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Classifications

Harrison's Part

ICIMD (Inherited Metabolic Disorders)

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Inheritance

1

Autosomal Dominant HP:0000006

Heterozygous PCSK9 gain-of-function variants segregate as an autosomal dominant trait, as first shown by linkage of the HCHOLA3 locus at 1p32 in French ADH pedigrees.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"APOB-, LDLR-, and PCSK9-related FH are inherited in an autosomal dominant manner."

GeneReviews states the mode of inheritance for PCSK9-related FH explicitly.

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Each child of an individual with a heterozygous pathogenic variant in APOB, LDLR, or PCSK9 has a 50% chance of inheriting the pathogenic variant and having FH."

GeneReviews states the 50% transmission risk for a heterozygous PCSK9 variant, the recurrence figure used in genetic counselling.

PMID:12730697 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH."

The founding report identifies PCSK9 as the third autosomal dominant hypercholesterolemia locus, establishing the disease entity curated here.

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Discussions and Knowledge Gaps

3

How do allele-specific intracellular and extracellular routes contribute to the human LDL phenotype?

KNOWLEDGE GAP OPEN adh3_allele_specific_routes

The extracellular pathway is experimentally sufficient, but no universal secretion requirement follows from the high-expression parabiosis experiment. S127R cells can show reduced secretion with impaired LDL uptake, and two S127R carriers had increased apoB production by tracer modelling. These observations support heterogeneous, potentially parallel contributions rather than a single obligatory biochemical sequence.

Show evidence (3 references)

PMID:26586530 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake"

A patient-derived hepatocyte-like line had reduced uptake despite lower secretion; nonisogenic donor background limits allele attribution.

PMID:15166014 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"PCSK9 mutation dramatically increased the production rate of apolipoprotein B100 (3-fold) compared with controls or LDL-R mutated subjects, related to direct overproduction of VLDL (3-fold), IDL (3-fold), and LDL (5-fold)."

Stable-isotope compartmental modelling in two S127R carriers supports increased apoB production, not a mechanism demonstrated in every allele.

PMID:17080197 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"Considered together, the available data now suggest that PCSK9 can function both extra- and intracellularly, but we do not know which pathway predominates under normal and/or pathologic conditions."

The authors distinguish pathway sufficiency from unresolved physiological predominance.

Do candidate PCSK9 untranslated-region variants cause clinically meaningful gain of function?

KNOWLEDGE GAP OPEN adh3_candidate_regulatory_variants

A 2025 selected FH study found altered HepG2 reporter activity for several PCSK9 untranslated-region variants. Increased reporter output for c.*950C>T does not measure endogenous protein, receptor turnover or LDL uptake, and segregation and miRNA mediation remain unresolved. These findings are kept as candidate regulatory observations rather than an established additional ADH3 subtype.

Show evidence (1 reference)

PMID:40225943 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The luciferase expression of the c.∗171C > T and c.∗950C > T variants was 18% and 41% higher than that of PCSK9 WT (p < 0.006 and p < 0.0018)"

The measured output is a HepG2 luciferase reporter carrying the untranslated region. This does not directly measure endogenous PCSK9 expression, LDLR turnover, LDL uptake, or segregation.

Does lifelong LDL-cholesterol elevation in familial hypercholesterolemia, and in PCSK9 gain-of-function carriers specifically, raise the risk of ischemic stroke and other cerebrovascular disease?

CONTROVERSY OPEN adh3_cerebrovascular_risk

Attached to

phenotypes# pathophysiology#Arterial Thrombus Formation

Stroke occurrence is documented in a selected PCSK9 carrier series (6/98 assessed; PMID:26374825 Table 1), and GeneReviews includes stroke among FH manifestations. Whether PCSK9-related FH confers excess stroke risk remains unresolved. Broader molecularly defined FH cohorts reported no excess cerebrovascular risk, unlike their coronary risk. These designs do not establish an allele-specific effect or absence of stroke; no population frequency is inferred from selected carriers.

Stroke occurrence is curated as a phenotype, with a PCSK9-carrier count from PMID:26374825 Table 1 and broader FH synthesis. Excess risk and an allele-specific causal route remain unresolved; occurrence alone does not establish either.

Show evidence (5 references)

PMID:30580708 SUPPORT DIRECT BACKGROUND Human Clinical

"Whether FH increases the risk of cerebrovascular disease, including ischemic stroke, is debated."

States the controversy directly, in the background of the study that then reports a null result - establishing that this is a live disagreement in the field and not an artefact of this entry's reading.

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as..."

GeneReviews keeps stroke on the FH manifestation list while calling it rarer than the coronary events. Cited for the listing, not as a claim of excess risk - the clause itself is closer to the registry findings than to a positive association.

PMID:30580708 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In a large cohort of genetically verified FH, risks of cerebrovascular disease and ischemic stroke were not increased compared with the total Norwegian population."

Supports the opposing position, in 3144 genetically verified FH patients linked to a nationwide hospitalisation database.

+ 2 more references

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Pathophysiology

21

Pathogenic PCSK9 Sequence Variant or Duplication

Pathogenic heterozygous sequence variants and rare whole-gene duplication cause PCSK9-related FH. Their biochemical effects differ; altered processing alone does not distinguish gain from loss of function. Candidate reporter variants are not equated with clinically established alleles.

PCSK9 hgnc:20001

Genetic context PCSK9 hgnc:20001 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Established heterozygous PCSK9 gain-of-function sequence variants or dosage increase from whole-gene duplication. Variant-specific biochemical activity must be distinguished from increased abundance of otherwise wild-type protein.

Downstream

Production of Disease-Associated PCSK9 The causal allele is expressed; dosage and sequence variants need not increase secretion in the same way.

Show evidence (2 references)

PMID:12730697 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH."

The founding report identifies PCSK9 as the third autosomal dominant hypercholesterolemia locus, establishing the disease entity curated here.

PMID:30269829 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We identified a whole-gene duplication of PCSK9 in 2 unrelated Canadian FH index cases; this PCSK9 CNV was also found to cosegregate with affected status in family members."

