Familial Defective Apolipoprotein B-100: Disease-Characteristics Report

Executive summary and evidence boundaries

Familial defective apolipoprotein B-100 (FDB) is a Mendelian, usually autosomal-dominant/codominant hypercholesterolemia caused by ligand-defective APOB. The prototypic allele is APOB c.10580G>A, p.Arg3527Gln, historically called R3500Q; p.Arg3527Trp/R3500W is another established allele. Defective apoB-100 binding to hepatic LDL receptor (LDLR) reduces LDL clearance, causing lifelong elevation of LDL cholesterol (LDL-C) and cumulative atherosclerotic cardiovascular risk. FDB is now commonly classified as APOB-related familial hypercholesterolemia (FH) rather than managed as a separate clinical syndrome. On average it is milder and less penetrant than LDLR-related FH, but coronary disease and myocardial infarction can still occur prematurely. (kounatidis2024apob100andatherosclerosis pages 13-14, kounatidis2024apob100andatherosclerosis pages 11-13)

Evidence below is labeled implicitly by scope: statements about the apoB-binding defect and comparative FDB cohorts are FDB-specific human evidence; management targets, diagnostic criteria, and many risk modifiers are general FH evidence extrapolated to molecularly confirmed FDB. Recent disease-specific evidence is limited; the most directly relevant recent synthesis is Kounatidis et al., published February 2024, DOI 10.3390/metabo14020123. (kounatidis2024apob100andatherosclerosis pages 13-14)

The following compact table summarizes knowledge-base-ready assertions and their principal caveats.

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.

1. Disease information

Definition

FDB is an inherited disorder in which apoB-100 on LDL has reduced affinity for LDLR. The resulting under-clearance of LDL produces hypercholesterolemia and premature atherosclerosis. A recent review defines it as an “inherited autosomal codominant disorder characterized by hypercholesterolemia and premature atherosclerosis.” (kounatidis2024apob100andatherosclerosis pages 11-13)

Identifiers and synonyms

• Preferred name: familial defective apolipoprotein B-100.
• Synonyms: familial defective apoB-100; FDB; ligand-defective apolipoprotein B; APOB-related familial hypercholesterolemia; familial hypercholesterolemia type 2 due to APOB.
• OMIM: commonly mapped to 144010, Hypercholesterolemia, familial, 2 (FHCL2); APOB gene OMIM 107730. Database release should be verified before ingestion.
• Orphanet: commonly represented within familial hypercholesterolemia rather than consistently as a separate current disorder; verify the live Orphanet release.
• MONDO: use the current MONDO entry for familial hypercholesterolemia due to ligand-defective apolipoprotein B if present; exact live identifier could not be independently verified from the retrieved corpus.
• ICD-10-CM: E78.01 Familial hypercholesterolemia; no FDB-specific code.
• ICD-11: use the familial hypercholesterolaemia entity under disorders of lipoprotein metabolism; no allele-specific FDB code was established here.
• MeSH: Hyperlipoproteinemia Type II and Familial Hypercholesterolemia are appropriate indexing concepts; no reliably verified standalone current FDB MeSH descriptor was found.

These are aggregated disease-level assertions from reviews and guidelines, not individual EHR observations. Patient-level values cited below come from published cohorts; no identifiable patient records were accessed.

2. Etiology, risk, protection, and gene–environment interaction

Primary cause

The causal lesion is a germline APOB variant affecting the LDLR-binding region of apoB-100. The best-established variants are p.Arg3527Gln and p.Arg3527Trp. Older papers number these as Arg3500 because of historical protein-numbering conventions. The 2024 review reports that R3500Q raises LDL-C by approximately 60–70 mg/dL and that approximately 35 FH-associated APOB variants had been described, although every rare APOB missense variant requires contemporary classification and preferably functional validation. (kounatidis2024apob100andatherosclerosis pages 13-14)

Genetic risk and modifiers

Risk is greatest with biallelic/dose-enhanced disease, additional pathogenic variants in LDL-pathway genes, and a high polygenic LDL-C burden. Candidate modifiers include LDLR, PCSK9, APOE, LDLRAP1, ABCG5, and ABCG8. Digenic FH literature shows substantial intrafamilial variability and warns that computational prediction alone is insufficient; cosegregation, population frequency, and functional LDLR-binding/uptake evidence remain important. (haradashiba2023guidelinesforthe pages 8-11, kamar2021thedigeniccausality pages 14-15)

