| Domain | Current evidence | Suggested ontology/identifier |
|---|---|---|
| Scope / definition | Autosomal dominant non-syndromic intellectual disability is best treated as a heterogeneous umbrella disorder rather than a single uniform entity. Open Targets maps **autosomal dominant non-syndromic intellectual disability** to **MONDO:0015802** and lists representative associated genes including **TLK2, ASH1L, STAG1, CLTC, CAMK2A, CIC, NAA15, TRIP12, KMT5B, TRIO, SET, DLG4**; broader autosomal dominant ID is separated as **MONDO:0100172**. NSID denotes ID as the principal/isolated phenotype, though many reported “non-syndromic” cases may later accrue additional neurodevelopmental features (pqac-00000000, pqac-00000005). | **MONDO:0015802**; related umbrella: **MONDO:0100172** |
| Disease level vs patient level evidence | Available evidence is mainly aggregated from disease/gene discovery studies, sequencing cohorts, and reviews; this is not primarily an EHR-derived single-disease registry. Most current knowledge comes from heterogeneous DD/ID/NDD cohorts in which AD de novo etiologies are overrepresented (pqac-00000001, pqac-00000004, pqac-00000005). | Evidence type: aggregated disease/gene-level resource |
| Cardinal phenotype: intellectual disability | ID is defined by impaired intellectual functioning and adaptive behavior; overall ID prevalence is commonly cited at **1–3%** worldwide, with GDD/ID together affecting nearly **2%** of the pediatric population. Severity can range mild to profound; severe/profound forms are more often monogenic (pqac-00000005, pqac-00000008, pqac-00000009). | **HPO:** Intellectual disability **HP:0001249**; Global developmental delay **HP:0001263** |
| Common associated neurodevelopmental phenotypes | Across DD/ID cohorts and mechanism reviews, common co-phenotypes include developmental delay, speech/language delay, seizures/epilepsy, autism/behavioral abnormalities, microcephaly, and dysmorphic features; these often increase diagnostic yield even when the target label is “non-syndromic” (pqac-00000001, pqac-00000004, pqac-00000010, pqac-00000013). | **HPO:** Developmental delay **HP:0001263**; Speech delay **HP:0000750**; Seizure **HP:0001250**; Autism **HP:0000717**; Behavioral abnormality **HP:0000708**; Microcephaly **HP:0000252**; Facial dysmorphism **HP:0001999** |
| Representative causal genes: synaptic / excitability | Representative AD genes linked in umbrella resources or cohort literature include **GRIN1, DLG4, CAMK2A, TRIO, NRXN1, STXBP1, DYRK1A, KIF1A, GNB1**; these converge on synapse formation/function, neuronal signaling, and plasticity (pqac-00000000, pqac-00000011, pqac-00000014). | HGNC gene symbols; **GO:** synapse organization **GO:0050808**; regulation of synaptic plasticity **GO:0048167** |
| Representative causal genes: chromatin / transcription / cohesin | Representative AD genes include **ASH1L, KMT5B, STAG1, CIC, TLK2, ARID1B, KANSL1, WDR5** and related chromatin modifiers highlighted as strong ASD/ID susceptibility factors affecting dendritic spine and synapse biology (pqac-00000000, pqac-00000011, pqac-00000014). | HGNC gene symbols; **GO:** chromatin organization **GO:0006325**; regulation of transcription by RNA polymerase II **GO:0006357** |
| Representative causal genes: cytoskeleton / trafficking / neuronal morphogenesis | Reviews emphasize convergence of many ID genes on cytoskeleton dynamics and Rho GTPase-regulated neuronal migration, neuritogenesis, and synaptic plasticity; examples include **TRIO, KIF1A, CLTC** and Rho-pathway-related genes in broader ID biology (pqac-00000009). | **GO:** actin cytoskeleton organization **GO:0030036**; microtubule cytoskeleton organization **GO:0000226**; neuron projection development **GO:0031175** |
| Variant classes / molecular lesion types | Relevant pathogenic mechanisms include coding **missense, nonsense, frameshift, splice**, **CNVs**, **small structural variants**, and increasingly **regulatory de novo mutations in fetal-brain enhancers**. Vas et al. showed regulatory DNMs enriched in fetal brain-specific enhancers, with recurrent enhancer clusters linked to **CSMD1, OLFM1, POU3F3** (pqac-00000011, pqac-00000013). | Variant classes per ACMG/AMP; regulatory regions / enhancers |
| Inheritance / de novo contribution | AD ID is often caused by **de novo** variants, especially in moderate/severe disease. In a Finnish ID cohort, **75%** of variants in known ID genes were de novo/suspected de novo, including **64% autosomal dominant** and **11% X-linked**; only **25%** were inherited (pqac-00000016). Trio-WES in unexplained DD/ID also concluded that de novo variants in AD genes are major contributors, especially in non-consanguineous families (pqac-00000001). | Inheritance: **autosomal dominant**; de novo germline origin |
| Mosaicism / recurrence risk | Apparent de novo AD findings do not guarantee negligible recurrence risk. In a trio genome-wide study of 500 families, **12 cases of apparent mosaicism** were identified, including **9 parental** and **3 proband** mosaic cases; empirical recurrence for a child with a de novo dominant condition is often cited as ~**1%**, but parental gonadal mosaicism can raise risk substantially (pqac-00000017). | Counseling concept: parental/gonadal mosaicism; somatic mosaicism |
