| domain | key fact | quantitative/current evidence | suggested ontology identifiers |
|---|---|---|---|
| Disease identity | TSC1-related tuberous sclerosis complex is the TSC subtype caused by pathogenic variants in **TSC1**, a multisystem mTORopathy with hamartomas/hamartia affecting brain, skin, kidney, heart, lung, and eye | MONDO disease association for **tuberous sclerosis 1**: **MONDO:0008612**; broader TSC disease listed as autosomal dominant and multisystem in consensus/gene reviews (pqac-00000000, pqac-00000003, pqac-00000014) | MONDO:0008612; MeSH: Tuberous Sclerosis; ICD terms: tuberous sclerosis complex |
| Disease identifiers | Broader disease identifiers are better established than subtype-specific coding; subtype can be represented by MONDO disease + causal gene | TSC consensus recognizes diagnosis by clinical criteria or pathogenic **TSC1/TSC2** variant in normal tissue (pqac-00000014, pqac-00000023) | MONDO:0008612; OMIM disease: tuberous sclerosis complex (OMIM exact disease subtype IDs not confirmed here) |
| Causal gene | **TSC1** encodes **hamartin**, core component of TSC complex, negative regulator of mTORC1 | TSC1 maps to **9q34.1**, has **23 exons**; in one 2024 cohort, 18/106 molecular diagnoses (17%) were TSC1 and 88/106 (83%) TSC2 (pqac-00000014) | HGNC: **TSC1**; Ensembl: **ENSG00000165699** (pqac-00000000); OMIM gene: **TSC1 / MIM 605284** (pqac-00000014) |
| Inheritance | Usually **autosomal dominant** with high penetrance and marked variable expressivity; many cases are de novo or mosaic | Incidence/prevalence estimates across TSC: ~1:5,800 to 1:13,520 live births in review; global incidence often cited ~1 per 6,000–10,000 live births (pqac-00000003, pqac-00000017) | Inheritance: HP:0000006 Autosomal dominant inheritance |
| Mosaicism | Somatic mosaicism is an important cause of milder or mutation-negative presentations and can still transmit to offspring | 10–15% of clinically diagnosed TSC has no variant found by conventional testing; high-depth NGS can reveal low-level mosaic variants; mosaic individuals may have fewer manifestations but require surveillance (pqac-00000003, pqac-00000021, pqac-00000023) | HP:0001417 Mosaicism |
| TSC1 variant spectrum | TSC1 pathogenic variants include intragenic deletions, nonsense, missense, duplication, splice/intronic changes; loss of function predominates | Sicilian TSC1 cohort: intragenic deletions **48.4%**, nonsense **38.7%**, missense **9.6%**, duplication **3.2%**; 45.1% inherited and 54.9% sporadic/de novo in that cohort (pqac-00000002) | Sequence ontology terms: nonsense_variant, frameshift_variant, splice_region_variant, intragenic_deletion, missense_variant |
| Phenotype: epilepsy | Epilepsy is a core neurologic phenotype and often the earliest clinically important manifestation | Consensus: focal seizures and epileptic spasms occur in **63–78%** of infants with TSC; in one TSC1 cohort epilepsy in **64.5%**, mean onset **35.4 months** (pqac-00000010, pqac-00000002) | HPO: Seizure; Focal seizure; Epileptic spasm; Developmental epileptic encephalopathy (if applicable) |
| Phenotype: cortical tubers / migration lines | Structural brain lesions are hallmark brain findings underlying seizures and neurodevelopmental morbidity | TSC1 cohort: cortical tubers **67.8%**, subependymal nodules **51.6%** (pqac-00000002); consensus revised criterion to “multiple cortical tubers and/or radial migration lines” (pqac-00000023) | HPO: Cortical tuber; Radial migration line; Subependymal nodule |