Whole-gene duplication provides a distinct dosage mechanism in two families.

Production of Disease-Associated PCSK9

Hepatic expression supplies variant PCSK9 or additional wild-type protein after gene duplication. This is the synthesis step targeted by RNA silencing. It does not assert increased synthesis or secretion for every allele: S127R hepatocyte-like cells secreted less protein despite impaired LDL uptake. Intracellular and extracellular actions need not share a secretion requirement.

hepatocyte CL:0000182

liver UBERON:0002107

Downstream

Increased Circulating PCSK9 Abundance The duplication branch can increase circulating abundance; processing and secretion intervene.

Reduced PCSK9 Association with LDL Particles Selected expressed variants impair LDL-particle association.

PCSK9 Binding to the LDL Receptor EGF-A Domain Secreted protein can bind LDLR; D374Y increases activity in the tested extracellular assays.

Increased Production of ApoB-Containing Lipoproteins S127R expression is associated with increased apoB production; the intervening human molecular mechanism remains unresolved.

Show evidence (2 references)

PMID:12730697 SUPPORT DIRECT BACKGROUND Human Clinical

"PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis."

The discovery study establishes hepatic expression; expression of disease-associated alleles is the upstream context, not evidence that all variants increase synthesis.

PMID:26586530 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake"

A patient-derived hepatocyte-like line had reduced uptake despite lower secretion; nonisogenic donor background limits allele attribution.

Increased Circulating PCSK9 Abundance

Whole-gene duplication can increase circulating PCSK9 abundance. A concentration near 5000 ng/mL was reported in one index case. This dosage branch must not be generalized to sequence variants with normal or reduced secretion.

Downstream

PCSK9 Binding to the LDL Receptor EGF-A Domain Greater extracellular exposure can increase receptor engagement; the one duplication measurement does not establish a quantitative dose-response.

Show evidence (1 reference)

PMID:30269829 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Features in affected individuals included severely elevated LDL cholesterol levels that were refractory to intensive statin therapy, pronounced clinical stigmata, premature cardiovascular events, and a plasma PCSK9 of approximately 5000 ng/mL in 1 index case."

Very high circulating PCSK9 was measured in one duplication index case; this is not a universal concentration in ADH3.

Reduced PCSK9 Association with LDL Particles

Selected prodomain and C-terminal variants impair PCSK9 association with LDL particles in vitro. LDL can inhibit extracellular receptor-depleting activity in the tested systems. How much this regulatory association contributes to each human phenotype remains unresolved; reduced particle binding is not increased binding to LDLR.

Downstream

Increased Lysosomal LDL Receptor Degradation Loss of LDL-particle inhibition may increase receptor-depleting activity, but human mediation is unresolved.

Show evidence (1 reference)

PMID:36187800 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Herein, we identify additional GOF mutations that inhibit LDL association, localized either within CM1 or a surface-exposed region in the PCSK9 prodomain."

Purified-protein and cell experiments establish impaired association with LDL particles for selected variants; this differs from LDL-receptor binding.

PCSK9 Binding to the LDL Receptor EGF-A Domain

Extracellular PCSK9 binds the LDL receptor EGF-A domain in calcium- and pH-dependent assays. D374Y has enhanced binding and receptor-depleting activity in the tested systems. This branch describes an experimentally supported extracellular route; neither universal secretion necessity nor equivalent affinity changes across all alleles are established.

hepatocyte CL:0000182

PCSK9 hgnc:20001

low-density lipoprotein particle receptor binding GO:0050750 ↑ INCREASED

liver UBERON:0002107

Downstream

Reduced LDL Receptor Recycling PCSK9 binding interferes with receptor recycling; the acid-dependent conformational explanation remains a model.

Show evidence (5 references)

PMID:17452316 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR."

Localises the PCSK9 binding site on the LDL receptor to the EGF-A repeat.

PMID:17452316 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Binding to EGF-A was calcium-dependent and increased dramatically with reduction in pH from 7 to 5.2."

Establishes the pH dependence that makes the complex persist through endocytosis rather than dissociating in the endosome.

PMID:17080197 SUPPORT DIRECT PRIMARY RESULT In Vitro

"This activity was approximately 10-fold greater for a gain-of-function mutant, PCSK9(D374Y), that causes hypercholesterolemia."

D374Y has greater LDLR-depleting activity in the tested exogenous-protein assay, not a uniform tenfold effect of all alleles.

+ 2 more references

Reduced LDL Receptor Recycling

PCSK9 association reduces the return of internalized LDL receptor to the cell surface. Interference with an acid-dependent receptor conformational change is a proposed explanation rather than a directly resolved molecular intermediate in the cited study.

hepatocyte CL:0000182

receptor recycling GO:0001881 ↓ DECREASED

liver UBERON:0002107

Downstream

Increased Lysosomal LDL Receptor Degradation Failure to recycle favors lysosomal receptor loss through the experimentally observed rerouting process.

Show evidence (1 reference)

PMID:17452316 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"These data are consistent with a model in which PCSK9 binding to EGF-A interferes with an acid-dependent conformational change required for receptor recycling."

The proposed conformational explanation is inferential; receptor redistribution is measured separately.

Increased Lysosomal LDL Receptor Degradation

PCSK9 promotes receptor delivery to lysosomes and loss of LDLR protein. PCSK9 is not asserted to proteolytically cleave LDLR itself. The cited route depends on cell context; uptake into mouse embryonic fibroblasts did not produce the same receptor loss.

hepatocyte CL:0000182

low-density lipoprotein particle receptor catabolic process GO:0032802 ↑ INCREASED

liver UBERON:0002107

Downstream

Reduced Hepatocyte Surface LDL Receptor Abundance Receptor degradation reduces the available surface pool.

Show evidence (2 references)

PMID:17452316 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The addition of PCSK9, but not heat-inactivated PCSK9, to the medium of cultured hepatocytes resulted in redistribution of the receptor from the plasma membrane to lysosomes."