Possible protective modifiers include LDL-lowering PCSK9 loss-of-function alleles and APOB truncating alleles, but an APOB truncation causes a biologically distinct hypobetalipoproteinemia phenotype and should not be treated as a protective FDB allele. PCSK9 knockout mice showed an approximately 80% LDL-C decrease, illustrating the pathway rather than proving an FDB-specific human modifier effect. (kamar2021thedigeniccausality pages 14-15)

Environmental and lifestyle modifiers

The pathogenic variant is sufficient to predispose to disease, but cumulative LDL exposure and clinical events are modified by diet, smoking, physical activity, obesity/visceral adiposity, diabetes, hypertension, high triglycerides, and low HDL-C. These associations are best established in broader FH cohorts. A Western diet rich in saturated fat can impede LDL apoB-100 clearance; Mediterranean-style eating enhances LDL catabolism, while aerobic training modestly lowers apoB. In a meta-analysis of 57 trials involving 3,194 participants, aerobic exercise lowered apoB-100 by about 2.073 mg/dL; this was not an FDB-only analysis. (kounatidis2024apob100andatherosclerosis pages 13-14, haradashiba2023guidelinesforthe pages 8-11)

There is no infectious, toxic, occupational, or radiation cause. Such exposures may affect background cardiovascular risk but do not cause the Mendelian disorder.

3. Phenotypes

In one comparative study summarized in 2024, CHD was present in 5.6% of FDB subjects at median age 52, versus nearly 40% of FH patients at mean age 41; carotid stenosis occurred in 4% versus 15%. These figures should not be interpreted as lifetime penetrance because age distributions and ascertainment differed. (kounatidis2024apob100andatherosclerosis pages 13-14)

Hyper-LDL-cholesterolemia itself is generally asymptomatic. Quality-of-life loss arises mainly from diagnostic burden, lifelong medication, cardiovascular procedures, angina, infarction, and anxiety about relatives. No validated FDB-specific EQ-5D, SF-36, or PROMIS estimates were identified.

4. Genetic and molecular information

• Gene: APOB, chromosome 2p24.1; protein apolipoprotein B-100. HGNC and transcript identifiers should be pulled from the current HGNC/NCBI release during production curation.
• Primary variant: NM_000384.3:c.10580G>A, p.Arg3527Gln, legacy R3500Q.
• Additional established allele: p.Arg3527Trp, legacy R3500W.
• Other reported ligand-defective alleles: nearby residues such as p.Arg3558Cys/legacy R3531C and other APOB missense variants have been reported, but pathogenicity is not uniform and must be checked variant by variant.
• Origin/type: germline, usually heterozygous missense; rare homozygotes occur. This is not a somatic cancer disorder.
• Functional class: partial loss of ligand function—reduced LDLR binding—rather than loss of apoB production. It is neither a classical null allele nor a demonstrated dominant-negative protein in the usual sense.
• Classification: p.Arg3527Gln is an established pathogenic FH allele. Current ClinVar assertions, review status, gnomAD frequency, and ancestry-stratified counts should be imported directly from live databases; exact values were not available in the retrieved papers.
• Structural abnormalities: no recurrent aneuploidy, translocation, inversion, or copy-number lesion defines FDB. CMA, karyotyping, and FISH therefore have no routine role.
• Epigenetics: no reproducible disease-defining methylation, histone, or chromatin signature has been established. Epigenetic studies of atherosclerosis are downstream and not diagnostic of FDB.

APOB variants were estimated in the retrieved reviews to account for approximately 5–12% of autosomal-dominant FH, depending strongly on population and ascertainment. This is not the prevalence of FDB in the general population. (kounatidis2024apob100andatherosclerosis pages 13-14, siddiqi2026familialhypercholesterolemiastateoftheart pages 3-4)

5. Environmental information

No environmental exposure is necessary or sufficient to produce FDB. Environment modifies biochemical expression and ASCVD progression:

• Adverse: saturated/trans-fat-rich diet, smoking, inactivity, obesity, insulin resistance/diabetes, and hypertension.
• Protective: Mediterranean-style dietary pattern, replacement of saturated with unsaturated fats, regular aerobic activity, avoidance of tobacco, and control of blood pressure, weight, and diabetes.
• Alcohol: no FDB-specific protective effect should be inferred; alcohol is not recommended for prevention.
• Infection: not etiologic. Inflammation contributes to downstream plaque biology, but FDB is not infectious.