| Phenotype: TAND / neurodevelopment | TSC-associated neuropsychiatric disorders span behavioral, psychiatric, intellectual, academic, and psychosocial domains | TAND issues affect up to ~90% across TSC literature review; TSC1 cohort autism spectrum disorder **12.9%** and cognitive outcome ranged from normal **51.6%** to severe deficit **16.1%** (pqac-00000004, pqac-00000002) | HPO: Autism; Intellectual disability; Attention-deficit/hyperactivity disorder; Anxiety; Behavioral abnormality |
| Phenotype: renal angiomyolipoma | Renal angiomyolipoma is a common, clinically actionable manifestation | TOSCA: **1,062/2,211 (48%)** had angiomyolipoma; median angiomyolipoma diagnosis age **13 years**; more common in females; TSC1-associated lesions develop later and are smaller/less likely growing on average (pqac-00000019) | HPO: Renal angiomyolipoma; Chronic kidney disease; Hypertension |
| Phenotype: pulmonary LAM | Pulmonary lymphangioleiomyomatosis is mainly an adult female complication, milder in TSC-LAM than sporadic LAM | LAM occurs in **30–40% of adult females** with TSC at childbearing age; spontaneous pneumothorax in up to **70%** of LAM patients (pqac-00000017) | HPO: Lymphangioleiomyomatosis; Pneumothorax; Dyspnea |
| Phenotype: skin lesions | Facial angiofibromas and other cutaneous hamartomas are major diagnostic clues | Skin lesions are major criteria in consensus; topical and systemic mTOR-targeted therapies are in active clinical use/trials (pqac-00000023, pqac-00000028) | HPO: Facial angiofibromas; Fibrous cephalic plaque; Hypomelanotic macule; Ungual fibroma |
| Phenotype: cardiac rhabdomyoma | Cardiac rhabdomyomas are common prenatal/infant manifestations and can trigger diagnosis | In a Japanese claims study, cardiac rhabdomyoma was the highest-incidence manifestation among those diagnosed before age 2 (**54.8%**) (from abstract summary) (pqac-00000003) | HPO: Cardiac rhabdomyoma; Arrhythmia |
| Mechanism | TSC1/hamartin forms complex with TSC2/tuberin and TBC1D7; the complex acts as a GAP toward **RHEB**, restraining **mTORC1** | Loss of TSC1/2 increases **RHEB-GTP**, activates TORC1, elevates p70 S6 kinase signaling, upregulates anabolic metabolism and cell growth (pqac-00000014, pqac-00000013) | GO: regulation of TORC1 signaling; GTPase activator activity; negative regulation of cell growth |
| Pathophysiology chain | Upstream: TSC1 loss of function → TSC complex destabilization → RHEB activation → mTORC1 hyperactivation; downstream: altered growth, migration, synaptogenesis, metabolism, autophagy suppression, hamartoma formation, epileptogenesis | Single-cell cortical tuber study found preserved neuronal subtypes but major transcriptomic shifts in principal neurons and upper-layer GABAergic neurons, reduced mitochondrial respiration, switch to fatty-acid metabolism, and neuron-specific AMPA signaling candidate in epileptogenesis (pqac-00000015) | GO: positive regulation of cell growth; regulation of neuron differentiation; synaptogenesis; fatty acid metabolic process; mitochondrial respiration; macroautophagy |
| Cellular processes | mTOR dysregulation affects neuronal maturation, axonal growth, myelination, gliosis, BBB integrity, and seizure networks | Human BBB microphysiologic model showed increased permeability in TSC-mutant BBB rescued by wild-type astrocytes or rapamycin; glial/myelination abnormalities described in TSC models and tissue (pqac-00000016, pqac-00000022) | GO: blood-brain barrier establishment/maintenance; gliogenesis; myelination; astrocyte activation |
| Anatomy | Primary affected organs: brain, kidney, skin, heart, lung, eye; secondary systemic effects include neuropsychiatric, renal, respiratory and cardiovascular complications | Consensus surveillance spans brain MRI, abdominal MRI, chest CT/PFTs, dermatology, dental, cardiac echo/EKG, ophthalmology (pqac-00000024) | UBERON: brain, kidney, skin, heart, lung, retina |