| Anatomy / organ systems | Primary affected organ/system is the **central nervous system**, especially cortical and hippocampal circuits supporting cognition, learning, and adaptive behavior. Reviews also note involvement of excitation/inhibition balance and, in some genetic subgroups, broader multisystem findings despite a nominally nonsyndromic label (pqac-00000009, pqac-00000014). | **UBERON:** brain **UBERON:0000955**; cerebral cortex **UBERON:0000956**; hippocampus **UBERON:0002421** |
| Cells / subcellular processes | Mechanistic evidence highlights **neurons**, especially **pyramidal neurons**, dendrites, dendritic spines, and synapses; abnormal neuronal migration, neuritogenesis, and synaptic plasticity are recurrent themes. Subcellular emphasis includes chromatin, actin/microtubule cytoskeleton, and synaptic compartments (pqac-00000009, pqac-00000014). | **CL:** neuron **CL:0000540**; pyramidal neuron **CL:0000598**; **GO CC:** dendrite **GO:0030425**; dendritic spine **GO:0043197**; synapse **GO:0045202**; nucleus **GO:0005634** |
| Pathophysiology / causal chain | Upstream lesions include de novo coding or regulatory variants affecting chromatin regulation, transcription, enhancer activity, cytoskeleton dynamics, trafficking, and synaptic proteins. Downstream consequences include altered neuronal migration/neuritogenesis, abnormal dendritic spine and synapse morphogenesis, impaired network formation, excitation/inhibition imbalance, and finally impaired cognition/adaptive behavior (pqac-00000009, pqac-00000011, pqac-00000014). | **GO:** neuron migration **GO:0001764**; axonogenesis **GO:0007409**; dendrite morphogenesis **GO:0048813**; learning or memory **GO:0007611** |
| Diagnostic workflow | Current evidence supports **trio exome sequencing as first-tier** for unexplained DD/ID/NDD, with **genome sequencing** used early or after nondiagnostic CMA/exome, particularly where structural, intronic, or regulatory variants are suspected. Standard pre-genomic workup often includes history/exam, CMA, Fragile X or targeted testing when indicated, and phenotype-guided metabolic testing (pqac-00000008, pqac-00000010, pqac-00000012, pqac-00000013). | ACMG-aligned genome-wide testing strategy |
| Recent diagnostic yield data (2023–2024 priority) | Recent cohorts report: trio-WES **49.7% (86/173)** in unexplained DD/ID; syndromic **57.8%** vs non-syndromic **47.2%** (pqac-00000001). Trio-ES in severe pediatric NDDs **48.9% (44/90)**, with **53.2%** of causative variants novel (pqac-00000010). Singleton WES in undiagnosed rare pediatric disease **43% (25/58)** and clinical utility/actionability **76%** (pqac-00000015). Trio-WGS after prior chromosome analysis/CMA/CES gave an additional **19.2% (10/52)** diagnoses, **8/10** due to AD de novo variants (pqac-00000013). First-line GS review found mean diagnostic yield **45%** for first-line GS and management changes **24–100%** depending on cohort (pqac-00000012). | Diagnostic modalities: WES, WGS, CMA |
| Real-world implementation | Real-world implementation now centers on clinical genetics and pediatric neurology pathways using trio-based ES/GS, ACMG-guided variant classification, and phenotype-driven reanalysis. ES/GS findings influence surveillance, reproductive counseling, and personalized management even when no disease-specific drug exists (pqac-00000010, pqac-00000012, pqac-00000015). | ACMG/AMP variant classification framework |
| Management / treatment | There is **no single disease-specific pharmacotherapy** for the umbrella disorder. Care is supportive and phenotype-directed: developmental therapies, speech/language therapy, educational support, behavioral management, seizure treatment when present, surveillance based on the molecular diagnosis, and genetic counseling. Reviews note that no pharmacological therapies are currently available for ID broadly, although pathway-based therapeutic opportunities are being explored (pqac-00000009, pqac-00000015). | **MAXO:** genetic counseling; developmental therapy; speech therapy; educational intervention; seizure management |
| Prevention / family planning | Primary prevention is generally not available for de novo monogenic disease; practical prevention focuses on **genetic counseling**, discussion of recurrence including mosaicism, and reproductive options after molecular diagnosis. Earlier genomic diagnosis can shorten the diagnostic odyssey and inform family planning (pqac-00000013, pqac-00000015, pqac-00000017). | **MAXO:** genetic counseling; reproductive counseling |
| Model systems / mechanistic platforms | Evidence includes animal and neuronal model studies summarized in reviews, especially mouse models of chromatin modifiers (**ARID1B, KANSL1, WDR5, ZMIZ1**) and systems-biology approaches emphasizing convergent neuronal network defects. These models are useful for studying dendritic spine, synapse, and developmental circuitry abnormalities (pqac-00000009, pqac-00000014). | Model categories: mouse models; neuronal cultures; systems biology |
| Evidence limitations | Disease boundaries are porous: “non-syndromic” cases may later show additional features; many data come from mixed DD/ID/NDD cohorts rather than pure MONDO:0015802 cohorts; gene lists change rapidly; penetrance/expressivity are often incompletely quantified; and few disorder-specific natural history or treatment trials exist (pqac-00000005, pqac-00000010, pqac-00000015). | Curation note: maintain umbrella-vs-gene-specific distinction |


*Table: This table compacts the most actionable current evidence for autosomal dominant non-syndromic intellectual disability into a knowledge-base-ready format. It emphasizes scope, representative mechanisms and genes, ontology suggestions, modern diagnostic practice, and key evidence limitations.*