| Domain | Best-supported finding/statistic | Suggested ontology terms | Evidence type/strength |
|---|---|---|---|
| Identifiers / naming | OMIM names the condition **“Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities” (OMIM #618505)**, but the larger 85-person cohort argues coarse facies/distal skeletal findings are **rare and not typical**; “**KDM6B-related neurodevelopmental disorder**” is the more accurate disease label. Initial disease-defining report described **12 unrelated patients** with de novo KDM6B variants. (pqac-00000007, pqac-00000023) | OMIM: 618505; MONDO: not confirmed from available sources; NCIT: neurodevelopmental disorder; HPO: HP:0001263 Global developmental delay; HP:0001249 Intellectual disability | Human cohort data; strong for naming revision, moderate for formal identifier set |
| Genetics / inheritance | Disease is caused by **heterozygous pathogenic/likely pathogenic KDM6B variants**; in the expanded cohort **64/85 (75%) were de novo** and **9/85 (11%) inherited** from mildly affected or apparently unaffected parents, indicating **high but incomplete penetrance/variable expressivity**. KDM6B is constrained for LoF (**pLI=1, LOEUF=0.14; earlier gnomAD o/e 0.06, 90% CI 0.03–0.14**), supporting haploinsufficiency/functional loss. (pqac-00000024, pqac-00000023, pqac-00000025) | HGNC: KDM6B; inheritance: autosomal dominant; SO: loss_of_function_variant, missense_variant, stop_gained, frameshift_variant | Human genetic cohort + population constraint; strong |
| Variant classes / protein regions | **71 different KDM6B variants** were considered likely pathogenic across **85 individuals**. Pathogenicity is strongest for variants disrupting the **JmjC catalytic region** or **Zn-containing domain**; some linker/surface missense changes were reclassified as **VUS** in functional assays. Truncating variants in the last/penultimate exons may **escape NMD** yet still cause loss of function by removing the Zn-containing domain. (pqac-00000024, pqac-00000023, pqac-00000025) | SO: missense_variant, frameshift_variant, nonsense_variant; GO: GO:0032454 histone demethylase activity; protein region terms: JmjC domain, zinc-binding domain | Human cohort + Drosophila functional assay; moderate-strong |
| Core neurodevelopmental phenotype | In the 85-person pathogenic/likely pathogenic cohort, neurodevelopmental abnormalities were present in **all assessed individuals**; developmental delay was present in **all except two**. **ID 63%**, usually mild; **ASD 61%**; **other behavioral problems 60%**. (pqac-00000024) | HPO: HP:0001263, HP:0001249, HP:0000717 Autism, HP:0000708 Behavioral abnormality | Human cohort; strong |
| Neurologic features | **Hypotonia 57%**, **sleep disturbance 32%**, **movement disorders 24%** (gait abnormality, dystonia-like movements, spasticity, hypertonia, toe walking), **seizures 13%**. Psychotic disorder was reported in **4/20 (20%)** individuals aged ≥12 years. (pqac-00000024, pqac-00000023) | HPO: HP:0001252 Hypotonia; HP:0002360 Sleep disturbance; HP:0100022 Movement disorder; HP:0001250 Seizure; HP:0000709 Psychosis | Human cohort; strong for frequencies, moderate for age-related psychiatric risk |
| Growth / craniofacial / musculoskeletal | Postnatal overgrowth features occurred in **30%**; **macrocephaly 26%**, **tall stature 8%**, **increased weight 14%**, **increased birth weight 16% (10/63)**. Dysmorphism is usually **mild/variable with no recognizable gestalt**. Limb/skeletal findings: **broad fingers/hands or broad toes/feet 20%**, **spine curvature 13%**, **toe syndactyly 9%**, **short fingers/toes 9%**. (pqac-00000024, pqac-00000023) | HPO: HP:0000256 Macrocephaly; HP:0000098 Tall stature; HP:0001159 Syndactyly; HP:0001165 Brachydactyly; HP:0000928 Abnormality of the vertebral column | Human cohort; strong |
| GI / feeding / congenital anomalies | **Neonatal feeding difficulty or GERD 51%**, **constipation 18%**. Congenital anomalies: **heart defects 13%**, **genitourinary anomalies 10%**, **cleft lip/palate 4%**. (pqac-00000024) | HPO: HP:0011968 Feeding difficulties; HP:0002019 Gastroesophageal reflux; HP:0002019/HP:0001508 Constipation; HP:0001627 Abnormal heart morphology; HP:0000078 Abnormality of the genital system; HP:0000175 Cleft palate | Human cohort; strong |
| Sex distribution / modifiers | Cohort shows a **male bias (~75%)**; authors hypothesize a possible **female protective effect** and contribution from **other genetic/environmental modifiers**, but no definitive modifier genes are established. (pqac-00000023) | PATO: male-biased frequency; HPO: variable expressivity | Human cohort observation; moderate |
| Molecular mechanism | KDM6B/JMJD3 is an **H3K27me2/3 demethylase** that counteracts Polycomb repression to regulate developmental gene expression. Human disorder is best explained by **loss of function / reduced function**, not a clearly established dominant-negative mechanism. (pqac-00000006, pqac-00000025, pqac-00000014) | GO: GO:0032454 histone demethylase activity; GO:0016575 histone deacetylation? not applicable; GO:0045664 regulation of neuron differentiation; GO:0006357 regulation of transcription by RNA polymerase II | Human genetics + mechanistic review; strong for upstream mechanism |