Demonstrates the plasma-membrane-to-lysosome rerouting that defines this node.

PMID:16571601 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"The two gain-of-function mutations had a 23% decreased level of cell surface LDLR and a 38% decreased level of internalization of LDL as compared with WT-PCSK9."

Reduced surface LDLR in transfected HepG2 cells corroborates receptor loss but does not itself localize degradation to lysosomes.

Reduced Hepatocyte Surface LDL Receptor Abundance

Enhanced receptor loss decreases the surface LDLR pool. Surface abundance is a separate readout from lysosomal location, LDLR transcription and whole-body LDL clearance.

hepatocyte CL:0000182

liver UBERON:0002107

Downstream

Reduced Hepatic Clearance of Circulating LDL Particles Fewer surface receptors reduce receptor-mediated LDL uptake.

Show evidence (1 reference)

PMID:16571601 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The two gain-of-function mutations had a 23% decreased level of cell surface LDLR and a 38% decreased level of internalization of LDL as compared with WT-PCSK9."

Directly measures the reduced cell-surface LDLR level in HepG2 cells expressing the two gain-of-function alleles relative to wild-type PCSK9, which is this node's claim.

Reduced Hepatic Clearance of Circulating LDL Particles

Reduced receptor availability impairs hepatocyte LDL uptake. Patient-derived cell uptake and human isotope-derived LDL catabolic rates support related but distinct aspects of this route; neither assay alone measures all liver flux.

hepatocyte CL:0000182

low-density lipoprotein particle clearance GO:0034383 ↓ DECREASED

liver UBERON:0002107

Experimental models

Urine-derived iPSC hepatocyte-like cells from a PCSK9 S127R carrier (HLC-S127R) IPSC DERIVED MODEL Hepatocyte-like cells carrying the patient's S127R allele take up 71% less LDL than control cells, the cellular readout of this node.

Animal models

D374Y-PCSK9 transgenic Yucatan minipig Pig recapitulates Transgenic pigs show the receptor-depletion-to-clearance-failure step directly, with both hepatic LDL receptor level and LDL clearance measured in the same animals.

Downstream

Chronic Elevation of Plasma LDL Cholesterol Reduced removal contributes to circulating LDL accumulation.

Show evidence (2 references)

PMID:26586530 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake"

A patient-derived hepatocyte-like line had reduced uptake despite lower secretion; nonisogenic donor background limits allele attribution.

PMID:15166014 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"LDL fractional catabolic rate was slightly decreased (by 30%) compared with controls but still higher than LDL-R-mutated subjects."

This human kinetic comparison supports impaired removal in two S127R carriers, without conflating hepatic cell uptake with a whole-body rate.

Increased Production of ApoB-Containing Lipoproteins

A parallel contribution is supported by compartmental tracer kinetics in two S127R carriers and secretion experiments in rat hepatoma cells. The human model estimated increased apoB production in VLDL, IDL and LDL fractions. The route is allele- and assay-limited and is not placed downstream of secreted PCSK9 or LDLR loss as a proven dependency.

hepatocyte CL:0000182

liver UBERON:0002107

Downstream

Chronic Elevation of Plasma LDL Cholesterol Greater apoB-particle production can add to LDL burden; VLDL/IDL metabolism and clearance intervene.

Show evidence (2 references)

PMID:15166014 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"PCSK9 mutation dramatically increased the production rate of apolipoprotein B100 (3-fold) compared with controls or LDL-R mutated subjects, related to direct overproduction of VLDL (3-fold), IDL (3-fold), and LDL (5-fold)."

Stable-isotope compartmental modelling in two S127R carriers supports increased apoB production, not a mechanism demonstrated in every allele.

PMID:15772090 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"This suggests that the variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers."

The authors' own statement of the alternative mechanism this node represents.

Chronic Elevation of Plasma LDL Cholesterol

Increased LDL cholesterol exposure reflects impaired removal and, in some studied carriers, altered production of apoB lipoproteins. Severity varies across alleles and individuals. The British D374Y series reported total cholesterol, which is not substituted for LDL-C here.

cholesterol homeostasis GO:0042632 ↕ DYSREGULATED

Animal models

AAV-hPCSK9(D374Y) mouse Mouse recapitulates Liver expression of human PCSK9 D374Y produces long-term elevation of serum LDL in three mouse backgrounds.

Downstream

Extra-Arterial Cholesterol Deposition Prolonged cholesterol excess supports tissue deposition.

Subendothelial Retention of ApoB-Containing Lipoproteins Greater circulating particle exposure contributes to arterial retention.

Hypercholesterolemia This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.

Elevated LDL Cholesterol This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.

Show evidence (2 references)

PMID:12730697 SUPPORT DIRECT BACKGROUND Human Clinical

"Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels"

The disease is defined by increased LDL cholesterol, distinct from total-cholesterol measurements.

PMID:15166014 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"LDL fractional catabolic rate was slightly decreased (by 30%) compared with controls but still higher than LDL-R-mutated subjects."

This human kinetic comparison supports impaired removal in two S127R carriers, without conflating hepatic cell uptake with a whole-body rate.

Extra-Arterial Cholesterol Deposition

Sustained cholesterol excess can produce deposits in tendons, periocular skin and the corneal margin. The sites are distinct clinical expressions of cholesterol deposition and are variably present.

Downstream

Tendon Xanthomas This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.

Xanthelasma This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.

Corneal Arcus This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.

Show evidence (3 references)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels."

GeneReviews describes tendon xanthomas as an FH cholesterol-deposition sign.

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids."

GeneReviews describes xanthelasma as an FH cholesterol-deposition sign.

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH."

GeneReviews describes early corneal arcus as an FH cholesterol-deposition sign.

Subendothelial Retention of ApoB-Containing Lipoproteins

ApoB particles entering susceptible arterial regions can be retained in the intima. Endothelial state, particle modification and inflammation influence subsequent lesion development; retention alone does not imply an immediate symptomatic stenosis.

tunica intima UBERON:0002523

Downstream

Macrophage Foam Cell Formation Particle modification, immune-cell recruitment and uptake connect retained lipoproteins to foam cells.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Indeed, infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis."