6. Mechanism and pathophysiology

Causal chain

1. Upstream genetic trigger: ligand-region APOB missense variant.
2. Protein dysfunction: apoB-100 on LDL binds LDLR with reduced affinity.
3. Cellular defect: receptor-mediated uptake by hepatocytes falls despite a generally intact LDLR.
4. Metabolic abnormality: LDL residence time and plasma LDL particle concentration rise.
5. Arterial initiation: apoB-containing particles cross and are retained in arterial intima, then undergo oxidation and other modifications.
6. Inflammatory amplification: endothelial VCAM1/ICAM1/E-selectin expression recruits monocytes; macrophage scavenger receptors such as CD36 and LOX-1 internalize oxidized LDL, generating foam cells. TLR, NF-κB, p38-MAPK/JAK-STAT, ROS, and NLRP3–IL-1 signaling contribute.
7. Tissue injury: foam-cell death, defective efferocytosis, smooth-muscle activation, extracellular-matrix deposition, necrotic core formation, calcification, and fibrous-cap remodeling produce stenotic or rupture-prone plaque.
8. Clinical endpoints: stable angina, coronary calcification/stenosis, plaque rupture, thrombosis, acute myocardial infarction, and premature death. (kounatidis2024apob100andatherosclerosis pages 4-5, kounatidis2024apob100andatherosclerosis pages 5-7, kounatidis2024apob100andatherosclerosis pages 11-13)

ApoB-100 is the LDLR ligand, and each VLDL, IDL, LDL, and Lp(a) particle contains one apoB molecule; thus apoB concentration approximates atherogenic particle number. More than 90% of circulating apoB-containing particles are LDL in many settings. (kounatidis2024apob100andatherosclerosis pages 5-7)

Suggested GO biological processes: LDL particle receptor binding; receptor-mediated endocytosis; plasma lipoprotein clearance; cholesterol homeostasis; lipid transport; response to oxidized LDL; macrophage-derived foam-cell differentiation; leukocyte adhesion; inflammatory response; regulation of NLRP3 inflammasome complex assembly.

Suggested GO cellular components: LDL particle; VLDL particle; plasma membrane; clathrin-coated pit; endosome; extracellular space.

Suggested CL terms: hepatocyte; vascular endothelial cell; classical monocyte; macrophage; foam cell; vascular smooth-muscle cell; dendritic cell; CD4-positive T cell; regulatory T cell. Exact IDs should be verified against current GO/CL releases.

No FDB-specific single-cell atlas, spatial transcriptomic map, diagnostic transcriptomic/proteomic signature, or integrated multi-omics classifier was identified. Modern single-cell atherosclerosis studies describe downstream plaque heterogeneity, not an FDB-specific state.

7. Anatomical structures affected

• Primary metabolic organ: liver—especially hepatocytes responsible for LDLR-mediated clearance. Suggested UBERON: liver; liver lobule.
• Primary injured system: arterial vasculature, particularly coronary arteries and aorta; carotid and peripheral arteries can also be involved. Suggested UBERON: artery; coronary artery; aorta; carotid artery; arterial wall/tunica intima.
• Secondary tissues: Achilles and extensor tendons, skin, and corneal periphery when lipid deposits form.
• Subcellular sites: hepatocyte plasma membrane, clathrin-coated pits and endosomes for LDLR uptake; extracellular/subendothelial matrix for LDL retention; macrophage lysosomal/lipid-droplet compartments during foam-cell formation.
• Lateralization: not applicable; vascular disease can be diffuse, bilateral, or anatomically asymmetric according to plaque burden.

8. Temporal development

The genotype is congenital and LDL-C elevation begins early, although clinical symptoms are usually absent for years. Disease is chronic, lifelong, and insidiously progressive. A useful staging model is:

1. biochemical hypercholesterolemia;
2. subclinical arterial retention, increased intima-media thickness, or coronary calcium;
3. clinically stable atherosclerotic disease;
4. acute plaque complication—ACS/MI—or diffuse advanced vascular disease.