| Cell types | High-value implicated cell types include principal/glutamatergic neurons, GABAergic interneurons, astrocytes, oligodendrocytes/NG2 glia, vascular endothelial/barrier cells, smooth muscle-like LAM cells | Single-cell tuber data highlight principal neurons and layer 1–2 GABAergic neurons; BBB model implicates astrocyte support and endothelial-barrier dysfunction; glial review emphasizes astrocytes, oligodendrocytes, NG2 glia, microglia (pqac-00000015, pqac-00000016, pqac-00000022) | CL: glutamatergic neuron; GABAergic interneuron; astrocyte; oligodendrocyte; NG2 glial cell; endothelial cell; microglial cell |
| Subcellular localization | Disease biology centers on lysosome-associated mTORC1 regulation and signaling to translation/metabolism pathways | TSC complex regulates RHEB-dependent TORC1; mTORC1-driven phosphorylation changes and metabolic rewiring are central (pqac-00000014, pqac-00000013, pqac-00000015) | GO Cellular Component: lysosome; lysosomal membrane; mTORC1 complex; cytosol |
| Diagnostics | Definite diagnosis can be established by clinical criteria or pathogenic **TSC1/TSC2** variant | Consensus: **11 major** and **7 minor** clinical features; failure to detect variant does **not** exclude TSC; high-depth NGS needed for low-level mosaicism/intronic causes (pqac-00000023) | HPO/clinical terms for major criteria; MONDO:0008612; gene-based diagnosis with TSC1 |
| Genetic testing strategy | Use multigene NGS panel or exome/genome with copy-number detection; escalate to high-read-depth methods and RNA/splice evaluation when negative but suspicion remains | Current molecular testing identifies pathogenic TSC1/TSC2 variant in nearly **90%** of definite TSC; 2024 Brazilian cohort identified alterations in **91%** (106/116) (pqac-00000014, pqac-00000023) | Testing ontology names: NGS gene panel; exome sequencing; genome sequencing; MLPA/CNV analysis; RNA splicing assay |
| Surveillance | Lifelong organ-based surveillance is standard; key intervals are consensus-defined | Brain MRI every **1–3 years** in asymptomatic patients <25 years; infant EEG every **6 weeks** to 12 months, then every **3 months** to 24 months; abdominal MRI every **1–3 years**; baseline chest CT in females and symptomatic males ≥18 years (pqac-00000024, pqac-00000011) | MAXO-like actions: brain MRI surveillance; EEG monitoring; abdominal MRI surveillance; pulmonary function testing |
| Treatment: seizure control | First-line infantile spasm therapy is **vigabatrin**; everolimus and a specific cannabidiol formulation are approved for TSC-associated seizures; surgery for refractory focal epilepsy | Real-world everolimus: epilepsy responders (≥50% reduction) **31%** overall, **46%** if <18 years vs **14%** if ≥18 years (pqac-00000018); consensus recommends epilepsy surgery after failure of 3 medications in appropriate candidates (pqac-00000024) | MAXO: antiseizure medication treatment; epilepsy surgery; CHEBI: vigabatrin, everolimus, cannabidiol |
| Treatment: mTOR inhibition | **Everolimus/sirolimus** target the core disease pathway and are used for SEGA, renal angiomyolipoma, LAM, and seizures in selected settings | Real-world everolimus adverse effects in **95%**; common oral ulceration/stomatitis **63%**, URTI **38%**, cholesterol increase **41%**, anemia **30%**, leucopenia **25%**; grade 3–4 AEs **36%** (pqac-00000018) | MAXO: mTOR inhibitor therapy; CHEBI: everolimus, sirolimus/rapamycin |
| Treatment: renal disease | For asymptomatic growing angiomyolipoma >3 cm, mTOR inhibitor is first-line; embolization + corticosteroids for acute hemorrhage | Consensus and kidney recommendations support MRI surveillance and pre-emptive intervention; TOSCA found no renal hemorrhage after starting mTOR inhibitor in substudy patients (pqac-00000011, pqac-00000019) | MAXO: renal angiomyolipoma treatment; arterial embolization; corticosteroid therapy; CHEBI: everolimus, sirolimus |