General atherosclerosis synthesis supports the retention step downstream of the ADH3 LDL burden, not an allele-specific arterial experiment.

Macrophage Foam Cell Formation

Intimal macrophages accumulate lipoprotein-derived cholesterol and form foam cells. Modified or aggregated lipoproteins and several uptake pathways contribute; the process is not identical to LDLR-mediated hepatic clearance.

macrophage CL:0000235

foam cell differentiation GO:0090077 ↑ INCREASED

Downstream

Vascular Smooth Muscle Cell Proliferation Inflammatory mediators can stimulate smooth-muscle proliferation.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis."

General lipoprotein uptake biology supports macrophage foam-cell formation.

Vascular Smooth Muscle Cell Proliferation

Plaque-associated mediators can stimulate smooth-muscle-cell proliferation. This is a conserved atherosclerosis process inferred downstream of lipid accumulation, not a directly measured response to every PCSK9 allele.

smooth muscle cell CL:0000192

positive regulation of smooth muscle cell proliferation GO:0048661 ↑ INCREASED

Downstream

Arterial Extracellular Matrix Deposition Smooth-muscle expansion contributes to matrix production; this is not its only determinant.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Macrophage inflammatory chemoattractants stimulate infiltration and proliferation of smooth muscle cells."

General plaque biology supplies the smooth-muscle response; this is not a PCSK9-specific cell assay.

Arterial Extracellular Matrix Deposition

Smooth muscle cells produce collagen, proteoglycans and elastin within the developing plaque. A fibrous cap can stabilize the lesion; matrix accumulation is not equated with cap degradation.

extracellular matrix organization GO:0030198 ↑ INCREASED

Downstream

Atherosclerotic Plaque Formation Matrix adds to the accumulating cellular and lipid components of plaque.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets."

Matrix deposition contributes to fibrous plaque structure and can be stabilizing.

Atherosclerotic Plaque Formation

Lipid-laden cells and extracellular material form arterial plaques. General lesion biology connects the cellular branches to plaque structure; clinical PCSK9 series establish atherosclerotic disease without resolving every histological intermediate.

Animal models

AAV-hPCSK9(D374Y) mouse Mouse partially recapitulates High-fat-fed AAV-PCSK9(D374Y) mice develop aortic atherosclerotic lesions that progress to macrophage-infiltrated, fibrous-capped plaques.

D374Y-PCSK9 transgenic Yucatan minipig Pig recapitulates Transgenic pigs developed progressive atherosclerotic lesions measurable by imaging. The cited abstract does not establish diet independence or superiority to mouse models.

Downstream

Arterial Luminal Narrowing Plaque growth can narrow the lumen despite compensatory remodeling.

Fibrous Cap Thinning Unresolved inflammation and cell death can lead to cap matrix loss.

Premature Coronary Artery Disease This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Indeed, infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis."

General atherosclerosis synthesis supports the retention step downstream of the ADH3 LDL burden, not an allele-specific arterial experiment.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets."

Matrix deposition contributes to fibrous plaque structure and can be stabilizing.

PMID:16224054 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"

Quantifies the earlier onset of premature coronary artery disease in PCSK9 D374Y carriers relative to LDLR-mutation heterozygotes.

Arterial Luminal Narrowing

Enlarging plaques can narrow arteries and impair perfusion. Compensatory remodeling and nonobstructive plaques mean that plaque burden is not identical to stenosis. This chronic flow-limiting branch is separate from acute rupture and thrombosis.

Downstream

Angina Pectoris This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.

Peripheral Arterial Disease This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"As the intimal volume enlarges due to accumulating cells, there is vascular remodeling to lessen protrusion of the lesion into the lumen"

General synthesis explains why plaque growth and luminal obstruction are distinct.

PMID:27444203 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Coronary artery-related manifestations and peripheral artery disease were more prevalent in FH patients than in controls, but no significant differences were found for cerebrovascular events."

Broader FH clinical peripheral arterial disease supports a downstream vascular consequence, not direct measurement of luminal narrowing in PCSK9 carriers.

Fibrous Cap Thinning

In some advanced plaques, unresolved inflammation, matrix degradation and smooth-muscle-cell loss weaken the fibrous cap. These known intervening processes are summarized in the edge; no ADH3-specific histological progression series is claimed.

extracellular matrix organization GO:0030198 ↓ DECREASED

Downstream

Atherosclerotic Plaque Rupture Weakened caps are susceptible to rupture.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Unresolved inflammation results in formation of vulnerable plaques characterized by enhanced macrophage apoptosis and defective efferocytosis of apoptotic cells resulting in necrotic cell death leading to increased smooth muscle cell death, decreased extracellular matrix production, and collagen..."

Several known inflammatory and cell-death processes can weaken the cap; the edge does not assert that every plaque progresses to rupture.

Atherosclerotic Plaque Rupture

A weakened fibrous cap can rupture and expose thrombogenic plaque components. Rupture is one acute complication and is not required for stable angina, chronic peripheral stenosis or every atherothrombotic event.

Downstream

Arterial Thrombus Formation Exposure of plaque procoagulants activates platelet/coagulation responses.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Plaque rupture leads to acute exposure of procoagulant and prothrombotic factors from the necrotic core of the lesion to platelets and procoagulant factors in the lumen, thereby causing thrombus formation"

General plaque biology connects rupture to thrombosis, not every stable coronary symptom to rupture.

Arterial Thrombus Formation

Exposure of thrombogenic plaque material can trigger platelet and coagulation responses producing luminal thrombus. Acute coronary occlusion can cause infarction. The graph depicts the rupture pathway without excluding erosion or other routes.

