| domain | key finding/statistic | ontology/identifier suggestions | evidence type |
|---|---|---|---|
| Disease identity | Tuberous sclerosis 2 is represented as MONDO:0013199 and is associated with target/gene TSC2 (ENSG00000103197) (pqac-00000000) | MONDO:0013199; Ensembl: ENSG00000103197; gene symbol: TSC2 | Aggregated disease-target resource |
| Nosology/relationship to broader disease | Clinically, TSC2-associated disease falls within tuberous sclerosis complex (TSC), a multisystem disorder caused by pathogenic variants in TSC1 or TSC2; requested entry is the TSC2-associated Mendelian subtype (pqac-00000014, pqac-00000015) | MONDO:0013199; MeSH term on trial records: D014402 Tuberous Sclerosis; category: Mendelian | Human review/clinical synthesis |
| Inheritance | TSC is autosomal dominant; approximately one third of cases are inherited and the other two thirds are due to de novo and/or mosaic pathogenic variants in TSC1/TSC2 (pqac-00000015) | HPO inheritance: Autosomal dominant inheritance [HP:0000006]; concept: mosaicism | Human review/clinical synthesis |
| Mosaicism / mutation-negative cases | About 15% of patients have no mutation identified by conventional testing; mosaic and intronic TSC1/TSC2 variants account for many such cases, with mosaic variants identified in up to 58% of no-mutation-identified individuals in cited studies summarized by the review (pqac-00000015, pqac-00000016) | Variant concept: somatic mosaicism; testing implication: deep sequencing/tissue testing | Human review/clinical synthesis |
| Molecular cause | TSC1/TSC2 normally inhibit RHEB and suppress mTORC1; pathogenic TSC2 loss-of-function disrupts the TSC complex, causing mTORC1 hyperactivation and abnormal cell growth/hamartomas (pqac-00000012, pqac-00000014, pqac-00000015, pqac-00000017) | Pathway: mTORC1 signaling; GO suggestion: regulation of TOR signaling; disease mechanism: loss of function | Human review/clinical synthesis + pathway mapping |
| Mechanistic causal chain | TSC2 inactivation → loss of inhibition of RHEB → mTORC1 hyperactivation → increased cell growth/protein synthesis and reduced autophagy → hamartomas and neurodevelopmental abnormalities, especially in brain, kidney, heart, lung, skin (pqac-00000002, pqac-00000012, pqac-00000014) | GO suggestions: autophagy, cell growth, protein phosphorylation; UBERON: brain, kidney, heart, lung, skin | Human review + foundational mechanistic review |
| Genotype-phenotype severity | TSC2 pathogenic variants are associated with more severe phenotypes than TSC1, including higher risk of renal malignancies, cardiac rhabdomyomas, intellectual disability, infantile epileptic spasms, drug-resistant epilepsy, developmental delay, ADHD, and ASD (pqac-00000016) | Phenotype terms: infantile spasms, intellectual disability, ASD, ADHD | Human review/clinical synthesis |
| Variant spectrum in a recent cohort | In 116 individuals with definite TSC, pathogenic DNA alterations were identified in 106 (91%); 88/106 (83%) were in TSC2 and 18/106 (17%) in TSC1; 35 variants were novel (pqac-00000001) | TSC2; variant classes assessed included missense and in-frame deletions | Human clinical molecular cohort |
| Contiguous gene syndrome | TSC2/PKD1 contiguous gene deletion syndrome occurs in up to 5% of TSC patients and is relevant when large deletions/coexisting cystic kidney disease are present (pqac-00000001) | PKD1; contiguous gene deletion syndrome | Human clinical molecular cohort/review |
| Major phenotype frequency: epilepsy | In TOSCA (n=2,093), epilepsy occurred in 83.5%; focal seizures were most common (66.9%); median age at epilepsy diagnosis was 1 year, and 78% were diagnosed at age ≤2 years (pqac-00000005, pqac-00000006) | HPO: Seizure [HP:0001250]; Focal-onset seizure [HP:0007359] | Human registry |