| Treatment: pulmonary disease | mTOR inhibitor is treatment of choice for clinically significant TSC-LAM | Recommended when FEV1 <70% predicted, abnormal DLCO, air trapping, oxygen desaturation, or rapid decline (pqac-00000011) | MAXO: pulmonary mTOR inhibitor treatment; pulmonary function monitoring |
| Treatment: dermatology | Topical sirolimus formulations are in real-world use and late-phase trials for facial angiofibromas/skin lesions | Phase 3 NPC-12Y topical sirolimus 0.2% gel trial completed; 43 participants, primary endpoint at 12 weeks for angiofibroma improvement (pqac-00000028) | MAXO: topical skin lesion treatment; CHEBI: sirolimus |
| Quality of life / burden | Disease burden is high for patients and caregivers, beyond tumor counts alone | TOSCA QoL study: negative effect on education/career in **42.1%** of patients; caregivers reported family-life impact **76.5%**; pain/discomfort **35%**; anxiety/depression **43.4%** (pqac-00000017) | HPO/clinical terms: pain, anxiety, depression; psychosocial burden terms |
| Prognosis | Prognosis is variable and improved by multidisciplinary surveillance and pathway-based treatment, but neurologic, renal, and pulmonary complications remain major causes of morbidity | TSC-related epilepsy and organ complications drive burden; kidney and pulmonary surveillance designed to prevent hemorrhage, CKD, pneumothorax, and progression (pqac-00000017, pqac-00000019, pqac-00000011) | Outcome ontology names: chronic disease course; variable expressivity |
| Prevention / early intervention | No primary prevention of genotype; secondary/tertiary prevention relies on early diagnosis, family testing, surveillance, pre-symptomatic EEG monitoring, and early treatment | Pre-emptive vigabatrin before clinical seizures may delay/prevent onset in high-risk infants with epileptiform EEG; genetic counseling recommended for all families (pqac-00000023, pqac-00000024) | MAXO: genetic counseling; cascade testing; EEG screening; early antiseizure therapy |
| Current trials | Active/complete 2022–2025 studies are testing pathway-targeted and adjunctive therapies | **NCT05534672** rapamycin vs placebo in drug-resistant TSC epilepsy; **NCT05104983** sirolimus prevention in infants; **NCT05323734** ganaxolone phase 3 completed; **NCT05059327** basimglurant phase 2 completed; **NCT02962414** long-term everolimus safety; **NCT05495425** topical sirolimus gel completed (pqac-00000025, pqac-00000026, pqac-00000027, pqac-00000028, pqac-00000029, pqac-00000030) | ClinicalTrials.gov IDs as identifiers |
| Model organisms / systems | Widely used models include mouse, rat, zebrafish, Drosophila, MEFs, patient iPSCs, organoids, and neurovascular chips | Tsc1/Tsc2 models recapitulate seizures, gliosis, myelination defects, tumor biology, and pathway dependence; human models add BBB and cell-type-specific developmental readouts but may not fully recapitulate full cortical complexity or lifelong multisystem disease (pqac-00000012, pqac-00000013, pqac-00000015, pqac-00000016, pqac-00000022) | NCBI Taxon: **10090** Mus musculus; **10116** Rattus norvegicus; **7955** Danio rerio; **7227** Drosophila melanogaster; model system names: patient-derived iPSC, cortical organoid, neurovascular unit chip |


*Table: This table condenses the most knowledge-base-ready facts for TSC1-related tuberous sclerosis complex, including identifiers, genetics, mechanisms, phenotypes, surveillance, treatment, and model systems. It emphasizes ontology-friendly mappings and quantitative evidence from consensus guidelines, recent studies, and active clinical trials.*