There is no spontaneous genetic remission. LDL-C can normalize or substantially improve with treatment, but established plaque may persist. Earlier statin initiation is associated with less carotid intima-media thickening in pediatric FH, supporting childhood as a critical prevention window. (haradashiba2023guidelinesforthe pages 2-4, haradashiba2023guidelinesforthe pages 24-25)

9. Inheritance and population

Inheritance

FDB is generally autosomal dominant/codominant. Each child of a heterozygous affected individual has a 50% transmission risk. Penetrance for the biochemical phenotype is incomplete/variable and age-dependent for clinical ASCVD. Expressivity varies with allele dosage, polygenic background, lifestyle, sex, and conventional risk factors. Genetic anticipation is not established; consanguinity is not required, although it raises the chance of biallelic disease. Germline mosaicism is not a recognized major feature.

Epidemiology

A reliable global prevalence or incidence for molecularly pure FDB is unavailable. Historical European estimates vary because of founder effects and because modern FH cohorts combine APOB and LDLR disease. APOB alleles account for approximately 5–12% of genetically defined autosomal-dominant FH in some series. General heterozygous FH prevalence is about 1:300 in the 2023 Japanese guideline, but applying that figure directly to FDB would be incorrect. (haradashiba2023guidelinesforthe pages 2-4)

p.Arg3527Gln is enriched in populations of northwestern/central European ancestry and in founder-derived groups. p.Arg3527Trp has been described more often in East Asian families. Both sexes inherit the allele equally; observed event rates may be earlier in men because ASCVD penetrance is sex- and age-dependent. Precise carrier frequencies should be sourced from live gnomAD ancestry data.

10. Diagnostics

Clinical and laboratory assessment

Obtain a fasting or nonfasting lipid profile, apoB, non-HDL-C, triglycerides, HDL-C, and Lp(a), and document the highest untreated LDL-C. Examine Achilles/extensor tendons and skin; obtain a three-generation history of hypercholesterolemia and premature CAD. The 2023 Japanese guideline diagnoses adult FH using at least two of: untreated LDL-C ≥180 mg/dL; tendon/cutaneous nodular xanthoma; first-degree family history of FH or premature CAD. Premature CAD is <55 years in men and <65 years in women. These are general FH, not FDB-specific, criteria. (haradashiba2023guidelinesforthe pages 8-11)

Imaging is for phenotype/risk assessment, not molecular diagnosis: Achilles tendon radiograph or ultrasound, coronary calcium CT in selected adults, carotid ultrasound, and stress testing or coronary imaging when ischemia is suspected. Japanese thresholds for Achilles thickening are radiographic ≥8.0 mm in men/≥7.5 mm in women or ultrasound ≥6.0/≥5.5 mm. (haradashiba2023guidelinesforthe pages 8-11)

Genetic testing

Preferred testing is an FH multigene panel including LDLR, APOB, PCSK9, and LDLRAP1, with deletion/duplication analysis where appropriate. If a familial APOB allele is known, targeted testing is efficient. WES/WGS is useful for panel-negative severe or atypical families and possible digenic disease, but incidental APOB missense variants require rigorous ACMG/AMP interpretation and functional evidence. CMA, karyotype, FISH, mitochondrial sequencing, and repeat-expansion testing are not routinely indicated.

Differential diagnosis

Exclude hypothyroidism, nephrotic syndrome, cholestatic liver disease, uncontrolled diabetes, medication-related dyslipidemia, familial combined hyperlipidemia, polygenic hypercholesterolemia, sitosterolemia, lysosomal acid lipase deficiency, elevated Lp(a), LDLR-related FH, PCSK9 gain-of-function FH, and LDLRAP1-related recessive hypercholesterolemia. FDB often has a milder LDL-C elevation and normal receptor structure/function but cannot be reliably distinguished from LDLR-FH by lipid profile alone. (kounatidis2024apob100andatherosclerosis pages 13-14, faiz2012molecularpathologyof pages 4-5)

No validated omics-based diagnostic beyond DNA testing and conventional lipoprotein biomarkers is established.

