loss of Kdm1a is embryonic-lethal in mouse.
KDM1A hgnc:29079 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDM1A (hgnc:29079). hgnc:29079 is a gene from the HUGO Gene Nomenclature Committee.
histone H3K4 demethylase activity GO:0032453 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone H3K4 demethylase activity (GO:0032453). GO:0032453 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Loss of LSD1-CoREST-Mediated Transcriptional Repression Reduced demethylase output and reduced steady-state LSD1 weaken repression at LSD1-CoREST target loci.
Show evidence (2 references)
PMID:27094131 SUPPORT In Vitro
"The three mutations (Glu403Lys, Asp580Gly and Tyr785His) affect active-site residues and lead to a partial impairment of catalytic activity."
Direct biochemical demonstration of partial catalytic impairment by the disease alleles.
PMID:27094131 SUPPORT In Vitro
"Moreover, cellular data indicate a decrease in the protein cellular half-life."
Reduced protein stability compounds the catalytic defect, lowering effective LSD1 activity in cells.
Impaired LSD1 Engagement of Developmental Transcription Factors
Beyond catalysis, the disease variants differentially perturb the ability of LSD1 to bind transcription factors that orchestrate developmental gene programs. Because LSD1 acts as a scaffold as well as an enzyme, this non-catalytic defect is a mechanistically separate arm of the pathology and may explain why different active-site substitutions produce overlapping but not identical phenotypes.
KDM1A hgnc:29079 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDM1A (hgnc:29079). hgnc:29079 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Dysregulated Neurodevelopmental and Craniofacial Gene Programs Failure to be recruited by developmental transcription factors misdirects the LSD1-dependent repressive program.
Show evidence (2 references)
PMID:27094131 SUPPORT In Vitro
"They also differentially perturb the ability of LSD1 to engage transcription factors that orchestrate key developmental programs."
Establishes a non-catalytic, protein-interaction arm of the molecular defect distinct from loss of demethylase activity.
PMID:27094131 SUPPORT In Vitro
"This depicts a perturbed interplay of catalytic and non-catalytic processes at the origin of the pathology."
The authors' own synthesis that the pathology arises from combined catalytic and non-catalytic dysfunction.
Loss of LSD1-CoREST-Mediated Transcriptional Repression
LSD1 functions within the BRAF-HDAC/CoREST corepressor complex, together with PHF21A (BHC80), to keep non-neuronal and neuronal gene sets correctly silenced and to time neuronal gene expression during development. Reduced LSD1 activity or occupancy therefore derepresses this target set. Two independent lines support the step. In mouse, inducible forebrain-restricted Kdm1a deletion activates non-neuronal genes normally silenced by the polycomb repressor complex and weakens their topological segregation from neighbouring active chromatin. In humans, haploinsufficiency of the LSD1 partner PHF21A derepresses the neuronal gene SCN3A with reduced LSD1 promoter occupancy, and PHF21A knockdown in zebrafish causes craniofacial abnormalities and neuronal apoptosis.
KDM1A hgnc:29079 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KDM1A (hgnc:29079). hgnc:29079 is a gene from the HUGO Gene Nomenclature Committee.
negative regulation of transcription by RNA polymerase II GO:0000122 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of transcription by RNA polymerase II (GO:0000122). GO:0000122 is a biological process from the Gene Ontology. ↓ DECREASED chromatin organization GO:0006325 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromatin organization (GO:0006325). GO:0006325 is a biological process from the Gene Ontology. ⚠ ABNORMAL
chromatin GO:0000785 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves chromatin (GO:0000785). GO:0000785 is a cellular component from the Gene Ontology.
Downstream
Dysregulated Neurodevelopmental and Craniofacial Gene Programs Derepression of LSD1-CoREST target genes mistimes neuronal and craniofacial developmental programs.
Show evidence (4 references)
PMID:22770980 SUPPORT In Vitro
"Along with lysine-specific demethylase 1 (LSD1), PHF21A, also known as BHC80, is a component of the BRAF-histone deacetylase complex that represses target-gene transcription."
Places LSD1 in the BRAF-HDAC/CoREST repressive complex whose disruption is the proposed proximal cellular lesion. Tagged IN_VITRO because this is a statement of complex composition from biochemical work, not a clinical observation.
PMID:22770980 SUPPORT In Vitro
"In lymphoblastoid cell lines from two translocation subjects in whom PHF21A was directly disrupted by the respective breakpoints, we observed derepression of the neuronal gene SCN3A and reduced LSD1 occupancy at the SCN3A promoter, supporting a direct functional consequence of PHF21A..."
Indirect (PARTIAL) support on two counts — the derepression was demonstrated for the LSD1 partner PHF21A rather than for KDM1A variants themselves, and it was measured in patient-derived lymphoblastoid cell lines (hence IN_VITRO) rather than in neural tissue. It nevertheless shows that impairing this complex derepresses neuronal targets and reduces LSD1 promoter occupancy.
PMID:38453932 SUPPORT Model Organism
"we find that Kdm1a elimination causes the neuronal activation of nonneuronal genes that are silenced by the polycomb repressor complex and interspersed with active genes."
Conditional Kdm1a deletion in adult mouse forebrain neurons directly demonstrates that loss of Kdm1a derepresses silenced target genes, the cellular step modelled by this node.
+ 1 more reference
Dysregulated Neurodevelopmental and Craniofacial Gene Programs
The convergent consequence of reduced LSD1 catalytic output, reduced LSD1 protein, and impaired transcription-factor engagement is mistimed and misplaced expression of the gene programs that build the developing brain and the craniofacial skeleton, including the palate. In zebrafish, kdm1a knockout suppresses CNS neurogenesis, shortens motor-neuron axons and downregulates neurodevelopmental genes, producing locomotor and learning/memory deficits. The craniofacial arm is the weaker link: it is supported by knockdown of the LSD1 partner PHF21A rather than by any patient-variant craniofacial model. Together these produce the two-part clinical picture — global developmental delay with hypotonia, and a recognisable facial gestalt with palatal anomalies — that defines the syndrome.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
regulation of neuron differentiation GO:0045664 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of neuron differentiation (GO:0045664). GO:0045664 is a biological process from the Gene Ontology. ⚠ ABNORMAL roof of mouth development GO:0060021 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal roof of mouth development (GO:0060021). GO:0060021 is a biological process from the Gene Ontology. ⚠ ABNORMAL embryonic cranial skeleton morphogenesis GO:0048701 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal embryonic cranial skeleton morphogenesis (GO:0048701). GO:0048701 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (3 references)
PMID:26656649 SUPPORT Human Clinical
"de novo variants in KDM1A cause a newly-delineated condition characterized by developmental delay, hypotonia, and characteristic facial features."
States the clinical output of the mechanism: a combined neurodevelopmental and craniofacial phenotype.
PMID:41351445 SUPPORT Model Organism
"Kdm1a deficiency suppressed central nervous system (CNS) neurogenesis in Tg (HuC:egfp) zebrafish, reduced motor neuron axon length in Tg (hb9:egfp) zebrafish and downregulated the expression of neurodevelopment related genes at 96 hours post fertilization (hpf)."
Loss of kdm1a directly impairs neurogenesis, axon growth and neurodevelopmental gene expression, the neural arm of this node.
PMID:22770980 SUPPORT Model Organism
"suppression of the latter led to both craniofacial abnormalities and neuronal apoptosis."
Indirect (PARTIAL) support from zebrafish knockdown of the LSD1 partner PHF21A, showing that disrupting this complex during development produces both the craniofacial and the neuronal arms of the phenotype. No patient-variant craniofacial model exists.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for KDM1A-Related 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.
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Phenotypes

12
Head and Neck 4
Cleft Palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24838796 SUPPORT Human Clinical
"We report on a male with developmental delays, cleft palate, craniofacial dysmorphism, hypotonia, and central nervous system anomalies including diminished white matter with thinning of the corpus callosum."
Cleft palate in the index proband carrying the de novo KDM1A p.Tyr785His variant.
PMID:40530541 SUPPORT Human Clinical
"this first reported individual without palate abnormalities highlights the variable expressivity of this feature in the KDM1A-related phenotype."
PARTIAL — confirms cleft palate as a canonical feature of the syndrome while explicitly documenting that it is not present in every affected individual.
Prominent Forehead FREQUENT HP:0011220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent forehead (HP:0011220). HP:0011220 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26656649 SUPPORT Human Clinical
"In particular, all three individuals share a prominent forehead, slightly arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips, and wide-spaced teeth (Figure 1)."
Prominent forehead was present in all three delineating probands.
PMID:40530541 SUPPORT Human Clinical
"mild intellectual disability, and unspecific facial features but without palate abnormalities."
Supplies the fourth-proband denominator: the distinctive gestalt was absent in this individual, so the derived frequency across the published cohort is 3/4 = 75%, which maps to FREQUENT (30-79%) rather than VERY_FREQUENT.
Arched Eyebrows FREQUENT Highly arched eyebrow HP:0002553 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arched eyebrows, annotated with Highly arched eyebrow (HP:0002553). HP:0002553 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26656649 SUPPORT Human Clinical
"In particular, all three individuals share a prominent forehead, slightly arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips, and wide-spaced teeth (Figure 1)."
Arched eyebrows in all three delineating probands.
PMID:40530541 SUPPORT Human Clinical
"mild intellectual disability, and unspecific facial features but without palate abnormalities."
Fourth-proband denominator: 3/4 = 75%, mapping to FREQUENT rather than VERY_FREQUENT.
Elongated Palpebral Fissures FREQUENT Long palpebral fissure HP:0000637 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elongated palpebral fissures, annotated with Long palpebral fissure (HP:0000637). HP:0000637 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26656649 SUPPORT Human Clinical
"In particular, all three individuals share a prominent forehead, slightly arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips, and wide-spaced teeth (Figure 1)."
Elongated palpebral fissures in all three delineating probands.
PMID:40530541 SUPPORT Human Clinical
"mild intellectual disability, and unspecific facial features but without palate abnormalities."
Fourth-proband denominator: 3/4 = 75%, mapping to FREQUENT rather than VERY_FREQUENT.
Musculoskeletal 1
Hypotonia VERY_FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscular hypotonia, annotated with Hypotonia (HP:0001252), qualified as congenital onset. HP:0001252 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:26656649 SUPPORT Human Clinical
"All three children with de novo KDM1A variants had similar, albeit non-specific, clinical findings (Table 1) including similar facial features, global developmental delay and hypotonia"
Hypotonia was shared by all three delineating probands; with the fourth published proband that is 4/4 = 100%, curated as VERY_FREQUENT rather than OBLIGATE because n=4 cannot establish complete penetrance.
PMID:40530541 SUPPORT Human Clinical
"this case report expands knowledge on the phenotypic spectrum, including intellectual disability with global developmental delay, muscular hypotonia, and variable dysmorphic anomalies"
Muscular hypotonia confirmed in the fourth published proband.
Nervous System 2
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26656649 SUPPORT Human Clinical
"All three children with de novo KDM1A variants had similar, albeit non-specific, clinical findings (Table 1) including similar facial features, global developmental delay and hypotonia"
All three delineating probands had global developmental delay. With the fourth published proband (PMID:40530541) that is 4/4 = 100%; VERY_FREQUENT rather than OBLIGATE is used because n=4 cannot establish complete penetrance.
PMID:40530541 SUPPORT Human Clinical
"KDM1A-related neurodevelopmental disorder (CPRF, OMIM #616728) is characterized by cleft palate, global developmental delay, and distinct facial gestalt"
The most recent report confirms global developmental delay as a defining feature.
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40530541 SUPPORT Human Clinical
"a 13-year-old boy with a novel heterozygous, likely pathogenic germline missense variant in exon 16 of KDM1A with developmental delay, hypotonia, mild intellectual disability, and unspecific facial features but without palate abnormalities."
Documents mild intellectual disability in a molecularly confirmed proband.
Other 5
Wide Nasal Bridge FREQUENT HP:0000431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide nasal bridge (HP:0000431). HP:0000431 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26656649 SUPPORT Human Clinical
"In particular, all three individuals share a prominent forehead, slightly arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips, and wide-spaced teeth (Figure 1)."
Wide nasal bridge in all three delineating probands.
PMID:40530541 SUPPORT Human Clinical
"mild intellectual disability, and unspecific facial features but without palate abnormalities."
Fourth-proband denominator: 3/4 = 75%, mapping to FREQUENT rather than VERY_FREQUENT.
Thin Lips FREQUENT Thin vermilion border HP:0000233 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin lips, annotated with Thin vermilion border (HP:0000233). HP:0000233 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26656649 SUPPORT Human Clinical
"In particular, all three individuals share a prominent forehead, slightly arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips, and wide-spaced teeth (Figure 1)."
Thin lips in all three delineating probands.
PMID:40530541 SUPPORT Human Clinical
"mild intellectual disability, and unspecific facial features but without palate abnormalities."
Fourth-proband denominator: 3/4 = 75%, mapping to FREQUENT rather than VERY_FREQUENT.
Widely Spaced Teeth FREQUENT HP:0000687 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Widely spaced teeth (HP:0000687). HP:0000687 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26656649 SUPPORT Human Clinical
"In particular, all three individuals share a prominent forehead, slightly arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips, and wide-spaced teeth (Figure 1)."
Wide-spaced teeth in all three delineating probands.
PMID:40530541 SUPPORT Human Clinical
"mild intellectual disability, and unspecific facial features but without palate abnormalities."
Fourth-proband denominator: 3/4 = 75%, mapping to FREQUENT rather than VERY_FREQUENT.
Thin Corpus Callosum HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24838796 SUPPORT Human Clinical
"We report on a male with developmental delays, cleft palate, craniofacial dysmorphism, hypotonia, and central nervous system anomalies including diminished white matter with thinning of the corpus callosum."
Thinning of the corpus callosum reported on neuroimaging in the index proband.
Reduced Cerebral White Matter Volume HP:0034295 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diminished cerebral white matter, annotated with Reduced cerebral white matter volume (HP:0034295). HP:0034295 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24838796 SUPPORT Human Clinical
"central nervous system anomalies including diminished white matter with thinning of the corpus callosum."
Diminished cerebral white matter was reported on neuroimaging in the index proband.
🧬

