| domain | curated finding | suggested ontology/identifier | evidence scope/caveat |
|---|---|---|---|
| Disease identity | Familial defective apolipoprotein B-100 (FDB) is an inherited ligand-defective APOB disorder characterized by hypercholesterolemia and premature atherosclerosis; often treated clinically within the APOB-related familial hypercholesterolemia spectrum. | Disease label: Familial defective apolipoprotein B-100; consider MONDO/Orphanet/OMIM cross-map, verify current release | Disease-specific review supports identity, but many modern sources subsume FDB under broader familial hypercholesterolemia (FH) rather than list it separately (pqac-00000009, pqac-00000007, pqac-00000011) |
| Synonyms / naming | Common names include FDB, familial defective apoB-100, APOB-related familial hypercholesterolemia, ligand-defective apoB hypercholesterolemia. Legacy residue numbering uses R3500Q/R3500W; current full-length APOB numbering uses p.Arg3527Gln / p.Arg3527Trp. | APOB gene (HGNC: APOB label; verify HGNC ID/current transcript) | Important curation issue: legacy codon 3500 and current codon 3527 refer to the same canonical disease hotspot under different numbering systems (pqac-00000002, pqac-00000012) |
| Causal gene / variant hotspot | Core causal gene is APOB; the best-established pathogenic variant is p.Arg3527Gln (legacy R3500Q). p.Arg3527Trp (legacy R3500W) is the second most common FDB mutation; additional nearby APOB exon 26 variants are reported. | Gene: APOB; variant labels: p.Arg3527Gln, p.Arg3527Trp; ClinVar/ClinGen/HGVS mapping recommended | Disease-specific review reports ~35 FH-causing APOB variants overall; exact pathogenicity for rarer nearby variants should be checked in ClinVar/ClinGen (pqac-00000007, pqac-00000002) |
| Inheritance | Usually autosomal codominant / autosomal dominant in clinical practice, with dose effect between heterozygous and rare homozygous states. | HPO inheritance term: Autosomal dominant inheritance / codominant qualifier, verify preferred ontology usage | Source wording varies: recent apoB review uses “autosomal codominant,” while FH guidelines often simplify dominant FH inheritance (pqac-00000009, pqac-00000011) |
| Core laboratory phenotype | Lifelong elevation of LDL-C is the hallmark; the R3500Q variant increases serum LDL-C by about 60–70 mg/dL. ApoB-containing LDL particles accumulate because hepatic clearance is impaired. | HPO labels: Hypercholesterolemia, Increased LDL cholesterol level; LOINC/NCIT lipid panel terms, verify current release | Quantitative increase is variant-specific and may be modified by background genetics and environment (pqac-00000007, pqac-00000009, pqac-00000002) |
| Clinical phenotype | May present with hyper-LDL cholesterolemia, premature coronary disease, and sometimes xanthomas/coronary artery calcification, but phenotype is often milder than classic LDLR-mediated FH. | HPO labels: Premature coronary artery disease, Coronary artery calcification, Tendon xanthoma, Myocardial infarction | Much of the visible-xanthoma literature comes from broader FH cohorts; FDB-specific severity is generally lower/variable (pqac-00000007, pqac-00000005, pqac-00000013) |
| Complications | FDB is associated with coronary artery disease, ischemic heart disease, myocardial infarction, and coronary artery calcification. Comparative data suggest lower CHD prevalence and later onset than classic FH: 5.6% CHD at median age 52 in FDB vs 40% at mean age 41 in FH; carotid stenosis 4% vs 15%. | HPO labels: Coronary artery disease, Myocardial infarction, Carotid artery stenosis | These comparative risk figures are disease-informative but derive from FDB-vs-FH comparison rather than population prevalence estimates (pqac-00000007, pqac-00000005) |
| Molecular mechanism | ApoB100 normally serves as an LDL receptor ligand. Pathogenic APOB hotspot variants reduce apoB100 binding affinity to LDLR, lowering LDL uptake/clearance by hepatocytes and increasing circulating LDL; excess LDL is retained/oxidized in arterial intima, triggering foam-cell inflammation and plaque formation. | GO labels: low-density lipoprotein particle receptor binding, receptor-mediated endocytosis, cholesterol homeostasis, foam cell differentiation, inflammatory response; Reactome/KEGG LDL metabolism pathways, verify current release | Upstream defect is FDB-specific (apoB-LDLR binding); downstream atherogenesis steps are general apoB/LDL biology extrapolated from atherosclerosis literature (pqac-00000009, pqac-00000006, pqac-00000008) |
| Anatomy / cells | Primary organs/systems: liver and arterial vasculature; target tissues include arterial intima and atherosclerotic plaque. Key cells: hepatocytes, endothelial cells, monocytes/macrophages, vascular smooth muscle cells, CD4+ T cells. | UBERON labels: liver, blood vessel, carotid artery, coronary artery; CL labels: hepatocyte, endothelial cell, macrophage, smooth muscle cell, CD4-positive T cell; GO cellular components/pathways verify current release | Cell-level cascade is derived mainly from apoB atherosclerosis biology rather than FDB-only experiments (pqac-00000006, pqac-00000008) |