11. Outcome and prognosis

FDB increases lifelong ASCVD morbidity, particularly coronary calcification, ischemic heart disease, and MI. Average severity appears lower than LDLR-FH, but individual prognosis is heterogeneous. General FH data show CAD odds approximately 10–20 times and peripheral arterial disease odds 5–10 times those of non-FH populations; these effect sizes should not be assigned directly to FDB. (haradashiba2023guidelinesforthe pages 2-4)

Prognostic factors are untreated and on-treatment LDL-C/apoB, duration of exposure, existing ASCVD or coronary calcium, smoking, diabetes, hypertension, low HDL-C, high triglycerides, Lp(a), male sex/older age, family history, allele dosage, and additional LDL-pathway variants. No FDB-specific 5- or 10-year survival, disability, mortality, or quality-of-life model was identified. Recovery from the genotype is impossible, but LDL normalization can markedly reduce future risk.

12. Treatment

FDB is treated according to heterozygous FH algorithms, with response monitored by LDL-C, non-HDL-C, and apoB.

1. Lifestyle foundation: Mediterranean-style diet; reduced saturated/trans fats; regular aerobic exercise; weight, diabetes, and blood-pressure control; no tobacco. These measures are adjunctive and rarely sufficient alone. Suggested NCIt concepts: dietary intervention, exercise therapy, smoking cessation.
2. High-intensity statin: atorvastatin or rosuvastatin; reduces hepatic cholesterol synthesis and upregulates LDLR. Suggested NCIt: HMG-CoA reductase inhibitor therapy. Statins are the best-supported first-line class in FH and earlier pediatric use limits IMT progression. (haradashiba2023guidelinesforthe pages 2-4)
3. Ezetimibe: blocks NPC1L1-mediated intestinal cholesterol absorption; add when targets are not achieved. Suggested NCIt: ezetimibe therapy.
4. PCSK9 monoclonal antibody: evolocumab or alirocumab increases recycled hepatic LDLR. General HeFH trials report about 59–61% and 51–58% LDL-C reductions, respectively; intact LDLR in FDB provides a strong mechanistic rationale, but these are not FDB-only response estimates. (siddiqi2026familialhypercholesterolemiastateoftheart pages 1-2)
5. Inclisiran: hepatic PCSK9 siRNA; general FH evidence reports about 48% LDL-C lowering. Suggested NCIt: small interfering RNA therapy/inclisiran.
6. Bempedoic acid: oral ATP-citrate lyase inhibitor, useful when further lowering is needed or statin intolerance occurs. Suggested NCIt: ATP citrate lyase inhibitor therapy.
7. Bile-acid sequestrant: an option, including selected pregnancy contexts; gastrointestinal adverse effects and pill burden limit use.
8. Lipoprotein apheresis: reserved for exceptionally severe, refractory disease or advanced ASCVD; acutely lowers LDL-C approximately 50–75% per session in general FH. (siddiqi2026familialhypercholesterolemiastateoftheart pages 1-2)

Common adverse effects include statin-associated muscle symptoms and transaminase elevations, ezetimibe gastrointestinal symptoms, PCSK9/inclisiran injection-site reactions, bempedoic-acid-associated hyperuricemia/gout and tendon concerns, and apheresis-related vascular-access burden and hypotension. Pregnancy planning requires specialist management; many systemic lipid-lowering drugs are stopped, while bile-acid sequestrants and, in severe disease, apheresis may be considered. (haradashiba2023guidelinesforthe pages 19-21)

Targets used in contemporary FH practice are ≥50% LDL-C reduction and LDL-C <70 mg/dL for high-risk primary prevention, or <55 mg/dL for very-high-risk/established ASCVD; pediatric targets are commonly <135 mg/dL after age 10. (siddiqi2026familialhypercholesterolemiastateoftheart pages 1-2, fularski2024unveilingfamilialhypercholesterolemia—review pages 7-9)

No approved therapy edits APOB p.Arg3527Gln. APOB-silencing therapies are unattractive as a routine FDB correction because excessive apoB suppression can impair hepatic lipid export. No retrieved ClinicalTrials.gov study specifically enrolled FDB as a distinct molecular cohort.