Genetic Associations

1
KDM1A de novo missense variants (Causative)
Gene: KDM1A hgnc:29079 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KDM1A (hgnc:29079). hgnc:29079 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (3 references)
PMID:24838796 SUPPORT Human Clinical
"c.2353T>C, predicting p.Tyr785His in KDM1A, a gene not previously associated with a human phenotype."
First report of a deleterious KDM1A sequence variant in a human, in the proband who later became Family A of the delineating cohort.
PMID:26656649 SUPPORT Human Clinical
"KDM1A is in the top 2% of evolutionarily constrained genes, i.e. genes that are intolerant to functional variation, and this set of genes is enriched for genes known to underlie dominant Mendelian phenotypes"
Population-constraint evidence supporting KDM1A as a dominant disease gene and the pathogenicity of the de novo missense alleles.
PMID:27094131 SUPPORT In Vitro
"The three mutations (Glu403Lys, Asp580Gly and Tyr785His) affect active-site residues and lead to a partial impairment of catalytic activity."
Names the three index alleles and shows they are functionally deleterious, linking genotype to a measurable molecular consequence.
Variants (3)
KDM1A p.(Tyr785His) Pathogenic
Gene: KDM1A hgnc:29079 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in KDM1A (hgnc:29079). hgnc:29079 is a gene from the HUGO Gene Nomenclature Committee.
NM_001009999.2 c.2353T>C. De novo missense variant in the amine oxidase domain, identified in the index proband (Family A) who also carried an ANKRD11 in-frame deletion later argued not to be causal.
Functional effects
LSD1 histone H3K4 demethylase activity
Partial impairment of demethylase activity, perturbed engagement of developmental transcription factors, and reduced cellular protein half-life.
Show evidence (1 reference)
PMID:24838796 SUPPORT Human Clinical
"c.2353T>C, predicting p.Tyr785His in KDM1A, a gene not previously associated with a human phenotype."
Original description of the p.Tyr785His allele.
KDM1A p.(Glu403Lys) Pathogenic
Gene: KDM1A hgnc:29079 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in KDM1A (hgnc:29079). hgnc:29079 is a gene from the HUGO Gene Nomenclature Committee.
De novo missense variant affecting an active-site residue of the LSD1 amine oxidase domain.
Functional effects
LSD1 histone H3K4 demethylase activity
Partial loss of catalytic activity with altered transcription-factor binding.
Show evidence (1 reference)
PMID:27094131 SUPPORT In Vitro
"The three mutations (Glu403Lys, Asp580Gly and Tyr785His) affect active-site residues and lead to a partial impairment of catalytic activity."
Functional characterisation of the p.Glu403Lys allele.
KDM1A p.(Asp580Gly) Pathogenic
Gene: KDM1A hgnc:29079 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in KDM1A (hgnc:29079). hgnc:29079 is a gene from the HUGO Gene Nomenclature Committee.
De novo missense variant affecting an active-site residue of the LSD1 amine oxidase domain.
Functional effects
LSD1 histone H3K4 demethylase activity
Partial loss of catalytic activity with altered transcription-factor binding.
Show evidence (1 reference)
PMID:27094131 SUPPORT In Vitro
"The three mutations (Glu403Lys, Asp580Gly and Tyr785His) affect active-site residues and lead to a partial impairment of catalytic activity."
Functional characterisation of the p.Asp580Gly allele.
💊

Medical Actions

4
Multidisciplinary Supportive Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No disease-modifying therapy exists. Management is supportive: coordinated developmental surveillance, educational and neuropsychological support for intellectual disability, and hearing and vision screening. Individual therapy modalities are curated separately below. No KDM1A-specific outcome study has been published; this recommendation is extrapolated from general practice for syndromic developmental delay.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Physical Therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Physiotherapy and occupational therapy for the congenital hypotonia and associated gross- and fine-motor delay, as for other syndromic neurodevelopmental disorders.
Target Phenotypes: Muscular hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Muscular hypotonia, annotated with Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Speech and Language Therapy
Action: speech and language therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech and language therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Speech-language therapy, including augmentative communication where needed, for the expressive-language component of the developmental delay and for the speech consequences of palatal clefting where present.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Cleft Palate Repair
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Surgical repair of the cleft palate, when present, follows standard cleft-team protocols with subsequent feeding, audiology, speech, dental and orthodontic support. As with supportive care, no KDM1A-specific surgical outcome data exist.
Target Phenotypes: Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
🔬

Diagnosis

1
Trio Exome or Genome Sequencing
There is no biochemical or imaging marker for this disorder and the clinical presentation (developmental delay, hypotonia, non-specific dysmorphism) is not distinctive enough to be diagnosed on examination. Diagnosis is molecular: trio exome or genome sequencing analysed under a de novo model, with KDM1A also included on broad developmental-delay/intellectual-disability, cleft-palate and chromatinopathy panels. Because every reported allele is a missense change, variant interpretation requires confirming de novo status by parental testing and weighing domain location and conservation; the index cohort was ascertained exactly this way, and the fourth proband was diagnosed by trio genome sequencing only after karyotype, microarray, FMR1 repeat testing and a metabolic workup were unrevealing.
No disease-specific DNA-methylation episignature has been validated for KDM1A, unlike several other chromatinopathies; the 2025 report proposes episignature analysis as a future means of classifying KDM1A variants of uncertain significance.
Show evidence (1 reference)
PMID:26656649 SUPPORT Human Clinical
"Analysis of variants from ES under a de novo mutation model confirmed the presence of a different de novo variant in KDM1A (Refseq NM_001009999.2) in each of Families A and B"
Exome sequencing analysed under a de novo model is the diagnostic route by which the disorder was established and by which affected individuals are identified.
📊

Prevalence

1
Worldwide
Unknown Ultra Rare
Only a handful of molecularly confirmed probands have been published since the condition was delineated in 2015-2016. No population-based prevalence estimate exists; the Orphanet record (ORPHA:477993) carries no numeric prevalence class.
Show evidence (1 reference)
PMID:40530541 SUPPORT Human Clinical
"phenotypic knowledge of this ultra-rare autosomal dominant disorder is limited."
The most recent published report characterises the disorder as ultra-rare with limited phenotypic knowledge, supporting the qualitative ULTRA_RARE prevalence class in the absence of any numeric estimate.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from KDM1A-Related Neurodevelopmental Disorder:

Kabuki syndrome MONDO:0016512
Overlapping Features Kabuki syndrome (KMT2D, KDM6A) is the principal differential: it shares developmental delay, hypotonia, elongated palpebral fissures, arched eyebrows, cleft palate and dental anomalies, and the index KDM1A proband was initially described as having features of Kabuki syndrome. Both are chromatin-modifier disorders acting on histone H3 lysine 4 methylation — KMT2D writes and KDM1A erases the mark — which plausibly explains the convergence. The delineating study concluded that the KDM1A condition overlaps with but is nonetheless distinct from Kabuki syndrome.
Distinguishing Features
  • Pathogenic KMT2D or KDM6A variants rather than de novo KDM1A missense variants.
  • Eversion of the lateral third of the lower eyelid, a Kabuki hallmark not described in the KDM1A phenotype.
  • Persistent fetal fingertip pads, postnatal growth deficiency, recurrent otitis media and immune deficiency, none of which is part of the described KDM1A phenotype.
Show evidence (1 reference)
PMID:26656649 SUPPORT Human Clinical
"mutations in KDM1A cause a condition that has phenotypic overlap with Kabuki syndrome but is nonetheless distinct."
Explicit statement that the KDM1A condition overlaps with, but is separable from, Kabuki syndrome.
KBG syndrome MONDO:0007846
Overlapping Features KBG syndrome (ANKRD11 haploinsufficiency) entered the differential because the index proband carried a second de novo variant, ANKRD11 c.2606_2608delAGA p.(Lys869del), and was initially reported as a dual diagnosis. The delineating study argued against a KBG contribution: nearly all KBG-causing ANKRD11 alleles are truncating, the in-frame deletion has a CADD score well below the dominant-disease range, and the proband lacked macrodontia of the upper central incisors. This is a resolved dual-diagnosis differential rather than a live clinical one, but it is a standing reminder to consider blended diagnoses in this disorder.
Distinguishing Features
  • Macrodontia of the upper central incisors is the hallmark of KBG syndrome and was absent in the KDM1A index proband, whose dental phenotype is widely spaced teeth.
  • KBG-causing ANKRD11 alleles are overwhelmingly truncating, whereas the KDM1A alleles are missense.
Show evidence (1 reference)
PMID:26656649 SUPPORT Human Clinical
"variant in ANKRD11 in Family A does not cause KBG syndrome."
The delineating study argues against a KBG syndrome contribution in the index proband. The quote is deliberately truncated because the full sentence contains a bracketed HGVS protein change that the reference validator strips; the full sentence reads "Additional evidence suggests that the c.2606_2608delAGA [p.(Lys869del)] variant in ANKRD11 in Family A does not cause KBG syndrome" — i.e. the authors hedge with "suggests" rather than asserting exclusion outright.
🐁

Animal Models

2
Inducible, forebrain-restricted conditional Kdm1a knockout Mus musculus Conditional knockout
Inducible deletion of Kdm1a restricted to adult forebrain neurons, profiled by transcriptomics, epigenomics, chromatin-conformation analysis and super-resolution microscopy. Loss of Kdm1a derepresses non-neuronal genes silenced by the polycomb repressor complex and weakens the topological segregation of those genes from neighbouring active chromatin. This is the strongest available demonstration of what the chromatin lesion does at the level of neuronal genome organisation, but it models complete somatic loss in mature neurons rather than a germline heterozygous missense allele.
Derepression of PRC2-silenced non-neuronal genes in neurons Weakened topological segregation of Kdm1a-repressed chromatin domains
Species
Mus musculus
Genotype
Inducible, forebrain-restricted conditional Kdm1a knockout
Show evidence (1 reference)
PMID:38453932 SUPPORT Model Organism
"To explore Kdm1a's function in adult neurons, we develop inducible and forebrain-restricted Kdm1a knockouts."
Describes the conditional mouse model and its design.
CRISPR/Cas9 kdm1a knockout Danio rerio Knockout
CRISPR/Cas9 kdm1a-deficient zebrafish larvae show developmental toxicity and abnormal neurobehaviour, with suppressed CNS neurogenesis, shortened motor-neuron axons, downregulated neurodevelopmental gene expression and increased autophagy/apoptosis gene expression. This supports impaired neurogenesis as a downstream consequence of loss of kdm1a, but it is a knockout rather than a patient-allele knock-in.
Locomotor abnormalities Learning and memory deficits Suppressed CNS neurogenesis Reduced motor neuron axon length
Species
Danio rerio
Genotype
CRISPR/Cas9 kdm1a knockout
Show evidence (1 reference)
PMID:41351445 SUPPORT Model Organism
"We found that kdm1a knockout zebrafish exhibited developmental toxicity and abnormal neurobehaviors, including locomotor abnormalities, and learning and memory deficits."
Establishes the neurobehavioural consequence of kdm1a loss in a vertebrate model.
{ }

