| Domain | Key facts | Ontology / controlled-term suggestions | Evidence |
|---|---|---|---|
| Disease identity / identifiers | Intellectual disability, autosomal dominant 52 (MRD52); ASH1L-related neurodevelopmental disorder; OMIM **617796**; MONDO **MONDO:0030918**. Disease-level knowledge is aggregated from published case reports/cohorts, reviews, and curated disease-target resources rather than EHR-only evidence. | MONDO:0030918 | (pqac-00000000, pqac-00000003) |
| Synonyms | ASH1L-related intellectual developmental disorder; ASH1L-related neurodevelopmental disorder; MRD52; intellectual developmental disorder with speech delay/autism features due to **ASH1L**. | MeSH/ICD-specific synonym mapping not established in retrieved evidence | (pqac-00000003) |
| Inheritance | **Autosomal dominant**; most reported pathogenic events are interpreted as **heterozygous loss-of-function / haploinsufficiency**, often de novo in sequencing cohorts. Penetrance and recurrence risk are not well quantified; parental testing is important to assess de novo status and mosaicism. | HP:0000006 Autosomal dominant inheritance | (pqac-00000000, pqac-00000003, pqac-00000006) |
| Causal gene / protein | **ASH1L** (also called **KMT2H**), encoding ASH1-like histone lysine methyltransferase, a Trithorax-family chromatin regulator expressed in brain and involved in transcriptional activation. | HGNC:19208 ASH1L; UniProt ASH1L protein | (pqac-00000003, pqac-00000006) |
| Pathogenic mechanism | Predominant mechanism is **germline monoallelic loss of function / haploinsufficiency** disrupting chromatin-mediated transcription. ASH1L catalyzes **H3K36me2** and contributes to **H3K4me3**, opposing **PRC2/H3K27me3** repression; downstream effects include altered neuronal gene expression, neurite growth, synaptic programs, and cortical excitability. The 2024 human-neuron study is a **bioRxiv preprint**. | GO:0046975 histone methyltransferase activity; GO:0018024 histone H3-K36 methylation; GO:0046968 H3-K4 methylation; GO:0006357 regulation of transcription by RNA polymerase II; GO:0030154 cell differentiation | (pqac-00000001, pqac-00000003, pqac-00000005, pqac-00000006, pqac-00000009) |
| Core phenotypes | Developmental delay and **intellectual disability** (mild to severe reported), marked **speech/language delay**, **autism spectrum disorder / autistic behaviors**, dysmorphic facial features, and behavioral abnormalities; some patients have seizures/epilepsy or broader neuropsychiatric manifestations. Precise phenotype frequencies are not robustly established in retrieved evidence. | HP:0001263 Global developmental delay; HP:0001249 Intellectual disability; HP:0000750 Delayed speech and language development; HP:0000729 Autism; HP:0001250 Seizure; HP:0000717 Autism spectrum disorder; HP:0001252 Hypotonia; HP:0001999 Facial dysmorphism | (pqac-00000003, pqac-00000006, pqac-00000012) |
| Principal anatomy / cell types | Primary system affected is the **central nervous system**, especially cortical circuits. Experimental data implicate **prefrontal cortex** and **cortical excitatory pyramidal neurons**; neuronal projections, axons, synapses, and nuclei are enriched among dysregulated compartments/features. | UBERON:0000955 brain; UBERON:0001870 cerebral cortex; UBERON:0000451 prefrontal cortex; CL:0000540 neuron; CL:0002608 pyramidal neuron; GO:0030424 axon; GO:0045202 synapse; GO:0005634 nucleus | (pqac-00000001, pqac-00000005, pqac-00000009) |
| Diagnosis | Molecular diagnosis relies on **exome/genome sequencing** or neurodevelopmental disorder/intellectual disability panels that include **ASH1L**; trio-based testing is particularly valuable to establish de novo occurrence. No disease-specific biochemical biomarker or imaging signature was established in retrieved evidence. | NCIT:C101294 Whole Exome Sequencing; NCIT:C84351 Whole Genome Sequencing; NCIT:C157640 Molecular Genetic Testing | (pqac-00000000, pqac-00000003) |
| Treatment / management | No **approved disease-specific therapy** identified. Current care is **supportive and multidisciplinary**: developmental pediatrics, neurology, speech-language therapy, occupational/physical therapy, behavioral/educational interventions, and seizure management when present. **Preclinical only:** in Ash1l mouse or edited human-neuron systems, chemogenetic PFC inhibition and epigenetic drugs (**tazemetostat**, **vorinostat**) rescued selected phenotypes; these are not established patient treatments. | NCIT:C51909 Supportive Care; NCIT:C17556 Speech Therapy; NCIT:C15635 Occupational Therapy; NCIT:C15313 Physical Therapy; NCIT:C146712 Behavioral Intervention; NCIT:C15246 Tazemetostat; NCIT:C1820 Vorinostat | (pqac-00000001, pqac-00000007, pqac-00000012) |
| Epidemiology / prognosis | Appears to be an **ultra-rare Mendelian disorder**; no reliable prevalence or incidence estimates were identified in retrieved evidence. Natural history is incompletely defined; morbidity is dominated by lifelong neurodevelopmental impairment, communication disability, behavioral challenges, and possible epilepsy. Disease-specific survival, life expectancy, and mortality rates are unavailable. | Orphan/rare disease category; chronic neurodevelopmental disorder | (pqac-00000003) |
| Model systems | **Mouse:** Ash1l haploinsufficiency/gene-trap models show social deficits, repetitive grooming, cognitive impairment, EEG epileptiform activity/absence-like seizures, and increased PFC excitability. **Human neuronal models:** CRISPR-engineered iPSC/ESC-derived cortical excitatory neurons (including **E2148*** catalytic-domain variant) show reduced neurite length/arborization and altered histone marks/transcriptomes; this 2024 study is a **bioRxiv preprint**. **Zebrafish:** ash1a knockdown reduces neuron numbers in pineal gland. | NCBITaxon:10090 Mus musculus; NCBITaxon:7955 Danio rerio; CL:0000540 neuron; CL:0002608 pyramidal neuron | (pqac-00000001, pqac-00000003, pqac-00000005, pqac-00000010) |
| Key evidence gaps | Major gaps include: small patient numbers; limited validated phenotype frequencies; scarce longitudinal natural-history data; poor estimates of penetrance/expressivity; no established episignature/clinical biomarker in retrieved evidence; no disease-specific interventional trials found; limited patient-cell functional studies in peer-reviewed literature; 2024 human-neuron rescue work remains **preprint/preclinical**. | Evidence-gap annotation | (pqac-00000003, pqac-00000006, pqac-00000012) |


*Table: Compact knowledge-base table summarizing identifiers, genetics, phenotypes, mechanism, diagnosis, management, models, and current evidence gaps for Intellectual disability, autosomal dominant 52 / ASH1L-related disorder. It separates established disease knowledge from preclinical and preprint findings.*