Downstream

Myocardial Infarction This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/ SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Plaque rupture leads to acute exposure of procoagulant and prothrombotic factors from the necrotic core of the lesion to platelets and procoagulant factors in the lumen, thereby causing thrombus formation"

General plaque biology connects rupture to thrombosis, not every stable coronary symptom to rupture.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Cardiovascular 5

Premature Coronary Artery Disease Coronary artery atherosclerosis HP:0001677

Course: PROGRESSIVE

Show evidence (2 references)

PMID:16224054 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"

Quantifies the earlier onset of premature coronary artery disease in PCSK9 D374Y carriers relative to LDLR-mutation heterozygotes.

PMID:17452316 SUPPORT INDIRECT BACKGROUND Human Clinical

"Gain-of-function mutations in PCSK9 cause hypercholesterolemia and premature atherosclerosis, whereas loss-of-function mutations result in hypocholesterolemia and protection from heart disease."

Background summary of prior human genetics, used as secondary corroboration of the PCSK9-carrier cohort above; this sentence is not an experimental result of the cited in-vitro study.

Myocardial Infarction HP:0001658

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as..."

GeneReviews lists myocardial infarction among the premature cardiovascular events of FH, of which PCSK9-related FH is one molecular form.

Angina Pectoris HP:0001681

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as..."

GeneReviews lists angina among the premature cardiovascular events of FH.

Peripheral Arterial Disease Peripheral arterial stenosis HP:0004950

The 164-carrier source includes PCSK9/LDLR double heterozygotes, and outcome-specific denominators are incomplete. No frequency band is inferred.

Show evidence (2 references)

PMID:30085243 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Compared with individuals with unlikely FH, multivariable adjusted ORs (95% CIs) of PAD were 1.84 (1.70 to 2.00) in those with possible FH and 1.36 (1.00 to 1.84) in individuals with probable/definite FH."

Quantifies elevated peripheral arterial disease risk in a general-population FH cohort of 106,172 individuals.

PMID:27444203 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Coronary artery-related manifestations and peripheral artery disease were more prevalent in FH patients than in controls, but no significant differences were found for cerebrovascular events."

Independent replication in a molecularly defined FH registry, and the cleanest statement that the excess arterial disease in FH is coronary and peripheral rather than cerebrovascular.

Stroke HP:0001297

Deliberately left unconnected in the causal graph: the selected PCSK9 cohort documents occurrence, but does not establish stroke subtype or a PCSK9-specific atherothrombotic route. The FH registry findings do not show excess cerebrovascular risk. The 6/98 count comes from Table 1 of PMID:26374825, inspected in the original table image; it is not a population-frequency estimate.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK174884/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely."

GeneReviews includes stroke among FH manifestations; occurrence does not establish a PCSK9-specific excess relative to controls.

Eye 1

Corneal Arcus HP:0001084

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH."

GeneReviews describes early corneal arcus as an FH cholesterol-deposition sign.

Head and Neck 1

Xanthelasma HP:0001114

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids."

GeneReviews describes xanthelasma as an FH cholesterol-deposition sign.

Integument 1

Tendon Xanthomas Tendon xanthomatosis HP:0010874

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels."

GeneReviews describes tendon xanthomas as an FH cholesterol-deposition sign.

Metabolism 2

Hypercholesterolemia HP:0003124

Temporal: CHRONIC

Show evidence (2 references)

PMID:16224054 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications."

Documents severe hypercholesterolemia as the defining clinical phenotype of PCSK9 D374Y carriers.

PMID:19191301 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Several PCSK9 variants have been identified, some of them are gain-of-function mutations causing hypercholesterolemia by a reduction of low-density lipoprotein (LDL) receptor levels; while others are loss-of-function variants associated with a reduction of LDL-cholesterol (LDL-C) levels and a..."

Attributes hypercholesterolemia to the gain-of-function PCSK9 alleles.

Elevated LDL Cholesterol Increased LDL cholesterol concentration HP:0003141

Temporal: CHRONIC

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"A clinical diagnosis of FH can be established in a proband with characteristic clinical features and significantly elevated LDL-C levels (typically >190 mg/dL in adults and >160 mg/dL in children)."

GeneReviews sets the elevated-LDL-C threshold that defines the biochemical phenotype in PCSK9-related FH as in the other FH genes.

🧬

Genetic Associations

1

PCSK9

Gene: PCSK9 hgnc:20001 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (6 references)

PMID:12730697 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH."

Establishes PCSK9 as the causal gene at the HCHOLA3 locus.

PMID:16211558 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Segregation with hypercholesterolemia is incomplete in one pedigree. Type and severity of hyperlipidemia and of cardiovascular disease could vary among subjects from the same family."

Documents incomplete segregation and within-family variability in severity for PCSK9 alleles, the observation behind the expressivity statement in this entry's notes.

PMID:15358785 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The S127R and D374Y mutations result in approximately 50-60% and > or =98% decrease in zymogen processing, respectively."

Supports the allele-level heterogeneity noted above: S127R and D374Y differ markedly from each other in their effect on zymogen processing.

+ 3 more references

Variants (5)

PCSK9 p.Ser127Arg Pathogenic

Gene: PCSK9 hgnc:20001 missense

One of the two founding ADH3 alleles. Markedly impairs autocatalytic zymogen processing and reduces cell-surface LDL receptor in patient lymphoblasts.

Show evidence (1 reference)

PMID:15358785 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The cell surface LDL receptor (LDLR) levels are reduced by 35% in lymphoblasts of S127R patients."

Functional consequence of S127R measured in patient-derived cells.

PCSK9 p.Phe216Leu Pathogenic

Gene: PCSK9 hgnc:20001 missense

The second founding ADH3 allele, reported alongside S127R in the original French pedigrees. Zymogen processing is normal, so its gain of function is not explained by the processing defect seen with S127R.

Show evidence (1 reference)

PMID:15358785 SUPPORT DIRECT PRIMARY RESULT In Vitro

"F216L, and R218S natural mutants resulted in normal zymogen processing."

Documents that F216L retains normal zymogen processing.

PCSK9 p.Asp374Tyr Pathogenic

Gene: PCSK9 hgnc:20001 missense

D374Y increases LDLR-depleting activity in the tested extracellular-protein assays. Small selected British families had unusually severe cholesterol elevation and early coronary disease; the clinical difference is not generalized to every PCSK9 variant.