Source YAML

click to show 
name: KDM1A-Related Neurodevelopmental Disorder
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: KDM1A-related neurodevelopmental disorder
  term:
    id: MONDO:0014751
    label: palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome
description: >-
  KDM1A-related neurodevelopmental disorder (CPRF; OMIM #616728;
  MONDO:0014751) is an ultra-rare autosomal dominant multiple congenital
  anomalies/dysmorphic syndrome caused by de novo heterozygous missense
  variants in KDM1A, which encodes lysine-specific histone demethylase 1
  (LSD1). Affected individuals share global developmental delay, hypotonia,
  and a recognisable facial gestalt comprising a prominent forehead, arched
  eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips and
  widely spaced teeth. Cleft palate is a defining feature of the originally
  delineated phenotype but is not obligate; the Orphanet description of the
  entity additionally reports a high, narrow palate. The facial gestalt is
  itself variable — the fourth published proband had unspecific facial features
  and no palate abnormality. The condition was delineated in 2015-2016 from three
  unrelated children ascertained through family-driven social networking, and
  the published cohort remains very small — on the order of four detailed
  probands — so the full phenotypic spectrum is still being defined.
synonyms:
- CPRF
- cleft palate, psychomotor retardation, and distinctive facial features
- palatal anomalies-multiple diastemata-facial dysmorphism-developmental delay syndrome
parents:
- hereditary disease
- multiple congenital anomalies/dysmorphic syndrome-intellectual disability
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014751
      label: palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier for this entity. MONDO:0014751 xrefs OMIM:616728
      and Orphanet:477993 and carries the RO:0004003 gene relation to
      HGNC:29079 (KDM1A), which is the identity anchor used for the
      named-entity-confusion preflight on this purely descriptive disease label.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    Only a handful of molecularly confirmed probands have been published since
    the condition was delineated in 2015-2016. No population-based prevalence
    estimate exists; the Orphanet record (ORPHA:477993) carries no numeric
    prevalence class.
  evidence:
  - reference: PMID:40530541
    reference_title: "Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A -Related Neurodevelopmental Disorder Spectrum: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      phenotypic knowledge of this ultra-rare autosomal dominant disorder is
      limited.
    explanation: >-
      The most recent published report characterises the disorder as ultra-rare
      with limited phenotypic knowledge, supporting the qualitative
      ULTRA_RARE prevalence class in the absence of any numeric estimate.
inheritance:
- name: Autosomal dominant, de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  description: >-
    All reported probands carry heterozygous KDM1A missense variants that arose
    de novo; no vertical transmission has been reported and parents are
    unaffected. Expressivity is variable — palatal involvement, the feature that
    names the MONDO/Orphanet entity, was absent in the fourth published proband.
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three variants in KDM1A were missense variants predicted to be
      deleterious (minimum Polyphen-2 HumVar score of 0.962), result in amino
      acid substitutions of highly conserved amino acid residues (minimum GERP
      score was 5.72) in KDM1A, and have high CADD scores suggestive of dominant
      mutations (minimum CADD score 27.2) (Table 1).
    explanation: >-
      The three index probands each carried a de novo heterozygous missense
      variant with CADD scores in the range expected for dominant disease
      alleles, establishing autosomal dominant, de novo inheritance.
  - reference: PMID:40530541
    reference_title: "Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A -Related Neurodevelopmental Disorder Spectrum: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this first reported individual without palate abnormalities highlights the
      variable expressivity of this feature in the KDM1A-related phenotype.
    explanation: >-
      Directly documents variable expressivity of the palatal phenotype within
      this autosomal dominant disorder.
genetic:
- name: KDM1A de novo missense variants
  gene_term:
    preferred_term: KDM1A
    term:
      id: hgnc:29079
      label: KDM1A
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  features: >-
    Every reported disease-associated KDM1A allele is a heterozygous missense
    change; no truncating, whole-gene-deletion or biallelic alleles have been
    reported in this phenotype. The three index variants — p.(Glu403Lys),
    p.(Asp580Gly) and p.(Tyr785His) — all alter conserved residues within the
    FAD-dependent amine oxidase domain, and a fourth proband carried a novel
    missense variant in exon 16. KDM1A sits in the top 2% of evolutionarily
    constrained human genes.
  evidence:
  - reference: PMID:24838796
    reference_title: De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      c.2353T>C, predicting p.Tyr785His in KDM1A, a gene not previously
      associated with a human phenotype.
    explanation: >-
      First report of a deleterious KDM1A sequence variant in a human, in the
      proband who later became Family A of the delineating cohort.
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KDM1A is in the top 2% of evolutionarily constrained genes, i.e. genes
      that are intolerant to functional variation, and this set of genes is
      enriched for genes known to underlie dominant Mendelian phenotypes
    explanation: >-
      Population-constraint evidence supporting KDM1A as a dominant
      disease gene and the pathogenicity of the de novo missense alleles.
  - reference: PMID:27094131
    reference_title: LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The three mutations (Glu403Lys, Asp580Gly and Tyr785His) affect
      active-site residues and lead to a partial impairment of catalytic
      activity.
    explanation: >-
      Names the three index alleles and shows they are functionally deleterious,
      linking genotype to a measurable molecular consequence.
  variants:
  - name: KDM1A p.(Tyr785His)
    description: >-
      NM_001009999.2 c.2353T>C. De novo missense variant in the amine oxidase
      domain, identified in the index proband (Family A) who also carried an
      ANKRD11 in-frame deletion later argued not to be causal.
    gene:
      preferred_term: KDM1A
      term:
        id: hgnc:29079
        label: KDM1A
    clinical_significance: PATHOGENIC
    functional_effects:
    - function: LSD1 histone H3K4 demethylase activity
      description: >-
        Partial impairment of demethylase activity, perturbed engagement of
        developmental transcription factors, and reduced cellular protein
        half-life.
    evidence:
    - reference: PMID:24838796
      reference_title: De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        c.2353T>C, predicting p.Tyr785His in KDM1A, a gene not previously
        associated with a human phenotype.
      explanation: Original description of the p.Tyr785His allele.
  - name: KDM1A p.(Glu403Lys)
    description: >-
      De novo missense variant affecting an active-site residue of the LSD1
      amine oxidase domain.
    gene:
      preferred_term: KDM1A
      term:
        id: hgnc:29079
        label: KDM1A
    clinical_significance: PATHOGENIC
    functional_effects:
    - function: LSD1 histone H3K4 demethylase activity
      description: Partial loss of catalytic activity with altered transcription-factor binding.
    evidence:
    - reference: PMID:27094131
      reference_title: LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The three mutations (Glu403Lys, Asp580Gly and Tyr785His) affect
        active-site residues and lead to a partial impairment of catalytic
        activity.
      explanation: Functional characterisation of the p.Glu403Lys allele.
  - name: KDM1A p.(Asp580Gly)
    description: >-
      De novo missense variant affecting an active-site residue of the LSD1
      amine oxidase domain.
    gene:
      preferred_term: KDM1A
      term:
        id: hgnc:29079
        label: KDM1A
    clinical_significance: PATHOGENIC
    functional_effects:
    - function: LSD1 histone H3K4 demethylase activity
      description: Partial loss of catalytic activity with altered transcription-factor binding.
    evidence:
    - reference: PMID:27094131
      reference_title: LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The three mutations (Glu403Lys, Asp580Gly and Tyr785His) affect
        active-site residues and lead to a partial impairment of catalytic
        activity.
      explanation: Functional characterisation of the p.Asp580Gly allele.
pathophysiology:
- name: De Novo Missense Variants in the LSD1 Amine Oxidase Domain
  biological_scale: MOLECULAR
  description: >-
    All three index disease alleles alter highly conserved residues inside the
    FAD-dependent amine oxidase domain of LSD1/KDM1A. This domain comprises the
    FAD-binding and substrate-binding subdomains, and the substrate-binding
    subdomain forms the active-site cavity through which LSD1 demethylates
    mono- and dimethylated histone H3 lysine 4. Clustering of independently
    ascertained de novo variants in a single functional domain is itself
    evidence that the lesion is domain-specific rather than a matter of gene
    dosage.
  genes:
  - preferred_term: KDM1A
    term:
      id: hgnc:29079
      label: KDM1A
  downstream:
  - target: Impaired LSD1 Catalytic Activity and Protein Stability
    description: >-
      Active-site substitutions partially inactivate the demethylase and
      destabilise the protein.
  - target: Impaired LSD1 Engagement of Developmental Transcription Factors
    description: >-
      The same substitutions differentially disrupt the protein-protein
      interfaces through which LSD1 is recruited by transcription factors.
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all three mutations alter residues in the amine-oxidase domain (Figure
      2B), which is composed of FAD-binding and substrate-binding functional
      subdomains
    explanation: >-
      Establishes that the disease-associated variants cluster in the catalytic
      amine oxidase domain of LSD1.
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The active site cavity of KDM1A is formed by the substrate-binding
      subdomain
    explanation: >-
      Links the affected substrate-binding subdomain to the active-site cavity;
      the source continues that this cavity "is required for KDM1A to
      demethylate H3K4me1/2 and repress transcription". Tagged IN_VITRO because
      this is a structural/biochemical assertion in the discussion rather than a
      clinical observation.
- name: Impaired LSD1 Catalytic Activity and Protein Stability
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Epigenetic Machinery Component Haploinsufficiency"
  biological_scale: MOLECULAR
  description: >-
    In vitro and cellular assays of the three index variants show partial —
    not complete — impairment of H3K4 demethylase activity, together with a
    reduction in the cellular half-life of the mutant protein. The hypomorphic
    rather than null character of the biochemical defect is consistent with the
    survival of affected individuals, given that complete loss of Kdm1a is
    embryonic-lethal in mouse.
  genes:
  - preferred_term: KDM1A
    term:
      id: hgnc:29079
      label: KDM1A
  molecular_functions:
  - preferred_term: histone H3K4 demethylase activity
    term:
      id: GO:0032453
      label: histone H3K4 demethylase activity
    modifier: DECREASED
  downstream:
  - target: Loss of LSD1-CoREST-Mediated Transcriptional Repression
    description: >-
      Reduced demethylase output and reduced steady-state LSD1 weaken repression
      at LSD1-CoREST target loci.
  evidence:
  - reference: PMID:27094131
    reference_title: LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The three mutations (Glu403Lys, Asp580Gly and Tyr785His) affect
      active-site residues and lead to a partial impairment of catalytic
      activity.
    explanation: >-
      Direct biochemical demonstration of partial catalytic impairment by the
      disease alleles.
  - reference: PMID:27094131
    reference_title: LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, cellular data indicate a decrease in the protein cellular
      half-life.
    explanation: >-
      Reduced protein stability compounds the catalytic defect, lowering
      effective LSD1 activity in cells.
- name: Impaired LSD1 Engagement of Developmental Transcription Factors
  biological_scale: MOLECULAR
  description: >-
    Beyond catalysis, the disease variants differentially perturb the ability of
    LSD1 to bind transcription factors that orchestrate developmental gene
    programs. Because LSD1 acts as a scaffold as well as an enzyme, this
    non-catalytic defect is a mechanistically separate arm of the pathology and
    may explain why different active-site substitutions produce overlapping but
    not identical phenotypes.
  genes:
  - preferred_term: KDM1A
    term:
      id: hgnc:29079
      label: KDM1A
  downstream:
  - target: Dysregulated Neurodevelopmental and Craniofacial Gene Programs
    description: >-
      Failure to be recruited by developmental transcription factors misdirects
      the LSD1-dependent repressive program.
  evidence:
  - reference: PMID:27094131
    reference_title: LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      They also differentially perturb the ability of LSD1 to engage
      transcription factors that orchestrate key developmental programs.
    explanation: >-
      Establishes a non-catalytic, protein-interaction arm of the molecular
      defect distinct from loss of demethylase activity.
  - reference: PMID:27094131
    reference_title: LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This depicts a perturbed interplay of catalytic and non-catalytic
      processes at the origin of the pathology.
    explanation: >-
      The authors' own synthesis that the pathology arises from combined
      catalytic and non-catalytic dysfunction.
- name: Loss of LSD1-CoREST-Mediated Transcriptional Repression
  biological_scale: CELLULAR
  description: >-
    LSD1 functions within the BRAF-HDAC/CoREST corepressor complex, together
    with PHF21A (BHC80), to keep non-neuronal and neuronal gene sets correctly
    silenced and to time neuronal gene expression during development. Reduced
    LSD1 activity or occupancy therefore derepresses this target set. Two
    independent lines support the step. In mouse, inducible forebrain-restricted
    Kdm1a deletion activates non-neuronal genes normally silenced by the
    polycomb repressor complex and weakens their topological segregation from
    neighbouring active chromatin. In humans, haploinsufficiency of the LSD1
    partner PHF21A derepresses the neuronal gene SCN3A with reduced LSD1
    promoter occupancy, and PHF21A knockdown in zebrafish causes craniofacial
    abnormalities and neuronal apoptosis.
  genes:
  - preferred_term: KDM1A
    term:
      id: hgnc:29079
      label: KDM1A
  biological_processes:
  - preferred_term: negative regulation of transcription by RNA polymerase II
    term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    modifier: DECREASED
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: chromatin
    term:
      id: GO:0000785
      label: chromatin
  downstream:
  - target: Dysregulated Neurodevelopmental and Craniofacial Gene Programs
    description: >-
      Derepression of LSD1-CoREST target genes mistimes neuronal and
      craniofacial developmental programs.
  evidence:
  - reference: PMID:22770980
    reference_title: Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Along with lysine-specific demethylase 1 (LSD1), PHF21A, also known as
      BHC80, is a component of the BRAF-histone deacetylase complex that
      represses target-gene transcription.
    explanation: >-
      Places LSD1 in the BRAF-HDAC/CoREST repressive complex whose disruption is
      the proposed proximal cellular lesion. Tagged IN_VITRO because this is a
      statement of complex composition from biochemical work, not a clinical
      observation.
  - reference: PMID:22770980
    reference_title: Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In lymphoblastoid cell lines from two translocation subjects in whom
      PHF21A was directly disrupted by the respective breakpoints, we observed
      derepression of the neuronal gene SCN3A and reduced LSD1 occupancy at the
      SCN3A promoter, supporting a direct functional consequence of PHF21A
      haploinsufficiency on transcriptional regulation.
    explanation: >-
      Indirect (PARTIAL) support on two counts — the derepression was
      demonstrated for the LSD1 partner PHF21A rather than for KDM1A variants
      themselves, and it was measured in patient-derived lymphoblastoid cell
      lines (hence IN_VITRO) rather than in neural tissue. It nevertheless shows
      that impairing this complex derepresses neuronal targets and reduces LSD1
      promoter occupancy.
  - reference: PMID:38453932
    reference_title: Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we find that Kdm1a elimination causes the neuronal activation of
      nonneuronal genes that are silenced by the polycomb repressor complex and
      interspersed with active genes.
    explanation: >-
      Conditional Kdm1a deletion in adult mouse forebrain neurons directly
      demonstrates that loss of Kdm1a derepresses silenced target genes, the
      cellular step modelled by this node.
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      during the perinatal period, alternative splicing of KDM1A results in
      expression of two neuron-specific isoforms that regulate neurite
      maturation
    explanation: >-
      Establishes a developmentally timed, neuron-specific role for KDM1A that
      links the chromatin lesion to neurodevelopment.
- name: Dysregulated Neurodevelopmental and Craniofacial Gene Programs
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Dysregulated Neurodevelopmental Transcriptional Program"
  biological_scale: TISSUE
  description: >-
    The convergent consequence of reduced LSD1 catalytic output, reduced LSD1