| Diagnosis | Suspect in patients with elevated untreated LDL-C and family history of premature CAD/FH; distinguish from LDLR-mediated FH and secondary dyslipidemia. Genetic testing for APOB variants is confirmatory. FH diagnostic frameworks use untreated LDL-C thresholds (e.g., ≥180 mg/dL in Japanese adult criteria) plus xanthomas/family history, and recommend cascade screening. | Disease/gene testing: APOB sequencing or FH multigene panel (APOB, LDLR, PCSK9, LDLRAP1); clinical criteria labels: Dutch Lipid Clinic Network, Simon Broome, MEDPED, JAS adult FH criteria | No FDB-specific modern standalone diagnostic criteria were identified; current practice usually diagnoses under FH algorithms and then subtypes genetically (pqac-00000013, pqac-00000011, pqac-00000012) |
| Differential diagnosis | Main differential diagnoses are LDLR-related FH, PCSK9-related FH, LDLRAP1-related hypercholesterolemia, polygenic hypercholesterolemia, elevated Lp(a)-driven LDL-C signal, and secondary dyslipidemias. | Disease labels as above; consider Lp(a), sitosterolemia, hypothyroidism, nephrotic syndrome, cholestatic liver disease, verify coding system | Differential structure comes mostly from general FH guidance, not FDB-specific cohorts (pqac-00000003, pqac-00000015, pqac-00000013) |
| Treatment | Managed similarly to heterozygous FH: lifestyle intervention, high-intensity statin first line, usually plus ezetimibe; consider PCSK9 inhibitors, inclisiran, bempedoic acid, and lipoprotein apheresis if targets are not reached. General FH targets include ≥50% LDL-C reduction and LDL-C <70 mg/dL for primary prevention or <55 mg/dL for very-high-risk patients. | NCIT labels: statin therapy, ezetimibe, PCSK9 inhibitor therapy, inclisiran, bempedoic acid, lipoprotein apheresis; CHEBI/DrugBank mapping verify current release | Evidence is mostly general FH guidance; a caveat for FDB is that LDLR is structurally normal, so response patterns may differ from LDLR-negative FH, but modern management still follows FH algorithms (pqac-00000004, pqac-00000003, pqac-00000005) |
| Prevention / screening | Cascade screening of relatives is recommended after identifying an index case; early diagnosis reduces cumulative LDL exposure and premature CAD risk. Lifestyle measures include Mediterranean-style diet and aerobic exercise, which can lower apoB-related risk markers. | Public health labels: cascade screening; HPO/family history terms; behavioral intervention terms verify current release | Screening and prevention evidence is mainly general FH implementation evidence, applicable to APOB-FDB because of shared inherited LDL burden (pqac-00000011, pqac-00000007) |
| Prognosis | Untreated FDB increases atherosclerotic risk, but available comparative evidence suggests lower severity than classic FH on average. Expressivity is variable and can be worsened by additional genetic hits or conventional cardiovascular risk factors. | Prognostic feature labels: premature CAD risk, variable expressivity, incomplete penetrance | Specific long-term survival estimates for pure FDB were not identified in retrieved recent sources (pqac-00000005, pqac-00000002, pqac-00000016) |
| Modifiers | Phenotype may be modified by smoking, diabetes, hypertension, low HDL-C, high TG, obesity/insulin resistance, and other lipid genes or digenic states. | HPO/ExO/environmental exposure labels; modifier genes to verify per case | Most modifier evidence is from broader FH rather than FDB-only cohorts; use cautiously when curating disease-specific assertions (pqac-00000013, pqac-00000016) |
| Models / other species | Relevant experimental systems include human APOB100 transgenic or knock-in atherosclerosis models and pathway models such as Ldlr-/- or Apoe-based mice, but these are not exact allele-faithful FDB models. No naturally occurring veterinary FDB equivalent was identified in retrieved sources. | Model labels: human APOB100 transgenic mouse; LDLR knockout mouse; APOE-related atherosclerosis mouse, verify model database accession | Useful for mechanism and drug testing, but limited for direct genotype-phenotype recapitulation of APOB p.Arg3527Gln FDB (pqac-00000014) |
| Evidence gaps | Uncertain/needs verification: exact MONDO/Orphanet/OMIM mapping for FDB as a distinct entity, current ClinVar classifications for all rare APOB hotspot-adjacent variants, precise prevalence/incidence of pure FDB by ancestry, penetrance estimates, QoL data, and disease-specific animal models. | Use ontology labels only and verify current release before database loading | Modern literature often collapses FDB into APOB-related FH, so separate disease-level curation requires careful source labeling (pqac-00000007, pqac-00000003, pqac-00000012) |


*Table: This table provides a compact curation-oriented summary of Familial Defective Apolipoprotein B-100, covering disease identity, variant hotspot, phenotype, mechanism, diagnosis, treatment, anatomy, and key evidence gaps. It is designed to support structured knowledge-base entry building while flagging where broader FH evidence is being extrapolated to FDB.*