Show evidence (2 references)

PMID:17080197 SUPPORT DIRECT PRIMARY RESULT In Vitro

"This activity was approximately 10-fold greater for a gain-of-function mutant, PCSK9(D374Y), that causes hypercholesterolemia."

Quantifies the increased receptor-degrading potency of D374Y.

PMID:15772090 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We have identified the D374Y mutant of PCSK9 in three FH families of English origin; all 12 affected individuals have unusually severe hypercholesterolaemia and require more stringent treatment than typical FH patients, who are heterozygous for defects in the LDL receptor."

Documents the severe clinical phenotype of D374Y carriers.

PCSK9 p.Arg496Trp Pathogenic

Gene: PCSK9 hgnc:20001 missense

R496W was reported as a C-terminal gain-of-function variant with impaired LDL-particle association in prior in-vitro work summarized by the 2022 study. The contribution of this association to human receptor turnover remains inferred.

Show evidence (2 references)

PMID:36187800 SUPPORT DIRECT BACKGROUND In Vitro

"We previously reported that an R496W GOF mutation in a region of PCSK9 known as cysteine-histidine-rich domain module 1 (CM1) prevents LDL binding in vitro"

Identifies R496W as a CM1-domain gain-of-function allele acting through loss of LDL binding.

PMID:36187800 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Herein, we identify additional GOF mutations that inhibit LDL association, localized either within CM1 or a surface-exposed region in the PCSK9 prodomain."

Establishes loss of LDL association as a shared mechanism spanning two distinct PCSK9 domains, which is what makes this a separate variant class from S127R/F216L/D374Y as classically described.

PCSK9 whole-gene duplication Pathogenic

Gene: PCSK9 hgnc:20001 duplication

Rare copy-number mechanism reported in two unrelated index cases with cosegregation in affected relatives. Very high plasma PCSK9 was measured in one index case; treatment resistance is not a universal prediction.

Show evidence (2 references)

PMID:30269829 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We identified a whole-gene duplication of PCSK9 in 2 unrelated Canadian FH index cases; this PCSK9 CNV was also found to cosegregate with affected status in family members."

Whole-gene duplication provides a distinct dosage mechanism in two families.

PMID:30269829 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Features in affected individuals included severely elevated LDL cholesterol levels that were refractory to intensive statin therapy, pronounced clinical stigmata, premature cardiovascular events, and a plasma PCSK9 of approximately 5000 ng/mL in 1 index case."

Very high circulating PCSK9 was measured in one duplication index case; this is not a universal concentration in ADH3.

💊

Medical Actions

10

Evolocumab

Action: Pharmacotherapy NCIT:C15986

Agent: evolocumab NCIT:C174672

Platform: Monoclonal antibody

Fully human monoclonal antibody that binds circulating PCSK9 and prevents it from engaging the hepatocyte LDL receptor, restoring receptor recycling and hepatic LDL clearance. In heterozygous familial hypercholesterolemia it lowers LDL cholesterol by approximately 60% on top of statin therapy, and in established atherosclerotic cardiovascular disease it reduces cardiovascular events. It is the mechanistically direct therapy for ADH3: the drug target is PCSK9 itself.

Mechanism Target:

INHIBITS PCSK9 Binding to the LDL Receptor EGF-A Domain — Antibody neutralisation of circulating PCSK9 blocks the EGF-A engagement that initiates receptor degradation.

Show evidence (1 reference)

PMID:28304224 SUPPORT INDIRECT BACKGROUND Human Clinical

"Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%."

States the drug's target and its effect on the LDL cholesterol output of this pathway. This is the trial's background statement of the established drug mechanism, cited for the drug-target identity; the trial's own outcome result is cited separately on the treatment.

Show evidence (2 references)

PMID:25282519 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo."

Randomised evidence of efficacy in heterozygous familial hypercholesterolemia, the clinical setting of ADH3.

PMID:28304224 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events."

Outcome evidence that PCSK9 inhibition reduces cardiovascular events, the clinical endpoint this disease threatens.

Alirocumab

Action: Pharmacotherapy NCIT:C15986

Agent: alirocumab NCIT:C174849

Platform: Monoclonal antibody

Monoclonal antibody against circulating PCSK9. A randomized placebo-phase study in 13 adults carrying D374Y, S127R, L108R or R218S demonstrated short-term LDL-C lowering on background therapy. Broader post-acute-coronary-syndrome trials support cardiovascular-event reduction in a different population.

Mechanism Target:

INHIBITS PCSK9 Binding to the LDL Receptor EGF-A Domain — Antibody binding to circulating PCSK9 prevents the receptor engagement step.

Show evidence (1 reference)

PMID:30403574 SUPPORT INDIRECT BACKGROUND Human Clinical

"We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy."

Identifies alirocumab's molecular target as PCSK9. This is the trial's aim sentence rather than a result; it is cited for the drug-target identity only, with the trial's outcome result cited separately on the treatment itself.

MODULATES Atherosclerotic Plaque Formation — ARCHITECT observed reduced CT plaque burden and shifts in CT-derived composition over 78 weeks on added alirocumab. The single-arm study does not isolate drug causality, demonstrate histological cap restoration, or establish a PCSK9-carrier-specific response.

Show evidence (1 reference)

PMID:37009731 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"an increase in the proportion of calcified (+0.3%; P<0.001) and mainly fibrous (+6.2%; P<0.001) plaque, accompanied by a decrease in the percentage of fibro-fatty (-3.9%; P<0.001) and necrotic plaque (-0.6%; P<0.001)"

Within-person changes in CT-derived tissue categories in an uncontrolled FH study; indirect evidence for plaque modification, not direct histological measurement.

Show evidence (3 references)

PMID:30403574 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo."

Randomised cardiovascular-outcome evidence for PCSK9 antibody therapy, but in patients after acute coronary syndrome rather than in PCSK9 gain-of-function carriers; applying it to this entry is an extrapolation across populations.