    protein, and impaired transcription-factor engagement is mistimed and
    misplaced expression of the gene programs that build the developing brain
    and the craniofacial skeleton, including the palate. In zebrafish, kdm1a
    knockout suppresses CNS neurogenesis, shortens motor-neuron axons and
    downregulates neurodevelopmental genes, producing locomotor and
    learning/memory deficits. The craniofacial arm is the weaker link: it is
    supported by knockdown of the LSD1 partner PHF21A rather than by any
    patient-variant craniofacial model. Together these produce the two-part
    clinical picture — global developmental delay with hypotonia, and a
    recognisable facial gestalt with palatal anomalies — that defines the
    syndrome.
  biological_processes:
  - preferred_term: regulation of neuron differentiation
    term:
      id: GO:0045664
      label: regulation of neuron differentiation
    modifier: ABNORMAL
  - preferred_term: roof of mouth development
    term:
      id: GO:0060021
      label: roof of mouth development
    modifier: ABNORMAL
  - preferred_term: embryonic cranial skeleton morphogenesis
    term:
      id: GO:0048701
      label: embryonic cranial skeleton morphogenesis
    modifier: ABNORMAL
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      de novo variants in KDM1A cause a newly-delineated condition characterized
      by developmental delay, hypotonia, and characteristic facial features.
    explanation: >-
      States the clinical output of the mechanism: a combined neurodevelopmental
      and craniofacial phenotype.
  - reference: PMID:41351445
    reference_title: Deficiency of Kdm1a Induces Locomotor Abnormalities and Learning and Memory Deficits in Zebrafish Larvae.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Kdm1a deficiency suppressed central nervous system (CNS) neurogenesis in
      Tg (HuC:egfp) zebrafish, reduced motor neuron axon length in Tg
      (hb9:egfp) zebrafish and downregulated the expression of neurodevelopment
      related genes at 96 hours post fertilization (hpf).
    explanation: >-
      Loss of kdm1a directly impairs neurogenesis, axon growth and
      neurodevelopmental gene expression, the neural arm of this node.
  - reference: PMID:22770980
    reference_title: Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      suppression of the latter led to both craniofacial abnormalities and
      neuronal apoptosis.
    explanation: >-
      Indirect (PARTIAL) support from zebrafish knockdown of the LSD1 partner
      PHF21A, showing that disrupting this complex during development produces
      both the craniofacial and the neuronal arms of the phenotype. No
      patient-variant craniofacial model exists.
phenotypes:
- name: Global Developmental Delay
  category: Neurologic
  frequency: VERY_FREQUENT
  description: >-
    Global developmental delay affecting motor, speech and cognitive domains is
    present in every reported proband and was one of the two features (with the
    facial gestalt) used to recognise the syndrome.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three children with de novo
      KDM1A variants had similar, albeit non-specific, clinical findings (Table
      1) including similar facial features, global developmental delay and
      hypotonia
    explanation: >-
      All three delineating probands had global developmental delay. With the
      fourth published proband (PMID:40530541) that is 4/4 = 100%;
      VERY_FREQUENT rather than OBLIGATE is used because n=4 cannot establish
      complete penetrance.
  - reference: PMID:40530541
    reference_title: "Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A -Related Neurodevelopmental Disorder Spectrum: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KDM1A-related neurodevelopmental disorder (CPRF, OMIM #616728) is
      characterized by cleft palate, global developmental delay, and distinct
      facial gestalt
    explanation: >-
      The most recent report confirms global developmental delay as a defining
      feature.
- name: Hypotonia
  category: Neurologic
  frequency: VERY_FREQUENT
  description: >-
    Muscular hypotonia is reported in every published case and was present from
    birth in the fourth proband. The unqualified HP:0001252 is used rather than
    HP:0001290 (generalized) or HP:0008936 (axial) because the sources conflict
    on distribution: the delineating report and the fourth case say only
    "hypotonia"/"muscular hypotonia", while the Orphanet description
    characterises it as axial.
  phenotype_term:
    preferred_term: Muscular hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
    onset:
      onset_category: CONGENITAL
      notes: Hypotonia was present from birth in the fourth published proband.
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three children with de novo
      KDM1A variants had similar, albeit non-specific, clinical findings (Table
      1) including similar facial features, global developmental delay and
      hypotonia
    explanation: >-
      Hypotonia was shared by all three delineating probands; with the fourth
      published proband that is 4/4 = 100%, curated as VERY_FREQUENT rather
      than OBLIGATE because n=4 cannot establish complete penetrance.
  - reference: PMID:40530541
    reference_title: "Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A -Related Neurodevelopmental Disorder Spectrum: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this case report expands knowledge on the phenotypic spectrum, including
      intellectual disability with global developmental delay, muscular
      hypotonia, and variable dysmorphic anomalies
    explanation: Muscular hypotonia confirmed in the fourth published proband.
- name: Intellectual Disability
  category: Neurologic
  description: >-
    Intellectual disability is the persisting cognitive outcome of the early
    global developmental delay. Severity has ranged from mild (the fourth
    proband, assessed at age 13) to the psychomotor retardation of the original
    OMIM phenotype description.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:40530541
    reference_title: "Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A -Related Neurodevelopmental Disorder Spectrum: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a 13-year-old boy with a novel heterozygous, likely pathogenic germline
      missense variant in exon 16 of KDM1A with developmental delay, hypotonia,
      mild intellectual disability, and unspecific facial features but without
      palate abnormalities.
    explanation: >-
      Documents mild intellectual disability in a molecularly confirmed proband.
- name: Cleft Palate
  category: Craniofacial
  description: >-
    Cleft palate is the palatal anomaly that names both the OMIM entity (CPRF)
    and, together with a high narrow palate, the MONDO/Orphanet label. It is
    not obligate — the fourth published proband had no palate abnormality.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:24838796
    reference_title: De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a male with developmental delays, cleft palate, craniofacial
      dysmorphism, hypotonia, and central nervous system anomalies including
      diminished white matter with thinning of the corpus callosum.
    explanation: >-
      Cleft palate in the index proband carrying the de novo KDM1A p.Tyr785His
      variant.
  - reference: PMID:40530541
    reference_title: "Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A -Related Neurodevelopmental Disorder Spectrum: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this first reported individual without palate abnormalities highlights the
      variable expressivity of this feature in the KDM1A-related phenotype.
    explanation: >-
      PARTIAL — confirms cleft palate as a canonical feature of the syndrome
      while explicitly documenting that it is not present in every affected
      individual.
- name: Prominent Forehead
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    A prominent forehead is one of six facial features shared by all three
    delineating probands and is part of the recognisable gestalt. The fourth
    published proband was described as having unspecific facial features, so
    the denominator for all six gestalt features is 3/4.
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In particular, all three individuals share a prominent forehead, slightly
      arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin
      lips, and wide-spaced teeth (Figure 1).
    explanation: >-
      Prominent forehead was present in all three delineating probands.
  - reference: PMID:40530541
    reference_title: "Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A -Related Neurodevelopmental Disorder Spectrum: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild intellectual disability, and unspecific facial features but without
      palate abnormalities.
    explanation: >-
      Supplies the fourth-proband denominator: the distinctive gestalt was
      absent in this individual, so the derived frequency across the published
      cohort is 3/4 = 75%, which maps to FREQUENT (30-79%) rather than
      VERY_FREQUENT.
- name: Arched Eyebrows
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Slightly arched eyebrows were shared by all three delineating probands.
    HP:0002553 carries "Arched eyebrows" as an exact synonym and is the only
    HPO concept for eyebrow arching; the reported degree of arching was mild,
    so the preferred term is kept as "Arched eyebrows". Denominator 3/4 as for
    the other gestalt features.
  phenotype_term:
    preferred_term: Arched eyebrows
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In particular, all three individuals share a prominent forehead, slightly
      arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin
      lips, and wide-spaced teeth (Figure 1).
    explanation: Arched eyebrows in all three delineating probands.
  - reference: PMID:40530541
    reference_title: "Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A -Related Neurodevelopmental Disorder Spectrum: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild intellectual disability, and unspecific facial features but without
      palate abnormalities.
    explanation: >-
      Fourth-proband denominator: 3/4 = 75%, mapping to FREQUENT rather than
      VERY_FREQUENT.
- name: Elongated Palpebral Fissures
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Elongated palpebral fissures were shared by all three delineating probands
    and contribute to the phenotypic overlap with Kabuki syndrome. Note that the
    Orphanet-derived description instead reports downslanting palpebral
    fissures; only the directly quotable "elongated" observation is curated here.
  phenotype_term:
    preferred_term: Elongated palpebral fissures
    term:
      id: HP:0000637
      label: Long palpebral fissure
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In particular, all three individuals share a prominent forehead, slightly
      arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin
      lips, and wide-spaced teeth (Figure 1).
    explanation: Elongated palpebral fissures in all three delineating probands.
  - reference: PMID:40530541
    reference_title: "Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A -Related Neurodevelopmental Disorder Spectrum: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild intellectual disability, and unspecific facial features but without
      palate abnormalities.
    explanation: >-
      Fourth-proband denominator: 3/4 = 75%, mapping to FREQUENT rather than
      VERY_FREQUENT.
- name: Wide Nasal Bridge
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    A wide nasal bridge was shared by all three delineating probands.
    Denominator 3/4 as for the other gestalt features.
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In particular, all three individuals share a prominent forehead, slightly
      arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin
      lips, and wide-spaced teeth (Figure 1).
    explanation: Wide nasal bridge in all three delineating probands.
  - reference: PMID:40530541
    reference_title: "Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A -Related Neurodevelopmental Disorder Spectrum: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild intellectual disability, and unspecific facial features but without
      palate abnormalities.
    explanation: >-
      Fourth-proband denominator: 3/4 = 75%, mapping to FREQUENT rather than
      VERY_FREQUENT.
- name: Thin Lips
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Thin lips were shared by all three delineating probands. HP:0000233 is used
    rather than its child HP:0000219 (upper lip only) because the source says
    "thin lips" without restricting to the upper lip; "Thin lips" is an exact
    synonym of HP:0000233. Denominator 3/4 as for the other gestalt features.
  phenotype_term:
    preferred_term: Thin lips
    term:
      id: HP:0000233
      label: Thin vermilion border
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In particular, all three individuals share a prominent forehead, slightly
      arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin
      lips, and wide-spaced teeth (Figure 1).
    explanation: Thin lips in all three delineating probands.
  - reference: PMID:40530541
    reference_title: "Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A -Related Neurodevelopmental Disorder Spectrum: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild intellectual disability, and unspecific facial features but without
      palate abnormalities.
    explanation: >-
      Fourth-proband denominator: 3/4 = 75%, mapping to FREQUENT rather than
      VERY_FREQUENT.
- name: Widely Spaced Teeth
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Wide-spaced teeth (multiple diastemata) are shared by all three delineating
    probands and give the disorder its MONDO/Orphanet name.
  phenotype_term:
    preferred_term: Widely spaced teeth
    term:
      id: HP:0000687
      label: Widely spaced teeth
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In particular, all three individuals share a prominent forehead, slightly
      arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin
      lips, and wide-spaced teeth (Figure 1).
    explanation: Wide-spaced teeth in all three delineating probands.
  - reference: PMID:40530541
    reference_title: "Phenotypical and Genotypical Expansion of Autosomal-Dominant KDM1A -Related Neurodevelopmental Disorder Spectrum: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild intellectual disability, and unspecific facial features but without
      palate abnormalities.
    explanation: >-
      Fourth-proband denominator: 3/4 = 75%, mapping to FREQUENT rather than
      VERY_FREQUENT.
- name: Thin Corpus Callosum
  category: Neurologic
  description: >-
    Thinning of the corpus callosum was documented on brain imaging in the index
    proband. Structural CNS findings have been reported in a minority of the
    small published cohort; brain imaging was not performed in the fourth
    proband, so the true frequency is unknown.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:24838796
    reference_title: De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a male with developmental delays, cleft palate, craniofacial
      dysmorphism, hypotonia, and central nervous system anomalies including
      diminished white matter with thinning of the corpus callosum.
    explanation: >-
      Thinning of the corpus callosum reported on neuroimaging in the index
      proband.
- name: Reduced Cerebral White Matter Volume
  category: Neurologic
  description: >-
    Diminished cerebral white matter accompanied the thin corpus callosum in the
    index proband. HP:0034295 is deliberately chosen over the atrophy-specific
    HP:0012762 and the hypoplasia-specific HP:0012430 because the report does
    not distinguish the two, mirroring the same agnostic choice made for the
    corpus callosum finding.
  phenotype_term:
    preferred_term: Diminished cerebral white matter
    term:
      id: HP:0034295
      label: Reduced cerebral white matter volume
  evidence:
  - reference: PMID:24838796
    reference_title: De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      central nervous system anomalies including diminished white matter with
      thinning of the corpus callosum.
    explanation: >-
      Diminished cerebral white matter was reported on neuroimaging in the index
      proband.
differential_diagnoses:
- name: Kabuki syndrome
  description: >-
    Kabuki syndrome (KMT2D, KDM6A) is the principal differential: it shares
    developmental delay, hypotonia, elongated palpebral fissures, arched
    eyebrows, cleft palate and dental anomalies, and the index KDM1A proband was
    initially described as having features of Kabuki syndrome. Both are
    chromatin-modifier disorders acting on histone H3 lysine 4 methylation —
    KMT2D writes and KDM1A erases the mark — which plausibly explains the
    convergence. The delineating study concluded that the KDM1A condition
    overlaps with but is nonetheless distinct from Kabuki syndrome.
  disease_term:
    preferred_term: Kabuki syndrome
    term:
      id: MONDO:0016512
      label: Kabuki syndrome
  distinguishing_features:
  - Pathogenic KMT2D or KDM6A variants rather than de novo KDM1A missense variants.
  - Eversion of the lateral third of the lower eyelid, a Kabuki hallmark not described in the KDM1A phenotype.
  - Persistent fetal fingertip pads, postnatal growth deficiency, recurrent otitis media and immune deficiency, none of which is part of the described KDM1A phenotype.
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutations in KDM1A cause a condition that has phenotypic overlap with
      Kabuki syndrome but is nonetheless distinct.
    explanation: >-
      Explicit statement that the KDM1A condition overlaps with, but is separable
      from, Kabuki syndrome.
- name: KBG syndrome
  description: >-
    KBG syndrome (ANKRD11 haploinsufficiency) entered the differential because
    the index proband carried a second de novo variant, ANKRD11
    c.2606_2608delAGA p.(Lys869del), and was initially reported as a dual
    diagnosis. The delineating study argued against a KBG contribution: nearly
    all KBG-causing ANKRD11 alleles are truncating, the in-frame deletion has a
    CADD score well below the dominant-disease range, and the proband lacked
    macrodontia of the upper central incisors. This is a resolved
    dual-diagnosis differential rather than a live clinical one, but it is a