| Major phenotype frequency: cortical and subependymal lesions | TOSCA frequencies: cortical tubers 82.2%; subependymal nodules 78.2%; SEGA 24.4%; median SEGA diagnosis age 8 years, with 26.4% diagnosed before age 2 (pqac-00000005, pqac-00000007) | HPO: Cortical tuber; Subependymal nodule; Subependymal giant cell astrocytoma; UBERON: cerebral cortex, lateral ventricle | Human registry |
| Major phenotype frequency: renal/cardiac/skin/lung | TOSCA baseline frequencies: renal angiomyolipoma 47.2%; cardiac rhabdomyoma 34.3%; facial angiofibromas 57.3%; hypomelanotic macules 66.8%; shagreen patch 27.4%; forehead plaque 14.1%; LAM 6.9% overall in registry (pqac-00000006) | HPO: Renal angiomyolipoma, Cardiac rhabdomyoma, Facial angiofibroma, Hypomelanotic macule; UBERON: kidney, heart, skin, lung | Human registry |
| Neuropsychiatric burden / QoL relevance | TAND affects ~90% of individuals over the lifetime; in TOSCA, academic/scholastic difficulties were reported in 57.8%, autism spectrum disorder in 20.7%, ADHD in 19.6%, anxiety in 9.1%, depression in 6.1%, and intellectual disability in 54.9% of tested patients (pqac-00000005, pqac-00000010) | HPO/psychiatric terms: Intellectual disability, Autism spectrum disorder, ADHD, Anxiety, Depression; TAND | Human registry + scoping review |
| Epidemiology | Reported incidence ranges from 1:5800 to 1:13,520 live births; other reviews summarize incidence as 1:6000 to 1:10,000 live births and prevalence around 1 in 20,000 people; Japan-specific prevalence cited as 1 in 10,300 live births (pqac-00000015, pqac-00000014, pqac-00000009) | Epidemiology field; rare disease | Human review + claims study |
| Mortality/morbidity | Leading morbidity/mortality drivers summarized in recent reviews include brain tumours/SEGA, epilepsy-related complications including SUDEP/status epilepticus, renal complications, and respiratory disease/LAM (pqac-00000014, pqac-00000015) | Outcome terms: SUDEP, renal complication, respiratory complication | Human review/clinical synthesis |
| Diagnostic delay / real-world implementation | In a Japanese claims study, renal tumors as first manifestation had the longest time-to-diagnosis (median 23 to up to 91 months); for patients with epilepsy, diagnosis was faster at TSC clinics than non-TSC clinics (median 11.5 vs 19.0 months; p=0.0379) (pqac-00000009) | Care pathway; specialized TSC clinic | Real-world human claims study |
| Diagnostic approach and genetics | Molecular diagnosis confirms the clinical diagnosis in a large proportion of cases; functional assessment of TSC2 variants can help establish pathogenicity; contemporary reviews emphasize sequencing plus evaluation for deep intronic variants, CNVs, and mosaicism, often requiring re-phenotyping/re-genotyping and sometimes non-blood tissues (pqac-00000001, pqac-00000016) | Gene testing: TSC2/TSC1 sequencing; CNV analysis; deep intronic analysis; mosaicism testing | Human clinical molecular cohort + review |
| Prenatal diagnosis | Prenatal TSC commonly presents with cardiac rhabdomyomas; prenatal management literature review identified 8 papers covering 10 pregnant women treated with mTOR inhibitors and 3 prenatal mouse studies (pqac-00000012) | Prenatal screening; fetal ultrasound/echo context | Human case-series review + animal prenatal studies |
| Approved/established targeted therapy | Everolimus is approved for TSC-associated partial-onset seizures (age ≥2 years), and for SEGA and AML; mTOR inhibitors also reduce TSC-related lesions including kidney AMLs, SEGAs, and facial angiofibromas (pqac-00000013, pqac-00000021) | CHEBI/drug: everolimus; MAXO suggestion: mTOR inhibitor therapy | Human review summarizing trials/approvals |
| Renal AML treatment statistic | In a 50-patient adult cohort, low-dose everolimus produced an average AML volume reduction of 52% versus 60% with conventional dose, with significantly less stomatitis and irregular menstruation in the low-dose group (pqac-00000005) | Renal angiomyolipoma; MAXO: everolimus treatment | Human clinical treatment cohort |