| Cellular / systems pathophysiology | Recent models show Kdm6b is required for **dentate gyrus neural stem-cell establishment and maintenance**; deletion causes **precocious neuronal differentiation**, depletion of NSCs, and transcriptomic disruption on **scRNA-seq**. In mosaic brain KO mice, Kdm6b loss causes **reduced excitatory synaptic transmission, impaired NMDAR-dependent LTP, altered NR2A/NR2B balance**, and autism-like/social/cognitive phenotypes. (pqac-00000009, pqac-00000011, pqac-00000008, pqac-00000010) | GO: neurogenesis, neuron differentiation, synaptic plasticity, NMDA receptor signaling; CL: neural stem cell, neuroblast, excitatory neuron; UBERON: hippocampus, dentate gyrus, cerebellum | Mouse in vivo + scRNA-seq/electrophysiology; moderate-strong |
| Anatomy most affected | Highest-confidence affected system is the **central nervous system**, especially **cortex/hippocampus/dentate gyrus** and likely broader neural circuits; secondary involvement includes **GI**, **cardiac**, **genitourinary**, and **musculoskeletal** systems. (pqac-00000024, pqac-00000009, pqac-00000008) | UBERON: brain, hippocampus, dentate gyrus, cerebellum, heart, gastrointestinal tract, urinary system; CL: neural stem cell, cerebellar granule neuron | Human phenotype + mouse mechanism; moderate-strong |
| Diagnostics | Current diagnosis is primarily **genomic**: **WES/WGS** or NDD/autism/ID panels including KDM6B; **CMA**, Fragile X testing, and metabolic testing were used in early workups; parental testing is important for de novo status. Disease is **unlikely to be recognized clinically alone** because dysmorphism is mild/variable. (pqac-00000019, pqac-00000018, pqac-00000016, pqac-00000023) | NCIT: Whole Exome Sequencing, Chromosomal Microarray Analysis; HPO-based phenotyping; ACMG/AMP variant classification | Human clinical cohort; strong for sequencing-based diagnosis |
| Epigenomic diagnostics | A **validated KDM6B-specific DNA methylation episignature** was **not established in the available disease-specific sources**. Recent chromatinopathy literature supports episignatures as a general approach for variant interpretation, but this remains an evidence gap for KDM6B in the accessible dataset. (pqac-00000023, pqac-00000017) | EFO/OBI: DNA methylation profiling; epigenetic biomarker | Indirect/general chromatinopathy evidence; weak for KDM6B-specific use |
| Management / real-world care | No disease-modifying therapy is established. Reported care is **supportive and multidisciplinary**: **physical, occupational, and speech therapy**, special education, management of constipation/GERD/feeding problems, and treatment of spasticity in some cases (including **botulinum toxin** in one report). Awareness of adolescent/adult psychiatric risk may affect follow-up. (pqac-00000019, pqac-00000020, pqac-00000024, pqac-00000023) | NCIT: Physical Therapy, Occupational Therapy, Speech Therapy, Special Education, Botulinum Toxin Therapy | Human case/cohort care data; moderate |
| Trials / registries | No interventional disease-specific trials were identified. **Simons Searchlight (NCT01238250)** is a **recruiting observational registry** that explicitly includes **KDM6B**, collects longitudinal medical/behavioral/developmental data, and aims to improve care for rare genetic NDDs. (pqac-00000021, pqac-00000022) | NCIT: Observational Study; ClinicalTrials.gov: NCT01238250 | Registry evidence; strong for data collection, not treatment efficacy |
| Prognosis / epidemiology | Natural history remains incompletely defined. Available evidence supports a **lifelong neurodevelopmental disorder** with usually **mild ID when present**, variable ASD/behavioral burden, and possible later **psychotic disorders**. No robust prevalence, incidence, life-expectancy, or disease-specific mortality estimates were found. Early GeneDx ascertainment found **12/10,619 exomes (0.12%)** among tested DD/ID cases, which is **not population prevalence**. (pqac-00000005, pqac-00000024, pqac-00000023) | HPO: chronic neurodevelopmental course; epidemiology terms unavailable | Limited cohort evidence; moderate for course, weak for prevalence/survival |
| Prevention / counseling | No primary prevention is known for the disorder itself. Best-supported prevention-related measures are **genetic counseling**, **recurrence-risk assessment based on de novo vs inherited status**, and consideration of **family testing/cascade testing** when a familial variant is found. (pqac-00000024, pqac-00000023) | NCIT: Genetic Counseling; prenatal/preimplantation testing terms if familial variant known | Inference from Mendelian inheritance pattern; moderate |
| Major evidence gaps | Key gaps: no confirmed population prevalence/incidence; no standardized diagnostic criteria beyond molecular diagnosis; no established **KDM6B episignature** in the accessible disease-specific literature; no disease-specific biomarkers; no interventional trials; sparse adult outcome, QoL, and survival data; no confirmed modifier genes or protective environmental factors. (pqac-00000023, pqac-00000024, pqac-00000016, pqac-00000017) | Evidence gap / no ontology term needed | Cross-source synthesis; strong as a gap assessment |


*Table: This table summarizes the most clinically and mechanistically supported findings for KDM6B-related neurodevelopmental disorder, emphasizing quantified human cohort data and clearly marking areas where evidence is still lacking.*