    standing reminder to consider blended diagnoses in this disorder.
  disease_term:
    preferred_term: KBG syndrome
    term:
      id: MONDO:0007846
      label: KBG syndrome
  distinguishing_features:
  - Macrodontia of the upper central incisors is the hallmark of KBG syndrome and was absent in the KDM1A index proband, whose dental phenotype is widely spaced teeth.
  - KBG-causing ANKRD11 alleles are overwhelmingly truncating, whereas the KDM1A alleles are missense.
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      variant in ANKRD11 in Family A does not cause KBG syndrome.
    explanation: >-
      The delineating study argues against a KBG syndrome contribution in the
      index proband. The quote is deliberately truncated because the full
      sentence contains a bracketed HGVS protein change that the reference
      validator strips; the full sentence reads "Additional evidence suggests
      that the c.2606_2608delAGA [p.(Lys869del)] variant in ANKRD11 in Family A
      does not cause KBG syndrome" — i.e. the authors hedge with "suggests"
      rather than asserting exclusion outright.
- name: Potocki-Shaffer syndrome (PHF21A-related disorder)
  description: >-
    PHF21A (BHC80) encodes a partner of LSD1 in the BRAF-HDAC/CoREST corepressor
    complex, and its haploinsufficiency causes the intellectual disability plus
    craniofacial anomaly component of Potocki-Shaffer syndrome. The two
    disorders are therefore mechanistically adjacent — different subunits of the
    same repressor complex — and PHF21A disruption is the best available human
    evidence that impairing this complex produces the ID-plus-craniofacial
    combination.
  disease_term:
    preferred_term: Potocki-Shaffer syndrome
    term:
      id: MONDO:0011022
      label: Potocki-Shaffer syndrome
  distinguishing_features:
  - Potocki-Shaffer syndrome is a contiguous-gene deletion disorder of 11p11.2, not a single-gene missense disorder.
  - Multiple exostoses and parietal foramina are part of Potocki-Shaffer syndrome and are not features of the KDM1A phenotype.
  - Epilepsy and autistic features are prominent in PHF21A-related disorder but are not established features of KDM1A-related neurodevelopmental disorder.
  evidence:
  - reference: PMID:22770980
    reference_title: Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we have uncovered evidence that the ID and CFA phenotypes are both caused
      by haploinsufficiency of a single gene, PHF21A, at 11p11.2.
    explanation: >-
      Establishes PHF21A haploinsufficiency, in the same complex as LSD1, as a
      cause of intellectual disability with craniofacial anomalies.
animal_models:
- species: Mus musculus
  genotype: Inducible, forebrain-restricted conditional Kdm1a knockout
  category: Conditional knockout
  description: >-
    Inducible deletion of Kdm1a restricted to adult forebrain neurons, profiled
    by transcriptomics, epigenomics, chromatin-conformation analysis and
    super-resolution microscopy. Loss of Kdm1a derepresses non-neuronal genes
    silenced by the polycomb repressor complex and weakens the topological
    segregation of those genes from neighbouring active chromatin. This is the
    strongest available demonstration of what the chromatin lesion does at the
    level of neuronal genome organisation, but it models complete somatic loss
    in mature neurons rather than a germline heterozygous missense allele.
  associated_phenotypes:
  - Derepression of PRC2-silenced non-neuronal genes in neurons
  - Weakened topological segregation of Kdm1a-repressed chromatin domains
  evidence:
  - reference: PMID:38453932
    reference_title: Kdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To explore Kdm1a's function in adult neurons, we develop inducible and
      forebrain-restricted Kdm1a knockouts.
    explanation: Describes the conditional mouse model and its design.
- species: Danio rerio
  genotype: CRISPR/Cas9 kdm1a knockout
  category: Knockout
  description: >-
    CRISPR/Cas9 kdm1a-deficient zebrafish larvae show developmental toxicity and
    abnormal neurobehaviour, with suppressed CNS neurogenesis, shortened
    motor-neuron axons, downregulated neurodevelopmental gene expression and
    increased autophagy/apoptosis gene expression. This supports impaired
    neurogenesis as a downstream consequence of loss of kdm1a, but it is a
    knockout rather than a patient-allele knock-in.
  associated_phenotypes:
  - Locomotor abnormalities
  - Learning and memory deficits
  - Suppressed CNS neurogenesis
  - Reduced motor neuron axon length
  evidence:
  - reference: PMID:41351445
    reference_title: Deficiency of Kdm1a Induces Locomotor Abnormalities and Learning and Memory Deficits in Zebrafish Larvae.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that kdm1a knockout zebrafish exhibited developmental toxicity
      and abnormal neurobehaviors, including locomotor abnormalities, and
      learning and memory deficits.
    explanation: >-
      Establishes the neurobehavioural consequence of kdm1a loss in a vertebrate
      model.
diagnosis:
- name: Trio Exome or Genome Sequencing
  description: >-
    There is no biochemical or imaging marker for this disorder and the clinical
    presentation (developmental delay, hypotonia, non-specific dysmorphism) is
    not distinctive enough to be diagnosed on examination. Diagnosis is
    molecular: trio exome or genome sequencing analysed under a de novo model,
    with KDM1A also included on broad
    developmental-delay/intellectual-disability, cleft-palate and chromatinopathy
    panels. Because every reported
    allele is a missense change, variant interpretation requires confirming de
    novo status by parental testing and weighing domain location and
    conservation; the index cohort was ascertained exactly this way, and the
    fourth proband was diagnosed by trio genome sequencing only after
    karyotype, microarray, FMR1 repeat testing and a metabolic workup were
    unrevealing.
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of variants from ES under a de novo mutation model confirmed the
      presence of a different de novo variant in KDM1A (Refseq NM_001009999.2)
      in each of Families A and B
    explanation: >-
      Exome sequencing analysed under a de novo model is the diagnostic route by
      which the disorder was established and by which affected individuals are
      identified.
  notes: >-
    No disease-specific DNA-methylation episignature has been validated for
    KDM1A, unlike several other chromatinopathies; the 2025 report proposes
    episignature analysis as a future means of classifying KDM1A variants of
    uncertain significance.
treatments:
- name: Multidisciplinary Supportive Care
  description: >-
    No disease-modifying therapy exists. Management is supportive: coordinated
    developmental surveillance, educational and neuropsychological support for
    intellectual disability, and hearing and vision screening. Individual
    therapy modalities are curated separately below. No KDM1A-specific outcome
    study has been published; this recommendation is extrapolated from general
    practice for syndromic developmental delay.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  notes: >-
    Deliberately uncited. No published study evaluates any intervention in
    KDM1A-related neurodevelopmental disorder, and fabricating an evidence item
    would misrepresent the state of the literature.
- name: Physical Therapy
  description: >-
    Physiotherapy and occupational therapy for the congenital hypotonia and
    associated gross- and fine-motor delay, as for other syndromic
    neurodevelopmental disorders.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Muscular hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  notes: >-
    Deliberately uncited — standard developmental management, not a
    disorder-specific published intervention.
- name: Speech and Language Therapy
  description: >-
    Speech-language therapy, including augmentative communication where needed,
    for the expressive-language component of the developmental delay and for
    the speech consequences of palatal clefting where present.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  notes: >-
    Deliberately uncited — standard developmental management, not a
    disorder-specific published intervention.
- name: Cleft Palate Repair
  description: >-
    Surgical repair of the cleft palate, when present, follows standard
    cleft-team protocols with subsequent feeding, audiology, speech, dental and
    orthodontic support. As with supportive care, no KDM1A-specific surgical
    outcome data exist.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  notes: >-
    Deliberately uncited — standard-of-care cleft management, not a
    disorder-specific published intervention.
discussions:
- discussion_id: kdm1a_loss_versus_gain_of_function
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired LSD1 Catalytic Activity and Protein Stability
  prompt: >-
    Do the disease-associated KDM1A missense variants act through loss of
    function, gain of function, or a dominant-negative effect on the
    LSD1-CoREST complex?
  rationale: >-
    Every reported allele is missense and clusters in the amine oxidase domain,
    and biochemistry shows only partial catalytic impairment plus reduced
    protein half-life — a hypomorphic profile. But mice heterozygous for a Kdm1a
    deletion are reported to be normal, which argues that simple
    haploinsufficiency is not sufficient to produce the phenotype. The absence
    of any reported truncating or whole-gene-deletion allele in this phenotype
    is consistent with a non-loss-of-function mechanism, but could equally
    reflect ascertainment in an ultra-rare cohort. Because LSD1 acts both
    catalytically and as a scaffold, a mutant protein that is stably
    incorporated into CoREST but catalytically crippled could poison the complex
    — a dominant-negative model that has not been tested. The distinction
    matters therapeutically: pharmacological LSD1 inhibition, which is
    beneficial in mouse models of Kabuki syndrome, would be expected to worsen a
    loss-of-function KDM1A disorder.
  proposed_experiments:
  - experiment_id: kdm1a_truncating_allele_cohort_screen
    name: Truncating-allele cohort screen
    description: >-
      Screen large developmental-disorder sequencing cohorts for truncating
      KDM1A alleles and phenotype any carriers.
    supporting_outcome:
    - Recovery of truncating carriers with the CPRF phenotype would support a simple loss-of-function/haploinsufficiency mechanism.
    refuting_outcome:
    - Truncating carriers who are unaffected, or complete absence of truncating alleles despite adequate power, would argue against haploinsufficiency and favour a dominant-negative or altered-specificity mechanism.
  - experiment_id: kdm1a_knockin_versus_null_comparison
    name: Patient-allele knock-in versus null allele comparison
    description: >-
      Generate mouse or human iPSC models carrying p.Glu403Lys, p.Asp580Gly or
      p.Tyr785His in the heterozygous state and compare craniofacial and
      neurodevelopmental phenotypes and transcriptomes with isogenic
      heterozygous-null controls.
    supporting_outcome:
    - A missense knock-in phenotype more severe than the heterozygous null would support a dominant-negative or gain-of-function mechanism.
    refuting_outcome:
    - Phenotypic equivalence between missense knock-in and heterozygous null would support simple loss of function.
  - experiment_id: kdm1a_corest_incorporation_profiling
    name: CoREST incorporation and target-locus chromatin profiling
    description: >-
      Determine whether mutant LSD1 is still incorporated into the CoREST
      complex, and measure H3K4me1/2 and target-gene expression at LSD1-CoREST
      loci in patient-derived neurons.
    supporting_outcome:
    - Retained complex incorporation with locally increased H3K4me1/2 and target derepression would support complex poisoning by a dominant-negative mechanism.
    refuting_outcome:
    - Failure of mutant LSD1 to be incorporated into CoREST would favour simple reduction of functional complex.
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nevertheless, it remains to be seen if the phenotypes we report to be
      caused by variants in KDM1A are due to loss or gain of function.
    explanation: >-
      The delineating study explicitly leaves the direction of effect
      unresolved.
  - reference: PMID:27094131
    reference_title: LSD1/KDM1A mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This depicts a perturbed interplay of catalytic and non-catalytic
      processes at the origin of the pathology.
    explanation: >-
      PARTIAL — biochemistry shows combined catalytic and non-catalytic
      perturbation but does not resolve loss versus gain versus
      dominant-negative at the level of the intact complex in vivo.
- discussion_id: kdm1a_heterozygous_mouse_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired LSD1 Catalytic Activity and Protein Stability
  - pathophysiology#Dysregulated Neurodevelopmental and Craniofacial Gene Programs
  prompt: >-
    Given that mice heterozygous for a Kdm1a deletion are reported to be
    apparently normal and fertile while homozygous knockout is embryonic-lethal,
    does any available model reproduce the human heterozygous missense-variant
    syndrome — and in particular its craniofacial arm?
  rationale: >-
    The mouse Kdm1a allelic series brackets the human condition without
    reproducing it. The homozygous null dies in early embryogenesis, so it
    cannot be used to study postnatal neurodevelopment or craniofacial
    patterning. The heterozygous null is reported as phenotypically normal, so
    it does not reproduce the human dysmorphism, hypotonia or developmental
    delay. Human disease sits between these: a stably expressed but
    catalytically impaired protein at one of two alleles. The two strongest
    modern datasets share this limitation — the adult forebrain conditional
    knockout models complete somatic loss in mature neurons, and the zebrafish
    line is a knockout. Most importantly, the craniofacial and palatal arm of
    the phenotype, which supplies the disorder's name, has never been modelled
    with a KDM1A patient allele at all; the supporting evidence comes from
    knockdown of the partner gene PHF21A. This is a model-fidelity question, not
    an absence of data.
  proposed_experiments:
  - experiment_id: kdm1a_heterozygous_knockin_mouse
    name: Heterozygous patient-allele knock-in mouse
    description: >-
      Build heterozygous knock-in mice carrying the human missense substitutions
      and phenotype palate, craniofacial skeleton, muscle tone and behaviour
      against both wild-type and heterozygous-null littermates.
    supporting_outcome:
    - Reproduction of palatal, craniofacial and neurodevelopmental phenotypes would validate the mouse as a model of the human disorder.
    refuting_outcome:
    - A normal heterozygous knock-in mouse would indicate that the mouse cannot model this disorder and would redirect effort to human cellular models.
  - experiment_id: kdm1a_ipsc_neural_crest_model
    name: Patient-derived iPSC neurons and cranial neural crest cells
    description: >-
      Differentiate patient-derived iPSCs into cortical neurons and cranial
      neural crest cells and test whether the human alleles perturb LSD1-CoREST
      target-gene repression in the relevant human cell types, against isogenic
      corrected controls.
    supporting_outcome:
    - Allele-dependent derepression of LSD1-CoREST targets in human neural crest would establish the craniofacial arm of the mechanism in human cells.
    refuting_outcome:
    - Absence of any transcriptional consequence in patient neural crest would argue that the craniofacial phenotype arises by a different route.
  evidence:
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mice heterozygous for a Kdm1a deletion are apparently normal and fertile
    explanation: >-
      The heterozygous null mouse does not recapitulate the human heterozygous
      phenotype, establishing the model-fidelity mismatch.
  - reference: PMID:26656649
    reference_title: "Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous knockout of Kdm1a in mice is lethal during early embryogenesis
    explanation: >-
      The homozygous null is embryonic-lethal, so it cannot model the postnatal
      human phenotype either; the two available mouse genotypes bracket rather
      than reproduce the human condition.
review_notes: >-
  NAMED-ENTITY-CONFUSION PREFLIGHT — PASSED. The MONDO label ("palatal
  anomalies-widely spaced teeth-facial dysmorphism-developmental delay
  syndrome") is purely descriptive and carries no gene handle, which is a
  high-risk NEC configuration: multi-feature descriptive syndrome names collide
  easily with other dysmorphology entities. Identity was therefore anchored
  before any deep-research output was consumed, using
  `runoak -i sqlite:obo:mondo info MONDO:0014751 -O obo`. That record supplies
  three independent anchors, all concordant: (i) the gene relation
  `RO:0004003 HGNC:29079 ! KDM1A`; (ii) `xref: OMIM:616728`, which is
  "CLEFT PALATE, PSYCHOMOTOR RETARDATION, AND DISTINCTIVE FACIAL FEATURES; CPRF";
  and (iii) the RELATED synonym "CPRF", matching that OMIM title. The literature
  is concordant: Burkart et al. (PMID:40530541) explicitly equate "KDM1A-related
  neurodevelopmental disorder" with "CPRF, OMIM #616728", and the facial gestalt
  behind the Orphanet definition matches that reported by Chong et al.
  (PMID:26656649). The Edison/falcon deep-research report independently returned
  KDM1A and OMIM 616728 as the dominant gene/entity, so the DR passes the
  gene-frequency-versus-MONDO check and was used. Two adjacent entities were
  checked and excluded: KDM5C (Claes-Jensen X-linked ID, curated separately) and
  PHF21A (Potocki-Shaffer / 11p11.2), which is a complex partner of LSD1 and is
  modelled here only as a differential diagnosis and as indirect (PARTIAL)
  mechanistic support, never as the causal gene.
notes: >-
  SCOPE AND SIZING. This entry is deliberately sized to a very small literature:
  three probands in the delineating report (PMID:26656649, one of whom was first
  published as PMID:24838796), functional characterisation of their three
  alleles (PMID:27094131), and one subsequent phenotype-expansion case report
  (PMID:40530541). Generic developmental-delay biology has not been imported to
  pad the pathograph.