13. Prevention

• Primary prevention of genotype: impossible after conception. Reproductive options include genetic counseling, prenatal diagnosis, and preimplantation genetic testing when the familial pathogenic variant is known.
• Secondary prevention: opportunistic/universal cholesterol screening according to national policy, molecular confirmation, and cascade testing of first-degree relatives. Each identified heterozygous relative has a 50% prior risk in an autosomal-dominant pedigree.
• Tertiary prevention: early and sustained LDL/apoB lowering, smoking avoidance, and management of blood pressure, diabetes, obesity, and Lp(a)-related residual risk.
• Vaccination/immunization: not applicable.
• Newborn screening: not universally established for FDB. Pediatric lipid screening or reverse-cascade screening can identify affected families before events.

The World Heart Federation emphasizes that adverse exposure to LDL/apoB particles is cumulative and preventable through earlier screening and treatment. (haradashiba2023guidelinesforthe pages 2-4)

14. Other species and natural disease

• Human: Homo sapiens, NCBI Taxonomy 9606; disease gene APOB.
• Orthologues: ApoB is evolutionarily conserved in mammals, including mouse (Mus musculus, Taxon 10090), rat (Rattus norvegicus, 10116), rabbit (Oryctolagus cuniculus, 9986), pig (Sus scrofa, 9823), and dog (Canis lupus familiaris, 9615). Current NCBI Gene IDs should be imported directly.
• Natural veterinary disease: no well-established naturally occurring animal disorder orthologous specifically to human APOB p.Arg3527Gln FDB was identified. Breed-specific VBO annotation is therefore not justified.
• Transmission: inherited vertically within a species; not contagious or zoonotic.

15. Model organisms and experimental systems

Relevant models include human apoB-100 transgenic mice, APOB variant-expression systems, primary or immortalized hepatocyte uptake assays, fibroblast/lymphocyte LDLR assays, and general atherosclerosis models such as Ldlr-null and Apoe-null mice. Human apoB-100-expressing mice can develop complex atherosclerotic lesions and are useful for lipoprotein metabolism and pharmacology. (zadelaar2007mousemodelsfor pages 3-4)

An allele-faithful APOB p.Arg3527Gln knock-in or transgenic system is conceptually the most specific model: expected readouts are reduced LDLR binding/uptake, prolonged LDL residence, hypercholesterolemia, and diet-dependent plaque. However, mice normally package much cholesterol in HDL and edit ApoB RNA differently from humans; background strain and diet strongly influence plaque, limiting direct quantitative translation. Ldlr−/− and Apoe−/− mice reproduce hypercholesterolemia and atherogenesis but not the defining apoB ligand defect. Cell-based LDLR-binding and uptake assays may therefore be more specific for variant classification than generic knockout models.

Recent developments and expert interpretation

The major 2023–2024 development is not a new FDB-specific therapy but integration of APOB-FDB into genotype-defined FH care: multigene panels/cascade screening, earlier combination treatment, apoB and non-HDL-C as particle-burden measures, and wider use of PCSK9-directed agents. The February 2024 apoB review emphasizes that apoB is both an atherogenic-particle biomarker and a participant in arterial inflammation; its abstract states that apoB-100 “has been suggested to play a crucial role in the formation of the atherogenic plaque.” [Published February 2024; DOI 10.3390/metabo14020123.] (kounatidis2024apob100andatherosclerosis pages 13-14, kounatidis2024apob100andatherosclerosis pages 5-7)

The 2023 Japanese guideline’s clinically important conclusion is that FH causes persistent LDL elevation from birth and therefore requires “early diagnosis and appropriate treatment” plus cascade screening. Published May 2023; DOI 10.5551/jat.CR005. This guidance is applicable to FDB, while its risk estimates and examination thresholds derive from mixed-genotype FH. (haradashiba2023guidelinesforthe pages 2-4, haradashiba2023guidelinesforthe pages 8-11)

Key curation cautions

1. Do not confuse ligand-defective APOB hypercholesterolemia with APOB-related familial hypobetalipoproteinemia, which is usually caused by truncating/loss-of-production variants and produces low LDL-C and hepatic steatosis.
2. Store both modern and legacy residue nomenclature: p.Arg3527Gln = R3500Q.
3. Do not assign every rare APOB missense variant as pathogenic; require current ClinVar/ClinGen assessment, population frequency, segregation, and ideally functional evidence.
4. Do not copy general FH prevalence, mortality, or treatment-response estimates into FDB-specific fields without an “extrapolated from mixed-genotype FH” qualifier.
5. Exact live MONDO, Orphanet, HGNC, HPO, GO, CL, UBERON, NCIt, ClinVar, and gnomAD identifiers should be validated against their current releases before production loading.