PMID:37009731 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Treatment with alirocumab in addition to high-intensity statin therapy resulted in significant regression of coronary plaque burden and plaque stabilization on coronary computed tomographic angiography over 78 weeks"

The FH-specific alirocumab trial, in a molecularly determined cohort - closer to this entry's population than the post-acute-coronary-syndrome outcome trial, though still not PCSK9-stratified.

PMID:26374825 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline and 53.7% compared with control PCSK9 GOF mutation patients treated with placebo for 2 weeks (P=0.0009; primary end point)."

The primary randomized contrast was a 53.7-percentage-point difference at week 2 in 13 adults carrying four PCSK9 variants; the 62.5% figure is a within-group change. This was not an event-outcome trial.

Inclisiran

Action: Pharmacotherapy NCIT:C15986

Agent: inclisiran NCIT:C170062

Platform: siRNA RNAi knockdown Delivery: Ligand conjugate Targeting: GalNAc

RNA target: PCSK9 hgnc:20001 PCSK9 mRNA

Dosing: once every 6 months every 182.5 days

A small interfering RNA that silences PCSK9 messenger RNA in the hepatocyte, suppressing synthesis of the protein rather than neutralising it after secretion. Given twice yearly after loading. In heterozygous familial hypercholesterolemia it lowered LDL cholesterol by roughly 40% versus baseline (about 48 percentage points versus placebo), with reductions reported across FH genotypes.

Mechanism Target:

INHIBITS Production of Disease-Associated PCSK9 — RNA interference suppresses hepatic PCSK9 synthesis. The cited LDL-C trial does not establish that an apoB-production mechanism was specifically reversed in PCSK9 carriers.

Show evidence (1 reference)

PMID:32197277 SUPPORT INDIRECT BACKGROUND Human Clinical

"In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia."

States inclisiran's mechanism as inhibition of hepatic PCSK9 synthesis. The sentence reports the earlier phase 2 result rather than this trial's own finding, and is cited for the mechanism only; ORION-9's own LDL-C result is cited separately on the treatment.

Show evidence (2 references)

PMID:32197277 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile."

Randomised evidence of efficacy in heterozygous familial hypercholesterolemia.

PMID:32197277 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia."

Reports that the LDL-lowering effect was seen across FH genotypes, the closest available evidence that it applies to PCSK9-gene carriers.

Statin Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: atorvastatin CHEBI:39548 simvastatin NCIT:C29454

Platform: Small molecule

HMG-CoA reductase inhibition is foundational FH therapy. Response varies: selected D374Y carriers remained severely hypercholesterolemic despite treatment, while a small S127R series had substantial LDL-C lowering. These observations do not establish universal PCSK9-related statin resistance.

Mechanism Target:

RESTORES Reduced Hepatic Clearance of Circulating LDL Particles — Statins promote LDL removal through the established hepatic cholesterol/LDLR response. The D374Y family series measured serum cholesterol rather than hepatic clearance flux, so it provides indirect support for this mechanism.

Show evidence (1 reference)

PMID:16224054 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"had higher pretreatment serum cholesterol levels (13.6+/-2.9 versus 9.6+/-1.6 mmol/L; P=0.004) that remained higher during treatment with simvastatin (10.1+/-3.0 versus 6.5+/-0.9 mmol/L; P=0.006)"

Treatment-associated total-cholesterol change in selected D374Y families, not a direct assay of hepatic LDL clearance.

Show evidence (4 references)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Adults: pharmacotherapy (statins with additional medications as needed) to reduce lipid levels; referral to a lipid specialist if necessary to reduce LDL-C levels"

GeneReviews states statins as first-line pharmacotherapy in FH.

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Children: referral to a lipid specialist; diet and lifestyle modifications; statins can be used in children starting around age eight years."

GeneReviews sets the paediatric starting point for statin therapy, which matters here because the LDL burden is present from birth.

url:https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-removal-strongest-warning-against-using-cholesterol-lowering-statins-during-pregnancy SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Health care professionals should discontinue statin therapy in most pregnant patients. Alternatively, health care professionals should consider the ongoing therapeutic needs of the individual patient"

FDA guidance replaces an absolute prohibition with usual discontinuation and individualized assessment for exceptional high-risk patients.

+ 1 more reference

Ezetimibe

Action: Pharmacotherapy NCIT:C15986

Agent: ezetimibe CHEBI:49040

Platform: Small molecule

Intestinal cholesterol-absorption inhibitor used with statins or other agents to achieve individualized FH LDL-C goals. Intensification depends on baseline LDL-C, ASCVD risk, tolerance and response; every patient need not follow a rigid sequence.

Mechanism Target:

MODULATES Chronic Elevation of Plasma LDL Cholesterol — Reduced intestinal cholesterol absorption lowers the plasma LDL burden downstream of the PCSK9 lesion rather than correcting it.

Show evidence (1 reference)

PMID:37322181 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"PCSK9-targeted therapy (monoclonal antibodies or a small interfering RNA (inclisiran)) should be added if LDL-cholesterol goals are not achieved with diet, maximally tolerated statins, ezetimibe, bempedoic acid and other adjunctive therapies"

FH-wide guidance supports ezetimibe as part of LDL-lowering care; it is not an isolated drug-mechanism experiment.

Bempedoic Acid

Action: Pharmacotherapy NCIT:C15986

Agent: bempedoic acid CHEBI:149601

Platform: Small molecule

ATP citrate lyase inhibitor used as an additional LDL-lowering option, including in statin intolerance. CLEAR Outcomes supports event reduction in statin-intolerant high-risk patients, without a PCSK9-specific estimate.

Mechanism Target:

MODULATES Chronic Elevation of Plasma LDL Cholesterol — ATP citrate lyase inhibition reduces hepatic cholesterol synthesis and so lowers the circulating LDL burden downstream of the PCSK9 lesion, without acting on PCSK9 or on LDL receptor degradation.

Show evidence (1 reference)

PMID:36876740 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events"

States the molecular target and the LDL-lowering effect that place this agent on the plasma-LDL node rather than on the PCSK9 node.