  DEEP RESEARCH. Edison/falcon
  (`research/KDM1A-Related_Neurodevelopmental_Disorder-deep-research-falcon.md`,
  646 s, 21 citations). The report independently converged on KDM1A / CPRF /
  OMIM 616728 and contributed two mechanistic sources used here (PMID:38453932
  forebrain conditional-knockout mouse; PMID:41351445 kdm1a-knockout zebrafish).
  It did NOT retrieve either of the two delineating clinical papers
  (PMID:26656649, PMID:24838796), which were found independently via PubMed and
  supply most of the phenotype evidence — a reminder that DR coverage of very
  small clinical literatures is unreliable. Its suggested identifiers were
  partly unusable (it declined to assign MONDO/Orphanet IDs; several suggested
  GO/HP terms are obsolete or non-preferred, e.g. GO:0070544 and HP:0001212),
  so every ontology term in this entry was independently verified with OAK
  rather than taken from the report.

  FEATURES IN THE MONDO/ORPHANET DEFINITION THAT ARE NOT CURATED AS PHENOTYPES.
  The Orphanet-derived definition additionally lists hypertelorism, downslanting
  palpebral fissures, high and narrow palate, short stature, axial hypotonia,
  lower-limb hypertonia, brachydactyly, clinodactyly, hypoplastic toenails, a
  single palmar crease, joint hypermobility, and ocular and urogenital
  anomalies. These are omitted, not overlooked: the Orphanet structured record
  (ORPHA:477993) is not present in `references_cache/`, `just refresh-orphadata`
  currently fails a manifest checksum against upstream drift, the targeted
  per-ID rebuild `just structured-rebuild-orphanet --id 477993` was also tried
  and fails with FileNotFoundError on the un-downloadable
  `data/orphadata/en_product1.xml`, and none of these features appears in a
  quotable form in any abstract or open full text available for this disorder.
  Curating them would require fabricating a
  snippet. Note also a real discrepancy worth preserving: the delineating study
  reports *elongated* palpebral fissures (a Kabuki-like feature), whereas the
  Orphanet definition reports *downslanting* palpebral fissures. Only the
  directly quotable "elongated" form is curated. The fourth proband additionally
  had myopia, mild thoracic kyphosis, broad fingertips, hypoplastic nails and
  clinodactyly, but the cached abstract does not quote them, so they are also
  left out. The same applies to that proband's allele: the deep-research report,
  working from the Burkart full text, gives it as c.1844G>A p.(Arg615Gln), but
  the cached abstract says only "exon 16", so no fourth `variants[]` entry is
  asserted. These should be added when the ORPHA:477993 cache can be rebuilt or
  when the Burkart full text becomes fetchable.

  NO GENEREVIEWS BASELINE. A PubMed search for a GeneReviews chapter
  ("KDM1A GeneReviews[All Fields]", and a title-restricted search) returned no
  results. There is no GeneReviews article for this disorder, so the mandatory
  GeneReviews phenotype baseline does not apply.
📚

References & Deep Research

Deep Research

1
Falcon ▸
KDM1A-Related Neurodevelopmental Disorder: Disease Characteristics Report
Edison Scientific Literature 21 citations 2026-08-01T18:32:39.625834

KDM1A-Related Neurodevelopmental Disorder: Disease Characteristics Report

Executive summary

KDM1A-related neurodevelopmental disorder (KDM1A-RD) is an ultra-rare, autosomal-dominant chromatin disorder caused by heterozygous germline variants in KDM1A, which encodes lysine-specific demethylase 1A (LSD1). The historical name is cleft palate, psychomotor retardation, and distinctive facial features syndrome (CPRF syndrome; OMIM 616728). Its core manifestations are congenital or early-childhood hypotonia, global developmental delay, variable intellectual disability, and craniofacial dysmorphism. Cleft palate is characteristic but not obligatory: it occurred in the three original detailed patients but was absent in the fourth detailed case, published in 2025. The evidence base remains exceptionally small, preventing reliable prevalence, penetrance, prognosis, or phenotype-frequency estimates beyond this four-person series. (burkart2025phenotypicalandgenotypical pages 2-2, burkart2025phenotypicalandgenotypical pages 1-2, burkart2025phenotypicalandgenotypical pages 4-4)

The best-supported molecular mechanism is disruption of FAD-dependent histone demethylation and transcriptional regulation. Three original active-site variants markedly reduced enzyme activity, while newer experimental work shows that KDM1A is also required for neurogenesis, neurite architecture, memory-associated transcription, and maintenance of neuronal chromatin boundaries. No disease-modifying therapy or KDM1A-RD-specific clinical trial was identified; care is presently supportive and phenotype directed. (pilotto2016lsd1kdm1amutationsassociated pages 2-3, wilson2022reprogrammingofthe pages 17-19, blanco2024kdm1asafeguardsthe pages 1-2, burkart2025phenotypicalandgenotypical pages 2-2)

Domain Established finding Evidence type/strength Knowledge-base annotation
Disease ID/name KDM1A-related neurodevelopmental disorder; CPRF syndrome; OMIM #616728. Unsupported identifiers (e.g., MONDO/Orphanet/ICD/MeSH) not confirmed here and therefore omitted. (wilson2022reprogrammingofthe pages 17-19, burkart2025phenotypicalandgenotypical pages 1-2) Human disease literature + review support; moderate Preferred label: KDM1A-related neurodevelopmental disorder; synonym: CPRF syndrome; OMIM: 616728
Inheritance Autosomal dominant, with reported detailed cases caused by de novo heterozygous missense variants in KDM1A. (burkart2025phenotypicalandgenotypical pages 2-2, pilotto2016lsd1kdm1amutationsassociated pages 2-3) Human genetic evidence; moderate Inheritance: AD; allelic origin: germline, typically de novo
Known detailed patient count 4 detailed patients are supported in the retrieved evidence set: 3 earlier detailed patients/functionally studied in 2016, plus 1 additional detailed case published in 2025 (latest available, outside the user’s 2023-2024 priority window). Four more ClinVar variants are mentioned without detailed phenotypes. (burkart2025phenotypicalandgenotypical pages 2-2) Human case-level evidence; moderate Minimum detailed case count in KB: 4; note ascertainment uncertainty beyond retrieved sources
Variant spectrum Reported disease-associated detailed variants: c.1207G>A (p.Glu403Lys/E379K), c.1739A>G (p.Asp580Gly/D556G), c.2353T>C (p.Tyr785His/Y761H), plus c.1844G>A (p.Arg615Gln) in 2025. Variants cluster in the amine oxidase/catalytic region, including the FAD-binding subdomain. (pilotto2016lsd1kdm1amutationsassociated pages 2-3, pilotto2016lsd1kdm1amutationsassociated pages 1-2, burkart2025phenotypicalandgenotypical pages 2-2, burkart2025phenotypicalandgenotypical pages 4-4) Human genetic + biochemical support; moderate-to-strong Causal gene: KDM1A; variant class so far: heterozygous missense; hotspot concept: catalytic/amino oxidase domain
Cardinal phenotypes Core phenotype includes global developmental delay, intellectual disability/psychomotor retardation, hypotonia, and distinctive/variable craniofacial dysmorphism. Cleft palate is present in 3/4 detailed patients; the 2025 case lacked palate abnormality, showing variable expressivity. Do not infer frequencies for other features from current evidence. (wilson2022reprogrammingofthe pages 17-19, burkart2025phenotypicalandgenotypical pages 1-2, burkart2025phenotypicalandgenotypical pages 2-2, burkart2025phenotypicalandgenotypical pages 4-4) Human case reports/review; moderate Suggested HPO anchors: developmental delay, intellectual disability, hypotonia, cleft palate, dysmorphic facies
Onset/course Pediatric neurodevelopmental onset; in the 2025 case, hypotonia at birth, delayed first words (2 years), independent walking (2.5 years), and persistent mild ID at age 13 were reported. Available evidence supports a chronic, developmental, variably expressive course rather than degenerative episodes. (burkart2025phenotypicalandgenotypical pages 2-2) Human case-level evidence; limited-to-moderate Onset: congenital/early childhood; course: lifelong neurodevelopmental disorder
Molecular mechanism KDM1A/LSD1 is a FAD-dependent histone demethylase acting mainly on H3K4me1/2 (and context-dependently H3K9me1/2) within complexes such as CoREST/REST. Disease variants impair demethylase activity and can weaken binding to some transcription factors; E379K is most severe, while D556G and Y761H show ~10-20-fold lower catalytic efficiency. Variants near the FAD-binding site may disrupt cofactor affinity/stability and chromatin regulation. (pilotto2016lsd1kdm1amutationsassociated pages 2-3, pilotto2016lsd1kdm1amutationsassociated pages 1-2, wilson2022reprogrammingofthe pages 17-19, burkart2025phenotypicalandgenotypical pages 4-5) Functional biochemistry + broader mechanistic biology; strong for enzyme defect, moderate for disease causal chain Mechanism tag: chromatinopathy / histone demethylase dysfunction; likely effect: loss-of-function or hypomorphic catalytic impairment
Diagnosis Current strongest diagnostic route is genomic sequencing (trio genome/exome style testing), with variant interpretation in clinical context. In the 2025 case, prior karyotype, array, FMR1 repeat testing, metabolic workup, ENT and cardiac evaluation were non-contributory/normal before diagnosis by trio genome sequencing. (burkart2025phenotypicalandgenotypical pages 2-2) Human case-level clinical evidence; limited Diagnostic strategy: sequence-based molecular diagnosis after nonspecific neurodevelopmental presentation
Treatment/trials No disease-specific therapy or clinical trials for KDM1A-related neurodevelopmental disorder were identified in the retrieved evidence. Do not repurpose oncology LSD1 inhibitor trials as treatment evidence for this disorder. Management evidence in retrieved sources is sparse and largely supportive/diagnostic rather than interventional. (burkart2025phenotypicalandgenotypical pages 2-2, burkart2025phenotypicalandgenotypical pages 4-4) Evidence gap; weak/absent Treatment status: supportive care only documented indirectly; trial status: no KDM1A-RD-specific trials identified
Prognosis/epidemiology The disorder is described as ultra-rare. Robust prevalence, incidence, life expectancy, mortality, and penetrance estimates were not available in the retrieved evidence. Available human data support variable expressivity and generally persistent neurodevelopmental impairment. (burkart2025phenotypicalandgenotypical pages 2-2, burkart2025phenotypicalandgenotypical pages 1-2, burkart2025phenotypicalandgenotypical pages 4-4) Human evidence sparse; weak Epidemiology: unknown / ultra-rare; prognosis: developmental impairment persists, severity variable
Key models Broader KDM1A biology strongly supports neurodevelopmental relevance: mouse loss/knockdown studies show roles in neurite morphogenesis, neuronal differentiation, and memory; 2024 adult forebrain-neuron conditional KO multi-omics showed derepression of PRC2-silenced nonneuronal genes and altered chromatin boundary maintenance; zebrafish deficiency causes reduced neurogenesis, shorter motor axons, and locomotor/learning deficits. These are supportive mechanism models, not direct patient-specific disease models. (blanco2024kdm1asafeguardsthe pages 1-2, zou2025deficiencyofkdm1a pages 5-7, wilson2022reprogrammingofthe pages 17-19, swahari2019histonedemethylasesin pages 1-3) Experimental model evidence; strong for gene function, indirect for human disorder Model-organism evidence supports nervous-system vulnerability and chromatin dysregulation as disease-relevant biology

Table: This table summarizes the highest-confidence disease facts for KDM1A-related neurodevelopmental disorder/CPRF syndrome, separating direct human case evidence from broader KDM1A mechanistic model evidence. It is designed for rapid knowledge-base ingestion and flags major evidence gaps, especially for epidemiology and treatment.

1. Disease information

Definition and identifiers

Field Recommended entry
Preferred name KDM1A-related neurodevelopmental disorder
Principal synonym Cleft palate, psychomotor retardation, and distinctive facial features syndrome
Abbreviation CPRF syndrome
OMIM 616728
Category Mendelian neurodevelopmental disorder; chromatinopathy
Inheritance Autosomal dominant, usually de novo in reported patients
Causal gene KDM1A/LSD1
MONDO A specific MONDO identifier was not verified in the retrieved literature; do not assign one without checking the current MONDO release.
Orphanet, MeSH, ICD-10/11 No disease-specific identifiers were verified. Cases would ordinarily be coded under broader congenital/neurodevelopmental categories.

CPRF is the historical phenotype-based label, but KDM1A-related neurodevelopmental disorder is preferable because cleft palate is variably expressive. The 2025 case was explicitly reported without any palate abnormality. (wilson2022reprogrammingofthe pages 17-19, burkart2025phenotypicalandgenotypical pages 4-4, burkart2025phenotypicalandgenotypical pages 1-2)

The present description is an aggregated disease-level synthesis of published case reports and experimental studies, not an EHR-derived patient profile. Only four individuals have sufficiently detailed published phenotypes in the retrieved evidence; four additional ClinVar missense variants were mentioned without detailed clinical records. (burkart2025phenotypicalandgenotypical pages 2-2)

2. Etiology

Causal and genetic factors

The disorder is caused by heterozygous germline KDM1A variants. All sufficiently characterized alleles are missense substitutions affecting the catalytic amino-oxidase region:

  • c.1207G>A, p.Glu403Lys—also numbered E379K in a shorter protein construct.
  • c.1739A>G, p.Asp580Gly—D556G in the experimental construct.
  • c.2353T>C, p.Tyr785His—Y761H in the experimental construct.
  • c.1844G>A, p.Arg615Gln, a de novo likely pathogenic allele reported in 2025.

The first three substitutions affect active-site residues; p.Arg615Gln lies in the amino-oxidase domain and near its FAD-binding subdomain. (burkart2025phenotypicalandgenotypical pages 2-2, burkart2025phenotypicalandgenotypical pages 4-4, pilotto2016lsd1kdm1amutationsassociated pages 2-3, pilotto2016lsd1kdm1amutationsassociated pages 1-2)

The reported inheritance pattern is autosomal dominant and de novo. One original individual also carried a de novo ANKRD11 deletion/variant and therefore had a potentially blended KDM1A/KBG phenotype, limiting the precision of phenotype attribution in that case. (pilotto2016lsd1kdm1amutationsassociated pages 2-3, vallianatos2015disruptedintricacyof pages 8-9)

Environmental, lifestyle, infectious, and protective factors

No reproducible environmental, infectious, dietary, occupational, lifestyle, or gene–environment risk factor has been established. Likewise, no protective variant, modifier allele, founder effect, or protective exposure has been reported. This is expected for a highly penetrant-appearing monogenic developmental disorder, but penetrance cannot yet be quantified.

No evidence supports smoking, alcohol, diet, pollution, infection, or vaccination status as determinants of KDM1A-RD. General prenatal-health recommendations remain appropriate but should not be presented as disease-specific prevention.