References

1. (kounatidis2024apob100andatherosclerosis pages 13-14): Dimitris Kounatidis, Natalia G. Vallianou, Aikaterini Poulaki, Angelos Evangelopoulos, Fotis Panagopoulos, Theodora Stratigou, Eleni Geladari, Irene Karampela, and Maria Dalamaga. Apob100 and atherosclerosis: what’s new in the 21st century? Metabolites, 14:123, Feb 2024. URL: https://doi.org/10.3390/metabo14020123, doi:10.3390/metabo14020123. This article has 64 citations.

2. (kounatidis2024apob100andatherosclerosis pages 11-13): Dimitris Kounatidis, Natalia G. Vallianou, Aikaterini Poulaki, Angelos Evangelopoulos, Fotis Panagopoulos, Theodora Stratigou, Eleni Geladari, Irene Karampela, and Maria Dalamaga. Apob100 and atherosclerosis: what’s new in the 21st century? Metabolites, 14:123, Feb 2024. URL: https://doi.org/10.3390/metabo14020123, doi:10.3390/metabo14020123. This article has 64 citations.

3. (haradashiba2023guidelinesforthe pages 2-4): Mariko Harada-Shiba, Hidenori Arai, Hirotoshi Ohmura, Hiroaki Okazaki, Daisuke Sugiyama, Hayato Tada, Kazushige Dobashi, Kota Matsuki, Tetsuo Minamino, Shizuya Yamashita, and Koutaro Yokote. Guidelines for the diagnosis and treatment of adult familial hypercholesterolemia 2022. Journal of Atherosclerosis and Thrombosis, 30:558-586, May 2023. URL: https://doi.org/10.5551/jat.cr005, doi:10.5551/jat.cr005. This article has 108 citations and is from a peer-reviewed journal.

4. (siddiqi2026familialhypercholesterolemiastateoftheart pages 3-4): Ahmed Kamal Siddiqi, Kumail Mustafa Ali, Rameen Shahid, Shamna Haris, Anandita Kulkarni, Iliyan Mithani, Wilhelm Haverkamp, and Muhammad Shahzeb Khan. Familial hypercholesterolemia: state-of-the-art. Jun 2026. URL: https://doi.org/10.4081/cardio.2026.102, doi:10.4081/cardio.2026.102. This article has 0 citations.

5. (haradashiba2023guidelinesforthe pages 24-25): Mariko Harada-Shiba, Hidenori Arai, Hirotoshi Ohmura, Hiroaki Okazaki, Daisuke Sugiyama, Hayato Tada, Kazushige Dobashi, Kota Matsuki, Tetsuo Minamino, Shizuya Yamashita, and Koutaro Yokote. Guidelines for the diagnosis and treatment of adult familial hypercholesterolemia 2022. Journal of Atherosclerosis and Thrombosis, 30:558-586, May 2023. URL: https://doi.org/10.5551/jat.cr005, doi:10.5551/jat.cr005. This article has 108 citations and is from a peer-reviewed journal.

6. (haradashiba2023guidelinesforthe pages 8-11): Mariko Harada-Shiba, Hidenori Arai, Hirotoshi Ohmura, Hiroaki Okazaki, Daisuke Sugiyama, Hayato Tada, Kazushige Dobashi, Kota Matsuki, Tetsuo Minamino, Shizuya Yamashita, and Koutaro Yokote. Guidelines for the diagnosis and treatment of adult familial hypercholesterolemia 2022. Journal of Atherosclerosis and Thrombosis, 30:558-586, May 2023. URL: https://doi.org/10.5551/jat.cr005, doi:10.5551/jat.cr005. This article has 108 citations and is from a peer-reviewed journal.

7. (kounatidis2024apob100andatherosclerosis pages 4-5): Dimitris Kounatidis, Natalia G. Vallianou, Aikaterini Poulaki, Angelos Evangelopoulos, Fotis Panagopoulos, Theodora Stratigou, Eleni Geladari, Irene Karampela, and Maria Dalamaga. Apob100 and atherosclerosis: what’s new in the 21st century? Metabolites, 14:123, Feb 2024. URL: https://doi.org/10.3390/metabo14020123, doi:10.3390/metabo14020123. This article has 64 citations.

