| 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. (pqac-00000001, pqac-00000013) | 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. (pqac-00000000, pqac-00000005, pqac-00000015) | 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. (pqac-00000000, pqac-00000014) | 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**. (pqac-00000005, pqac-00000006, pqac-00000000, pqac-00000003) | 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. (pqac-00000001, pqac-00000013, pqac-00000014, pqac-00000017) | 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. (pqac-00000000, pqac-00000014) | 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. (pqac-00000005, pqac-00000006, pqac-00000008, pqac-00000011) | 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. (pqac-00000015) | 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. (pqac-00000015, pqac-00000017) | 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. (pqac-00000000, pqac-00000013, pqac-00000017) | 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. (pqac-00000012, pqac-00000007, pqac-00000008, pqac-00000010) | 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.*