3. Phenotypes

Core phenotype and suggested HPO annotations

Phenotype Characteristics and evidence Suggested HPO term
Global developmental delay Early-childhood onset; apparently universal among detailed cases, but exact pooled frequency cannot be independently reconstructed HP:0001263 Global developmental delay
Intellectual disability Variable; mild ID and IQ 57 in the 2025 case; described as cognitive impairment/ID in original cases HP:0001249 Intellectual disability
Delayed speech First words at age 2 years in the 2025 case HP:0000750 Delayed speech and language development
Delayed walking Independent walking at 2.5 years in the 2025 case HP:0002060 Delayed motor development
Generalized hypotonia Congenital in the 2025 patient; part of the broader phenotype HP:0001252 Hypotonia
Cleft palate Present in the three previously detailed patients and absent in the 2025 case: 3/4, subject to severe ascertainment bias HP:0000175 Cleft palate
Facial dysmorphism Variable: long face, small forehead, mild ptosis, long/small nose, short philtrum, and small low-set ears in the newest case HP:0001999 Abnormal facial shape; HP:0000508 Ptosis; HP:0000369 Low-set ears
Digital/nail anomalies Broad fingertips, hypoplastic nails, finger/toe clinodactyly HP:0001212 Clinodactyly; HP:0001792 Small nail
Kyphosis Mild thoracic kyphosis in the newest case HP:0002808 Kyphosis
Myopia/visual impairment Moderate myopia with mild visual impairment in the newest case HP:0000545 Myopia; HP:0000505 Visual impairment
Social difficulties Reported at ages 3–4 years in the newest case; insufficient evidence for an autism diagnosis HP:0012433 Social and occupational deterioration or a more specific behavioral term after formal assessment

The newest patient had no seizures, recognized structural CNS abnormality, cardiac defect, hearing impairment, or persistent creatine-kinase elevation. Brain imaging was not performed in that report, so “no structural CNS abnormality” should not be interpreted as a definitive normal MRI. (burkart2025phenotypicalandgenotypical pages 2-2, burkart2025phenotypicalandgenotypical pages 3-4, burkart2025phenotypicalandgenotypical pages 1-2)

Severity, progression, and quality of life

Severity is variable. The 13-year-old patient had mild developmental impairment and ID, while the original syndrome descriptions included psychomotor retardation and more conspicuous craniofacial anomalies. Available evidence suggests a chronic, lifelong developmental disability, not a proven neurodegenerative or episodic disorder. Formal longitudinal natural-history data are unavailable. (wilson2022reprogrammingofthe pages 17-19, burkart2025phenotypicalandgenotypical pages 1-2)

No EQ-5D, SF-36, PROMIS, adaptive-function, or disease-specific quality-of-life study has been published in the retrieved evidence. Functional effects can nevertheless include delayed mobility, communication limitations, educational needs, and social difficulties.

4. Genetic and molecular information

Gene and protein

  • Gene: KDM1A, also called LSD1.
  • Protein class: FAD-dependent amine oxidase/histone lysine demethylase.
  • Substrates: principally H3K4me1 and H3K4me2 in repressive complexes; H3K9me1/2 activity can occur in other protein contexts.
  • Major complexes: CoREST/RCOR–REST and SIN3A/HDAC-associated transcriptional regulatory assemblies.
  • Subcellular location: predominantly nucleus/chromatin.

Suggested annotations include GO:0032452 histone demethylase activity, GO:0070544 histone H3-K4 demethylation, GO:0006355 regulation of DNA-templated transcription, GO:0005634 nucleus, and GO:0000785 chromatin. FAD may be annotated as CHEBI:57692 (FAD anion; database-release verification recommended). (zou2025deficiencyofkdm1a pages 5-7, wilson2022reprogrammingofthe pages 17-19, swahari2019histonedemethylasesin pages 1-3)

Functional effects of pathogenic variants

Biochemical testing supplied unusually strong mechanistic evidence:

  • E379K/p.Glu403Lys had barely detectable demethylase activity and severely impaired H3-tail binding.
  • D556G/p.Asp580Gly and Y761H/p.Tyr785His were approximately 10–20-fold less catalytically efficient, principally through reduced turnover.
  • The variants retained gross structural integrity and CoREST binding, but showed differential impairment of transcription-factor interactions and reduced cellular stability/half-life.
  • Tyr761 lies in the aromatic catalytic cage adjacent to FAD; Glu379 and Asp556 are near the histone-tail entrance.

Thus, the strongest interpretation is hypomorphic or loss-of-function-like catalytic dysfunction, rather than a uniform dominant-negative mechanism. A gain-of-function interpretation has occasionally been suggested for an individual allele, but the direct biochemical data overall favor impaired catalytic function and altered partner interactions. (pilotto2016lsd1kdm1amutationsassociated pages 2-3, pilotto2016lsd1kdm1amutationsassociated pages 1-2, wilson2022reprogrammingofthe pages 17-19)

Population frequencies were not supplied in the retrieved full texts. Given de novo occurrence and ultra-rarity, causative alleles are expected to be absent or extremely rare in gnomAD, but every candidate must be checked directly against the current gnomAD release. No somatic origin has been implicated in CPRF; somatic KDM1A biology in cancer is a separate subject.

Structural, modifier, and epigenetic findings

No recurrent pathogenic deletion, duplication, translocation, inversion, or aneuploidy defining KDM1A-RD has been established. No validated modifier gene is known. The co-occurring ANKRD11 alteration in one patient is best regarded as a potential second diagnosis rather than a proven modifier. (vallianatos2015disruptedintricacyof pages 8-9)

A disease-specific blood DNA-methylation episignature has not yet been validated. The 2025 authors proposed episignature analysis as a future means of distinguishing pathogenic from benign KDM1A variants. (burkart2025phenotypicalandgenotypical pages 3-4)

5. Environmental information

Environmental causation is not applicable on current evidence. No toxin, radiation exposure, pollutant, infection, microbiome pattern, or lifestyle behavior is known to produce this Mendelian syndrome. Environmental accommodations—educational support, accessible communication, and rehabilitation—may strongly affect functional outcome, but they do not alter the underlying genetic cause.

6. Mechanism and pathophysiology

Proposed causal chain

  1. A de novo heterozygous variant alters the KDM1A amino-oxidase/catalytic domain.
  2. FAD-dependent oxidative demethylation and/or recruitment of transcriptional partners is reduced.
  3. H3K4me1/2 regulation and CoREST/REST-dependent repression become mistimed or locus inappropriate.
  4. Neural progenitor differentiation, neuronal gene programs, neurite growth, synaptic transcription, and maintenance of mature neuronal identity are disrupted.
  5. Altered neural-circuit development produces hypotonia, delayed milestones, ID, and behavioral/learning impairment.
  6. Disturbed epigenetic control in cranial neural crest or craniofacial developmental programs plausibly contributes to cleft palate and dysmorphism, although this last link has not been demonstrated in a patient-variant craniofacial model. (pilotto2016lsd1kdm1amutationsassociated pages 2-3, wilson2022reprogrammingofthe pages 17-19, vallianatos2015disruptedintricacyof pages 8-9, swahari2019histonedemethylasesin pages 1-3)

Upstream and downstream processes

The upstream lesion is defective chromatin-enzyme activity or partner binding. Intermediate processes include transcriptional derepression, abnormal histone methylation, impaired neural-progenitor differentiation, and neurite/synapse abnormalities. Developmental delay and craniofacial anomalies are downstream organism-level consequences.

KDM1A–CoREST can oppose Notch/HES1 signaling in cortical progenitors and support NGN2-associated neuronal differentiation. An RCOR2/KDM1A complex also regulates cortical neurogenesis partly through repression of DLX2 and SHH. These findings identify candidate pathways, but they are not yet proven to be dysregulated in patient tissue. (swahari2019histonedemethylasesin pages 1-3)

Suggested biological-process terms include GO:0022008 neurogenesis, GO:0030182 neuron differentiation, GO:0048666 neuron development, GO:0031175 neuron projection development, and GO:0007399 nervous system development.

2024 multi-omics development

A March 2024 Nature Communications study used inducible, forebrain-restricted Kdm1a deletion with transcriptomics, epigenomics, chromatin-conformation analysis, and super-resolution microscopy. Loss of Kdm1a in adult excitatory neurons derepressed non-neuronal genes normally silenced by PRC2 and weakened their segregation from adjacent active chromatin. The N-terminal intrinsically disordered region was necessary for maintaining those topological boundaries, which also weakened during normal aging. This expands the model from a simple histone-demethylase defect to failure of three-dimensional neuronal genome organization and cell-identity maintenance. It is strong mechanistic evidence but not a direct model of any human CPRF allele. DOI: https://doi.org/10.1038/s41467-024-45773-3; published March 2024. (blanco2024kdm1asafeguardsthe pages 1-2)

The abstract’s key conclusion was: “Kdm1a elimination causes the neuronal activation of nonneuronal genes that are silenced by the polycomb repressor complex and interspersed with active genes.” (blanco2024kdm1asafeguardsthe pages 1-2)

No KDM1A-RD-specific patient transcriptome, proteome, metabolome, lipidome, single-cell atlas, spatial transcriptome, organoid study, or integrated multi-omics cohort was identified.

7. Anatomical structures affected

The principal affected system is the nervous system, particularly the developing brain and its neuronal circuits. Supporting model evidence implicates cerebral cortex, hippocampal circuits, neural progenitors, mature excitatory neurons, motor neurons, axons, dendrites, and synapses. Craniofacial structures—especially the secondary palate and facial skeleton/soft tissues—are also affected in many patients. Skeletal/digital, ocular, and muscular manifestations occur variably. (zou2025deficiencyofkdm1a pages 5-7, wilson2022reprogrammingofthe pages 17-19, swahari2019histonedemethylasesin pages 1-3, burkart2025phenotypicalandgenotypical pages 1-2)

Suggested anatomy/cell annotations:

  • UBERON:0000955 brain
  • UBERON:0001890 forebrain
  • UBERON:0001950 neocortex
  • UBERON:0002421 hippocampal formation
  • UBERON:0001716 secondary palate
  • CL:0000540 neuron
  • CL:0000679 glutamatergic neuron
  • CL:0000127 astrocyte only as a model-context candidate, not a proven primary patient cell
  • GO:0005634 nucleus and GO:0000785 chromatin at subcellular level

There is no established lateralization pattern.

8. Temporal development

Onset is congenital or in early infancy. Hypotonia may be apparent from birth; developmental delay becomes evident as motor and language milestones are missed. Cleft palate and dysmorphic features are congenital. The disorder appears chronic and lifelong, with variable severity. There are no validated stages, remission pattern, or end-stage phenotype. (burkart2025phenotypicalandgenotypical pages 1-2, burkart2025phenotypicalandgenotypical pages 2-2)

Embryonic and early postnatal development are probable critical periods because KDM1A regulates zygotic genome activation, gastrulation, neural differentiation, and craniofacial development. Mature-neuron experiments indicate that KDM1A remains important later in life, raising the theoretical possibility that some functional abnormalities may remain modifiable; this is not yet clinical evidence of reversibility. (vallianatos2015disruptedintricacyof pages 8-9, blanco2024kdm1asafeguardsthe pages 1-2)

9. Inheritance, penetrance, and population

  • Inheritance: autosomal dominant.
  • Origin: de novo in documented cases.
  • Penetrance: apparently high for neurodevelopmental manifestations among ascertained cases, but not measurable.
  • Expressivity: demonstrably variable, particularly for cleft palate and severity of ID.
  • Anticipation: not reported.
  • Germline mosaicism: not documented, but low residual recurrence risk remains biologically possible for apparently de novo variants.
  • Founder effects/consanguinity: none reported; consanguinity is not mechanistically relevant to typical de novo dominant disease.
  • Carrier frequency: unknown and expected to be extremely low.
  • Sex ratio, ancestry, and geographic distribution: cannot be estimated from four detailed cases.

No population prevalence or annual incidence has been established. “Ultra-rare” is more defensible than a numerical estimate. (burkart2025phenotypicalandgenotypical pages 2-2, burkart2025phenotypicalandgenotypical pages 1-2)

10. Diagnostics

Recommended genetic approach

  1. Clinical recognition: developmental delay/ID plus hypotonia and variable craniofacial, palate, digital, or nail abnormalities.
  2. First-line molecular test: trio exome or genome sequencing with copy-number analysis. KDM1A should also be included on broad developmental-delay/ID, cleft-palate, and chromatinopathy panels.
  3. Variant assessment: confirm heterozygosity and de novo status by parental testing; apply ACMG/AMP criteria; assess domain location, conservation, population frequency, computational evidence, and functional literature.
  4. Sanger confirmation may be used depending on laboratory policy.
  5. CMA: useful when sequencing does not include reliable CNV detection or when a blended diagnosis is suspected.
  6. Karyotype/FISH: not routine unless a structural chromosome abnormality is clinically suspected.
  7. FMR1 repeat testing: remains part of some unexplained-ID pathways but does not test KDM1A-RD.
  8. Mitochondrial and repeat-expansion tests are not specifically indicated unless the phenotype suggests another disorder.

In the 2025 patient, trio genome sequencing found de novo p.Arg615Gln after karyotype, microarray, FMR1 analysis, and metabolic investigations were unrevealing. (burkart2025phenotypicalandgenotypical pages 2-2)

Clinical evaluations

There is no diagnostic biochemical assay. Baseline assessment should include developmental and neuropsychological testing, speech/language evaluation, neurologic examination, hearing and vision screening, palate/feeding assessment, and musculoskeletal examination. EEG is symptom triggered; brain MRI is reasonable for seizures, focal findings, regression, abnormal head growth, or severe presentation. Echocardiography, metabolic studies, or CK measurement should be directed by clinical findings rather than assumed to be universally abnormal.

Differential diagnosis

Important alternatives include:

  • Kabuki syndrome—KMT2D or KDM6A; overlapping facial features, developmental delay, hypotonia, and palate anomalies.
  • KBG syndrome—ANKRD11; macrodontia, skeletal findings, characteristic face, developmental delay.
  • Other chromatinopathies involving KDM or KMT genes.
  • Syndromic cleft-palate disorders, 22q11.2 deletion syndrome, and nonsyndromic developmental-delay etiologies.

The initial patient’s simultaneous ANKRD11 and KDM1A findings particularly emphasize the need to consider dual diagnoses. (wilson2022reprogrammingofthe pages 17-19, vallianatos2015disruptedintricacyof pages 8-9)

No formal clinical criteria, validated episignature, protein biomarker, metabolomic signature, prenatal ultrasound signature, newborn-screening assay, or population-screening program exists.