8. (kounatidis2024apob100andatherosclerosis pages 5-7): Dimitris Kounatidis, Natalia G. Vallianou, Aikaterini Poulaki, Angelos Evangelopoulos, Fotis Panagopoulos, Theodora Stratigou, Eleni Geladari, Irene Karampela, and Maria Dalamaga. Apob100 and atherosclerosis: what’s new in the 21st century? Metabolites, 14:123, Feb 2024. URL: https://doi.org/10.3390/metabo14020123, doi:10.3390/metabo14020123. This article has 64 citations.

9. (siddiqi2026familialhypercholesterolemiastateoftheart pages 1-2): Ahmed Kamal Siddiqi, Kumail Mustafa Ali, Rameen Shahid, Shamna Haris, Anandita Kulkarni, Iliyan Mithani, Wilhelm Haverkamp, and Muhammad Shahzeb Khan. Familial hypercholesterolemia: state-of-the-art. Jun 2026. URL: https://doi.org/10.4081/cardio.2026.102, doi:10.4081/cardio.2026.102. This article has 0 citations.

10. (faiz2012molecularpathologyof pages 4-5): Fathimath Faiz, Amanda J. Hooper, and Frank M. van Bockxmeer. Molecular pathology of familial hypercholesterolemia, related dyslipidemias and therapies beyond the statins. Critical Reviews in Clinical Laboratory Sciences, 49:1-17, Feb 2012. URL: https://doi.org/10.3109/10408363.2011.646942, doi:10.3109/10408363.2011.646942. This article has 38 citations and is from a peer-reviewed journal.

11. (fularski2024unveilingfamilialhypercholesterolemia—review pages 7-9): Piotr Fularski, Joanna Hajdys, Gabriela Majchrowicz, Magdalena Stabrawa, Ewelina Młynarska, Jacek Rysz, and Beata Franczyk. Unveiling familial hypercholesterolemia—review, cardiovascular complications, lipid-lowering treatment and its efficacy. International Journal of Molecular Sciences, 25:1637, Jan 2024. URL: https://doi.org/10.3390/ijms25031637, doi:10.3390/ijms25031637. This article has 30 citations.

12. (kamar2021thedigeniccausality pages 14-15): Amina Kamar, Athar Khalil, and Georges Nemer. The digenic causality in familial hypercholesterolemia: revising the genotype–phenotype correlations of the disease. Frontiers in Genetics, Jan 2021. URL: https://doi.org/10.3389/fgene.2020.572045, doi:10.3389/fgene.2020.572045. This article has 31 citations and is from a peer-reviewed journal.

13. (zadelaar2007mousemodelsfor pages 3-4): Susanne Zadelaar, Robert Kleemann, Lars Verschuren, Jitske de Vries-Van der Weij, José van der Hoorn, Hans M. Princen, and Teake Kooistra. Mouse models for atherosclerosis and pharmaceutical modifiers. Arteriosclerosis, thrombosis, and vascular biology, 27 8:1706-21, Aug 2007. URL: https://doi.org/10.1161/atvbaha.107.142570, doi:10.1161/atvbaha.107.142570. This article has 758 citations and is from a domain leading peer-reviewed journal.

14. (haradashiba2023guidelinesforthe pages 19-21): Mariko Harada-Shiba, Hidenori Arai, Hirotoshi Ohmura, Hiroaki Okazaki, Daisuke Sugiyama, Hayato Tada, Kazushige Dobashi, Kota Matsuki, Tetsuo Minamino, Shizuya Yamashita, and Koutaro Yokote. Guidelines for the diagnosis and treatment of adult familial hypercholesterolemia 2022. Journal of Atherosclerosis and Thrombosis, 30:558-586, May 2023. URL: https://doi.org/10.5551/jat.cr005, doi:10.5551/jat.cr005. This article has 108 citations and is from a peer-reviewed journal.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

• DOI:10.5551/jat.CR005](https://doi.org/10.5551/jat.CR005 (1 mention) - Identifier did not resolve to a record