| Domain | Summary | Key IDs / ontology suggestions | Evidence qualifier |
|---|---|---|---|
| Identity / identifiers | Autosomal Dominant Hypercholesterolemia 3 (ADH3) is the PCSK9-related monogenic form of familial hypercholesterolemia; evidence here is disease-level, aggregated from databases, guidelines, trials, and literature rather than individual EHR records. | MONDO:0011369; MeSH disease family terms in trial metadata include Hypercholesterolemia/Hyperlipoproteinemia Type II; target gene PCSK9 = ENSG00000169174 (pqac-00000001, pqac-00000003) | Authoritative database + clinical literature; ADH3-specific MONDO supported, but other disease codes were not directly retrieved here. |
| Causal gene and inheritance | Causal gene: **PCSK9**; pathogenic **gain-of-function** alleles cause ADH3/FH3. Inheritance is monoallelic autosomal dominant. | PCSK9; inheritance: autosomal dominant / monoallelic; related FH gene class includes LDLR, APOB, PCSK9 (pqac-00000001, pqac-00000021, pqac-00000032) | Strong human genetic evidence; target-disease linkage also supported by drug-approval evidence. |
| Representative GOF variants | Recurrently cited GOF variants include **S127R, F216L, D374Y**; additional GOF variants in prodomain and C-terminal CM1/CHR regions impair LDL association and/or enhance LDLR binding/degradation. | Variant examples: p.Ser127Arg, p.Phe216Leu, p.Asp374Tyr, p.Arg496Trp (pqac-00000002, pqac-00000016, pqac-00000017, pqac-00000014) | Variant list is representative, not exhaustive; some classic primary papers were referenced indirectly or unobtainable in-tool. |
| Core mechanism | PCSK9 is a secreted hepatocyte-enriched protein that binds LDLR and diverts it to endo-lysosomal degradation, reducing receptor recycling and hepatic LDL clearance. GOF variants intensify this process by increasing LDLR affinity and/or altering LDL binding regulation, producing lifelong LDL-C elevation and accelerated atherosclerosis. | GO: LDL receptor catabolic process; GO: receptor-mediated endocytosis; GO CC suggestions: extracellular region, lysosome; CL: hepatocyte; UBERON: liver (pqac-00000015, pqac-00000017, pqac-00000020, pqac-00000021) | Human, in vitro, and animal evidence converge; LDLR-independent inflammatory roles are plausible but less disease-defining than hepatic LDLR degradation. |
| Hallmark phenotypes / HPO suggestions | Hallmarks align with heterozygous familial hypercholesterolemia: markedly elevated LDL-C/hypercholesterolemia, tendon/skin xanthomas, corneal arcus, premature coronary artery disease, premature atherosclerosis; stroke risk less consistently increased than CAD. | HPO suggestions: HP:0003124 Hypercholesterolemia; HP:0000991 Xanthoma; HP:0001084 Corneal arcus; HP:0001677 Coronary artery atherosclerosis; HP:0001716 Premature arteriosclerosis (suggestive) (pqac-00000009, pqac-00000010, pqac-00000012) | Phenotype frequencies were mainly available for FH broadly, not ADH3-only cohorts. |
| Diagnosis | Diagnosis generally follows FH frameworks: family history, LDL-C level, premature CAD, tendon xanthomas/Achilles tendon thickening, and confirmatory molecular testing. Japanese adult guideline updated Achilles tendon thresholds to **≥8.0 mm men / ≥7.5 mm women** to improve sensitivity. | Diagnostic systems: DLCN / Simon Broome / national FH criteria; test target genes include LDLR, APOB, PCSK9; HPO: HP:0003326 Elevated LDL cholesterol concentration (suggestive) (pqac-00000007, pqac-00000008, pqac-00000010) | Clinical diagnosis is usually FH-spectrum; molecular confirmation can specify ADH3. |
| Treatment algorithm | Stepwise care: lifestyle optimization + **high-intensity statin** first line; add **ezetimibe** if needed; add **PCSK9 inhibitor** (alirocumab/evolocumab) for very-high-risk or insufficient control; **inclisiran** or **bempedoic acid** are additional options; **lipoprotein apheresis** for refractory/severe disease. Typical very-high-risk LDL-C goal: **≥50% reduction and <55 mg/dL (<1.4 mmol/L)**. | NCIT suggestions: Statin therapy, Ezetimibe, Alirocumab, Evolocumab, Inclisiran, Bempedoic Acid, Lipoprotein Apheresis (pqac-00000029, pqac-00000025, pqac-00000026, pqac-00000022) | Algorithm is evidence-based for FH broadly; ADH3-specific response data are limited but PCSK9-targeted therapies are mechanistically central. |
| Epidemiology caveat | No robust prevalence estimate was retrieved for **ADH3 specifically**. Most published epidemiology concerns **all heterozygous FH**, estimated around **1:311 to 1:303** in the general population and **~1:17** among ASCVD patients; prevalence varies by ethnicity and founder effects. | Use disease-level caveat flag: “FH-wide estimate, not ADH3-specific”; MONDO:0011369 only identifies subtype (pqac-00000036, pqac-00000037, pqac-00000034, pqac-00000030) | Important limitation for knowledge-base curation: subtype-specific denominators are not established here. |
| Major trials / real-world implementation | PCSK9-directed implementation includes approved antibodies and emerging gene/RNA approaches. Trial examples: **VERVE-101** base editing in HeFH + ASCVD (**NCT05398029**, phase 1, n=13); pediatric **evolocumab** extension (**NCT02624869**, n=163); adolescent **inclisiran ORION-16** (**NCT04652726**, n=141); alirocumab plaque study **ARCHITECT** (**NCT05465278**, n=104). | NCT05398029; NCT02624869; NCT04652726; NCT05465278 (pqac-00000003, pqac-00000004, pqac-00000005, pqac-00000006) | Demonstrates real-world translation from gene discovery to antibodies, siRNA, and base editing. |
| Model organisms | Useful disease models include **AAV-hPCSK9 D374Y mice** causing sustained hypercholesterolemia and atherosclerosis, and **Yucatan miniature pigs/minipigs** carrying human **PCSK9 D374Y** with coronary/aortic lesions. A 2024 **PCSK9 nanoparticle vaccine** used AAV-hPCSK9D374Y mouse models. Limitation: pig models may not reproduce plaque rupture/thrombosis fully. | Species: Mus musculus; Sus scrofa; variant/model driver: PCSK9 D374Y; CL/UBERON relevance: hepatocyte, aorta, coronary artery (pqac-00000040, pqac-00000041, pqac-00000039, pqac-00000038) | Strong translational utility for mechanism and therapy testing; imperfect recapitulation of late human plaque complications. |


*Table: This compact table summarizes the most actionable knowledge-base fields for Autosomal Dominant Hypercholesterolemia 3, emphasizing what is directly supported for the PCSK9-related subtype versus what is only available for familial hypercholesterolemia more broadly.*