| Epilepsy treatment: vigabatrin | Preventive vigabatrin reduced risk of seizures, infantile spasms, and drug-resistant epilepsy in one summarized study, but no difference in developmental delay or autism at 2 years; PREVeNT delayed/reduced infantile spasms but not focal seizures/drug-resistant epilepsy or cognitive outcomes at age 2 (pqac-00000013, pqac-00000021) | Drug: vigabatrin; HPO: Infantile spasms | Human review summarizing trials |
| Epilepsy treatment: cannabidiol | Cannabidiol was authorized in the EU in April 2021 as adjunctive therapy for TSC-associated seizures in patients aged ≥2 years (pqac-00000013, pqac-00000021) | Drug: cannabidiol; MAXO: antiseizure pharmacotherapy | Human review/regulatory summary |
| LAM treatment | Sirolimus has been the FDA-approved mainstay treatment for LAM since 2015 and supports pulmonary function control/decreased lymphatic symptoms in LAM (pqac-00000013, pqac-00000021) | Drug: sirolimus; phenotype: lymphangioleiomyomatosis | Human review/clinical synthesis |
| Adverse effects of mTOR inhibitors | Important adverse effects include mouth ulceration/stomatitis, immunosuppression, and infection risk; in young patients sirolimus side effects summarized as common but not life- or health-threatening included anemia, hyperlipidemia, and thrombocytosis (pqac-00000013, pqac-00000021) | Safety annotation; AE terms | Human review/clinical synthesis |
| Experimental trial: seizure prevention | TSC-STEPS (NCT05104983) is a Phase II randomized, double-blind, placebo-controlled multisite trial testing early sirolimus in infants 0–6 months to prevent or delay seizure onset; planned enrollment 64; primary outcome time to seizure onset by 12 months (pqac-00000018) | ClinicalTrials.gov: NCT05104983; prevention trial | Interventional trial registry |
| Experimental trial: drug-resistant epilepsy | RaRE-TS (NCT05534672) is a Phase III randomized, double-blind, placebo-controlled trial of rapamycin versus placebo for drug-resistant epilepsy associated with TSC; estimated enrollment 200; primary endpoint includes ≥50% seizure reduction and adverse events (pqac-00000011) | ClinicalTrials.gov: NCT05534672 | Interventional trial registry |
| Experimental trial: NMDA-modulator | Astroscape (NCT06392009) is an open-label phase 1/2 study of radiprodil for treatment-resistant seizures/behavioral symptoms in TSC or FCD II; estimated enrollment 30 total, about 20 with TSC (pqac-00000019) | ClinicalTrials.gov: NCT06392009; drug: radiprodil | Interventional trial registry |
| Cellular/organoid models | 2024 TSC2 iPSC-derived cortical organoids showed disrupted neurogenesis, synaptogenesis, gliogenesis/reactive astrogliosis, neuron-reactive astrocyte crosstalk, synaptic transmission, neuronal network activity, mitochondrial translational integrity, and neurofilament formation; findings resembled resected TSC cortical tissue (pqac-00000004) | CL suggestions: neuron, astrocyte; GO: synaptogenesis, gliogenesis, mitochondrial translation | In vitro human organoid + matched surgical tissue comparison |
| Animal models | Zebrafish and other mTORopathy models are used to study TSC-related epilepsy and neuropathology; model summaries note TSC1/TSC2 overactivation of mTOR pathway with epilepsy/benign tumors, but translational limits remain for exact human multisystem phenotype capture (pqac-00000020) | Model organism: zebrafish; disease mechanism: mTORopathy | Model organism review |
| Evidence limitations | Much of the recent TSC2-specific mechanistic work is review-based or preprint/in vitro; several phenotype and treatment frequencies derive from broader TSC cohorts rather than TSC2-only cohorts, so TSC2-specific extrapolation should be done cautiously (pqac-00000004, pqac-00000005, pqac-00000015) | Evidence flag: broader TSC vs TSC2-specific | Evidence appraisal |


*Table: This compact table summarizes database-ready facts for TSC2-associated tuberous sclerosis, including identifiers, mechanism, phenotype frequencies, diagnostics, therapies, trials, and model systems. It is restricted to claims directly supported by gathered evidence contexts.*