11. Outcome and prognosis

There are no survival curves, mortality estimates, or life-expectancy data. Nothing in the limited literature establishes disease-specific premature mortality, but absence of evidence is not proof of normal life expectancy. The principal recognized burden is persistent neurodevelopmental disability affecting learning, communication, motor development, education, and social functioning. (burkart2025phenotypicalandgenotypical pages 1-2, burkart2025phenotypicalandgenotypical pages 4-4)

Known severity predictors and prognostic biomarkers are unavailable. Catalytic impairment varies by allele in vitro, but a genotype–phenotype relationship cannot be inferred from four detailed patients. Cleft palate may require surgical treatment and can contribute to feeding, speech, and hearing morbidity. Seizures are not established as obligatory; the newest patient had none. (pilotto2016lsd1kdm1amutationsassociated pages 2-3, burkart2025phenotypicalandgenotypical pages 2-2)

12. Treatment

Current management

No approved disease-modifying therapy or KDM1A-RD-specific treatment guideline exists. Recommended practice is individualized multidisciplinary care:

  • Early developmental intervention.
  • Physical therapy for hypotonia and gross-motor delay.
  • Occupational therapy for fine-motor and adaptive skills.
  • Speech-language therapy, including augmentative communication when required.
  • Educational and neuropsychological support.
  • Cleft-palate team management, including feeding, audiology, speech, dentistry, orthodontics, and surgery when indicated.
  • Ophthalmologic treatment for myopia or other visual abnormalities.
  • Orthopedic/physiatry monitoring for kyphosis, gait, and contractures.
  • Standard antiseizure therapy only if epilepsy emerges.

Suggested NCIT intervention concepts include Physical Therapy, Occupational Therapy, Speech Therapy, Developmental Intervention, and Cleft Palate Repair; exact NCIT codes should be checked against the current release.

Experimental therapeutics and trials

No gene therapy, CRISPR editing, ASO, RNA therapy, cell therapy, or targeted small-molecule trial has been reported for KDM1A-RD. Searches retrieved LSD1-inhibitor trials in leukemia and small-cell lung cancer, but these are oncology studies and must not be construed as treatment trials for a KDM1A loss-of-function neurodevelopmental disorder. Pharmacologic KDM1A inhibition could theoretically worsen insufficient KDM1A activity, depending on allele and developmental context. (pilotto2016lsd1kdm1amutationsassociated pages 2-3, burkart2025phenotypicalandgenotypical pages 2-2)

Inhibition of KDM1A has improved neurogenesis or memory in models of other chromatin disorders such as Kabuki syndrome, but that is mechanistically opposite and not evidence for treating KDM1A-RD. Genotype-specific functional studies are required before considering epigenetic drugs.

13. Prevention

Primary prevention by lifestyle change, vaccination, or environmental avoidance is not available. Appropriate strategies are genetic and developmental:

  • Genetic counseling: explain dominant, usually de novo inheritance.
  • Parental testing: confirms de novo status and identifies rare parental mosaicism.
  • Recurrence risk: low but above the population baseline after an apparently de novo event because germline mosaicism cannot be excluded.
  • Reproductive options: targeted prenatal diagnosis by chorionic-villus sampling or amniocentesis, and preimplantation genetic testing for a known familial variant.
  • Cascade testing: appropriate if a parent is found to carry the variant or mosaicism is suspected.
  • Secondary/tertiary prevention: early developmental assessment, therapy, hearing/vision surveillance, and proactive palate management to reduce avoidable complications.

KDM1A-RD is not currently suitable for population carrier or newborn screening because it is predominantly de novo, exceptionally rare, lacks a validated screening assay, and has no presymptomatic disease-modifying treatment.

14. Other species and natural disease

KDM1A is evolutionarily conserved, with experimentally studied orthologs including mouse Kdm1a, zebrafish kdm1a, and C. elegans spr-5. Relevant taxa include Mus musculus (NCBI Taxon 10090), Danio rerio (7955), and Caenorhabditis elegans (6239).

No naturally occurring veterinary counterpart or breed-associated KDM1A syndrome was identified. Consequently, there is no zoonotic potential or cross-species transmission. Comparative relevance comes from induced genetic models rather than natural animal disease.

15. Model organisms

Mouse

Complete Kdm1a loss causes early embryonic lethality around gastrulation, limiting its utility as a direct CPRF model. Conditional or knockdown studies show impaired cortical neurogenesis, reduced dendritic arborization and neurite width, altered synaptic transcription, and memory deficits. Adult forebrain-specific deletion demonstrates derepression of non-neuronal PRC2 targets and impaired chromatin-domain segregation. These models strongly establish gene function but do not reproduce a specific human heterozygous missense allele. (wilson2022reprogrammingofthe pages 17-19, vallianatos2015disruptedintricacyof pages 8-9, swahari2019histonedemethylasesin pages 1-3, blanco2024kdm1asafeguardsthe pages 1-2)

Zebrafish

A 2025 CRISPR kdm1a-deficiency model showed lower neuronal density, reduced neuronal reporter signal, shortened motor-neuron axons, locomotor abnormalities, and impaired learning/memory. Neurogenesis and maturation genes—including neurod1, neurog1, elavl3, tuba1, gfap, gap43, and syn2a—were downregulated, while autophagy/apoptosis-associated beclin1 and caspase expression increased. This supports neuronal loss/dysfunction as a downstream mechanism, although the model is a knockout rather than a patient-specific heterozygous knock-in. DOI: https://doi.org/10.31083/jin44394; published November 2025. (zou2025deficiencyofkdm1a pages 5-7)

Invertebrate and cellular models

C. elegans spr-5 studies support an evolutionarily conserved role in erasing H3K4 methylation and preventing inappropriate transcriptional memory. Cultured neurons and cortical-progenitor experiments are useful for neurite morphology, partner binding, enzyme kinetics, and transcriptomic rescue studies. No patient-derived iPSC neuron, neural-crest cell, brain organoid, or palate organoid model was identified.

Model limitations and research priorities

The principal limitation is the mismatch between severe knockout models and heterozygous human missense disease. Highest-priority resources are:

  1. Patient-variant knock-in mouse and zebrafish lines.
  2. Patient-derived iPSC cortical neurons and cranial neural-crest cells.
  3. Isogenic correction controls.
  4. H3K4me1/2 profiling, CUT&RUN, RNA-seq, and chromatin-conformation studies.
  5. Single-cell and spatial analyses during cortical and palatal development.
  6. Allele-specific assays to distinguish haploinsufficiency, dominant-negative effects, and altered substrate/partner specificity.

Key evidence quotations and bibliography

  • Pilotto et al., Human Molecular Genetics, June 2016: the three variants “impair demethylase activity and binding to transcription factors,” providing direct biochemical support for pathogenicity. DOI: https://doi.org/10.1093/hmg/ddw120. (pilotto2016lsd1kdm1amutationsassociated pages 2-3, pilotto2016lsd1kdm1amutationsassociated pages 1-2)
  • Del Blanco et al., Nature Communications, March 2024: “Kdm1a elimination causes the neuronal activation of nonneuronal genes that are silenced by the polycomb repressor complex and interspersed with active genes.” DOI: https://doi.org/10.1038/s41467-024-45773-3. (blanco2024kdm1asafeguardsthe pages 1-2)
  • Burkart et al., American Journal of Medical Genetics Part A, June 2025: the new patient carried a “novel heterozygous, likely pathogenic germline missense variant” and was the first detailed individual reported without palate abnormalities. DOI: https://doi.org/10.1002/ajmg.a.64144. (burkart2025phenotypicalandgenotypical pages 2-2, burkart2025phenotypicalandgenotypical pages 4-4)
  • Wilson et al., Critical Reviews in Biochemistry and Molecular Biology, October 2022. DOI: https://doi.org/10.1080/10409238.2021.1979457. This review places CPRF among neurodevelopmental chromatinopathies and summarizes KDM1A–CoREST/REST biology. (wilson2022reprogrammingofthe pages 17-19)

PMIDs were not present in the retrieved full-text metadata and therefore are not supplied rather than risk assigning incorrect identifiers. DOI links above provide stable primary-source access.

Overall evidence assessment

The gene–disease relationship is supported by multiple de novo alleles, clustering in a functionally critical domain, direct enzyme assays, and convergent neurodevelopmental model evidence. Nevertheless, clinical validity is constrained by the exceptionally small patient series, one potentially blended ANKRD11/KDM1A case, absence of systematic longitudinal follow-up, and lack of patient-derived molecular profiling. Phenotype frequencies other than the observed cleft-palate count of 3/4 should therefore be stored as unknown, not extrapolated percentages. The immediate clinical priorities are molecular diagnosis, careful documentation of additional cases, multidisciplinary supportive care, and international natural-history aggregation.

References

  1. (burkart2025phenotypicalandgenotypical pages 2-2): Sebastian Burkart, Melanie Spanjaard, Lilian Kaufmann, Katrin Hinderhofer, Christian P. Schaaf, Markus Ries, and Maja Hempel. Phenotypical and genotypical expansion of autosomal-dominant kdm1a-related neurodevelopmental disorder spectrum: a case report. American journal of medical genetics. Part A, pages e64144, Jun 2025. URL: https://doi.org/10.1002/ajmg.a.64144, doi:10.1002/ajmg.a.64144. This article has 1 citations and is from a peer-reviewed journal.

  2. (burkart2025phenotypicalandgenotypical pages 1-2): Sebastian Burkart, Melanie Spanjaard, Lilian Kaufmann, Katrin Hinderhofer, Christian P. Schaaf, Markus Ries, and Maja Hempel. Phenotypical and genotypical expansion of autosomal-dominant kdm1a-related neurodevelopmental disorder spectrum: a case report. American journal of medical genetics. Part A, pages e64144, Jun 2025. URL: https://doi.org/10.1002/ajmg.a.64144, doi:10.1002/ajmg.a.64144. This article has 1 citations and is from a peer-reviewed journal.

  3. (burkart2025phenotypicalandgenotypical pages 4-4): Sebastian Burkart, Melanie Spanjaard, Lilian Kaufmann, Katrin Hinderhofer, Christian P. Schaaf, Markus Ries, and Maja Hempel. Phenotypical and genotypical expansion of autosomal-dominant kdm1a-related neurodevelopmental disorder spectrum: a case report. American journal of medical genetics. Part A, pages e64144, Jun 2025. URL: https://doi.org/10.1002/ajmg.a.64144, doi:10.1002/ajmg.a.64144. This article has 1 citations and is from a peer-reviewed journal.

  4. (pilotto2016lsd1kdm1amutationsassociated pages 2-3): Simona Pilotto, Valentina Speranzini, Chiara Marabelli, Francesco Rusconi, Emanuela Toffolo, Barbara Grillo, Elena Battaglioli, and Andrea Mattevi. Lsd1/kdm1a mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors. Human molecular genetics, 25 12:2578-2587, Jun 2016. URL: https://doi.org/10.1093/hmg/ddw120, doi:10.1093/hmg/ddw120. This article has 66 citations and is from a domain leading peer-reviewed journal.

  5. (wilson2022reprogrammingofthe pages 17-19): Khadija D. Wilson, Elizabeth G. Porter, and Benjamin A. Garcia. Reprogramming of the epigenome in neurodevelopmental disorders. Critical Reviews in Biochemistry and Molecular Biology, 57:73-112, Oct 2022. URL: https://doi.org/10.1080/10409238.2021.1979457, doi:10.1080/10409238.2021.1979457. This article has 31 citations and is from a peer-reviewed journal.

  6. (blanco2024kdm1asafeguardsthe pages 1-2): Beatriz del Blanco, Sergio Niñerola, Ana M. Martín-González, Juan Paraíso-Luna, Minji Kim, Rafael Muñoz-Viana, Carina Racovac, Jose V. Sanchez-Mut, Yijun Ruan, and Ángel Barco. Kdm1a safeguards the topological boundaries of prc2-repressed genes and prevents aging-related euchromatinization in neurons. Nature Communications, Mar 2024. URL: https://doi.org/10.1038/s41467-024-45773-3, doi:10.1038/s41467-024-45773-3. This article has 16 citations and is from a highest quality peer-reviewed journal.

  7. (pilotto2016lsd1kdm1amutationsassociated pages 1-2): Simona Pilotto, Valentina Speranzini, Chiara Marabelli, Francesco Rusconi, Emanuela Toffolo, Barbara Grillo, Elena Battaglioli, and Andrea Mattevi. Lsd1/kdm1a mutations associated to a newly described form of intellectual disability impair demethylase activity and binding to transcription factors. Human molecular genetics, 25 12:2578-2587, Jun 2016. URL: https://doi.org/10.1093/hmg/ddw120, doi:10.1093/hmg/ddw120. This article has 66 citations and is from a domain leading peer-reviewed journal.

  8. (burkart2025phenotypicalandgenotypical pages 4-5): Sebastian Burkart, Melanie Spanjaard, Lilian Kaufmann, Katrin Hinderhofer, Christian P. Schaaf, Markus Ries, and Maja Hempel. Phenotypical and genotypical expansion of autosomal-dominant kdm1a-related neurodevelopmental disorder spectrum: a case report. American journal of medical genetics. Part A, pages e64144, Jun 2025. URL: https://doi.org/10.1002/ajmg.a.64144, doi:10.1002/ajmg.a.64144. This article has 1 citations and is from a peer-reviewed journal.

  9. (zou2025deficiencyofkdm1a pages 5-7): Li Zou, Jingyu Wang, Mengmeng Yao, Qu Xu, Qin Hong, Jiansheng Zhu, and Xia Chi. Deficiency of kdm1a induces locomotor abnormalities and learning and memory deficits in zebrafish larvae. Journal of Integrative Neuroscience, 24:44394, Nov 2025. URL: https://doi.org/10.31083/jin44394, doi:10.31083/jin44394. This article has 1 citations and is from a peer-reviewed journal.

  10. (swahari2019histonedemethylasesin pages 1-3): Vijay Swahari and Anne E West. Histone demethylases in neuronal differentiation, plasticity, and disease. Current Opinion in Neurobiology, 59:9-15, Dec 2019. URL: https://doi.org/10.1016/j.conb.2019.02.009, doi:10.1016/j.conb.2019.02.009. This article has 45 citations and is from a peer-reviewed journal.

  11. (vallianatos2015disruptedintricacyof pages 8-9): Christina N. Vallianatos and Shigeki Iwase. Disrupted intricacy of histone h3k4 methylation in neurodevelopmental disorders. Epigenomics, 7 3:503-19, Jun 2015. URL: https://doi.org/10.2217/epi.15.1, doi:10.2217/epi.15.1. This article has 229 citations and is from a peer-reviewed journal.

  12. (burkart2025phenotypicalandgenotypical pages 3-4): Sebastian Burkart, Melanie Spanjaard, Lilian Kaufmann, Katrin Hinderhofer, Christian P. Schaaf, Markus Ries, and Maja Hempel. Phenotypical and genotypical expansion of autosomal-dominant kdm1a-related neurodevelopmental disorder spectrum: a case report. American journal of medical genetics. Part A, pages e64144, Jun 2025. URL: https://doi.org/10.1002/ajmg.a.64144, doi:10.1002/ajmg.a.64144. This article has 1 citations and is from a peer-reviewed journal.

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