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)

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

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

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.

Artifacts

• Edison artifact artifact-00