Show evidence (1 reference)

PMID:36876740 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004)"

CLEAR Outcomes provides the cardiovascular outcome evidence that justifies curating bempedoic acid alongside ezetimibe and apheresis rather than as an investigational option.

Colesevelam

Action: Pharmacotherapy NCIT:C15986

Agent: colesevelam CHEBI:59594

Platform: Other

Nonabsorbed bile acid sequestrant used as an adjunct for LDL-C reduction. It can be considered in pregnancy under specialist care; limited pregnancy experience and potential effects on fat-soluble vitamin absorption require consideration.

Mechanism Target:

MODULATES Chronic Elevation of Plasma LDL Cholesterol — Adds LDL-C lowering on top of maximally tolerated statin plus ezetimibe, reducing the plasma LDL burden downstream of the PCSK9 lesion without correcting it.

Show evidence (1 reference)

PMID:23916045 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"In the study in adults with refractory FH, the addition of colesevelam to a maximally tolerated regimen of a statin plus ezetimibe provided a significantly greater reduction from baseline in LDL-C levels compared with placebo."

Establishes an incremental LDL-C reduction on top of the statin plus ezetimibe background this entry already curates.

Show evidence (3 references)

PMID:23916045 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"The bile acid sequestrant colesevelam is indicated to reduce elevated LDL-C levels in adults with primary hyperlipidemia and in boys and postmenarchal girls (aged 10-17 years) with heterozygous FH."

States the licensed indications: primary hyperlipidemia in adults, and heterozygous FH in the paediatric population this entry's progression section starts from.

PMID:38338916 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Bile acid sequestrants bind the bile acids and prevent the reabsorption of cholesterol into the blood. Thus, they increase the metabolism of cholesterol into bile acids and intensify the synthesis of LDLR, which reduces the levels of LDL in the blood"

Sources the class mechanism stated in this treatment's description - the LDL receptor upregulation that makes a sequestrant relevant to a receptor-degradation disease.

PMID:37322181 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Bile acid sequestrants should be considered to treat hypercholesterolaemia, ideally 3 months before a planned pregnancy, as well as during pregnancy and lactation;"

FH guidance permits consideration of this class; the recommendation is not a randomized pregnancy-safety result.

LDL Apheresis

Action: therapeutic apheresis Ontology label: Therapeutic Apheresis NCIT:C173286

Platform: Device

Specialist extracorporeal removal of apoB-containing lipoproteins for selected severe FH, particularly progressive ASCVD despite intensive combination treatment. The British D374Y series documents use of apheresis/partial ileal bypass among two intensively treated carriers; the abstract does not resolve each individual procedure.

Mechanism Target:

MODULATES Chronic Elevation of Plasma LDL Cholesterol — Apheresis removes circulating LDL directly, bypassing the failed hepatic receptor route rather than repairing it.

Show evidence (1 reference)

PMID:16224054 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"or current lipid-lowering therapy, including LDL apheresis and partial ileal bypass in 2 PCSK9 patients (7.0+/-1.6 versus 5.4+/-1.0 mmol/L; P=0.001)"

The family report documents intensive therapy including apheresis and partial ileal bypass in two patients; procedure-level allocation is not inferred from the abstract.

Show evidence (2 references)

PMID:16224054 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications."

Supports escalation to aggressive lipid-lowering management in this genotype. The sentence does not name apheresis; apheresis is one of the most intensive options, so its application here is an inference.

PMID:37322181 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Lipoprotein apheresis should be undertaken in adults with phenotypic HeFH and progressive ASCVD who do not achieve LDL-cholesterol goals despite combined treatment with a high-potency statin, ezetimibe and a PCSK9 inhibitor,"

FH-wide criteria support specialist escalation for selected refractory disease.

Cardiovascular Risk Factor Modification

Action: lifestyle and risk-factor therapy Ontology label: Lifestyle Therapy NCIT:C15900

Platform: Behavioral / lifestyle

Non-pharmacological management: smoking cessation, reduced saturated and trans fat intake, increased soluble fibre, physical activity, weight control, and treatment of hypertension and diabetes. These do not address the PCSK9 lesion but reduce the atherogenic burden it acts upon.

Mechanism Target:

MODULATES Subendothelial Retention of ApoB-Containing Lipoproteins — Lifestyle and risk-factor care can reduce cardiovascular risk through several lipid and vascular processes. The GeneReviews recommendation does not isolate a measured effect on intimal retention.

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."

GeneReviews names the modifiable exposures that aggravate atherosclerotic risk in FH.

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Prevention of primary manifestations: Heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day); increased physical activity; no smoking."

GeneReviews management recommendation for primary prevention in FH.

Age- and Risk-Adapted Pediatric Lipid-Lowering Care

Treatment decisions use repeated lipid measurements, age, family history and other risks. IAS 2023 guidance recommends offering medication at ages 8–10 for persistent LDL-C above 190 mg/dL, with lower thresholds considered when additional risk is present. Drug selection follows local pediatric approvals and specialist assessment; these are broader FH recommendations, not PCSK9-specific trial thresholds.

Show evidence (2 references)

PMID:37322181 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Pharmacological treatment should be offered at age 8–10 years with an LDL-cholesterol concentration >4.9 mmol/l (>190 mg/dl), recorded on two occasions with a fasting lipid profile"

Age and repeat LDL-C measurements qualify the pediatric FH recommendation.

PMID:37322181 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Use of a PCSK9 inhibitor may be considered according to clinical indications and regulatory approvals, with the caveat of limited evidence of long-term safety in children and adolescents"

Pediatric use remains conditional on indication and approval; no uniform age label is inferred.

🌍

Environmental Factors

3

High Saturated and Trans Fat Intake

High saturated and trans fat intake can add to LDL exposure. Dietary improvement complements pharmacological treatment in FH.

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Prevention of primary manifestations: Heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day); increased physical activity; no smoking."

The corresponding dietary recommendation, establishing this as a modifiable exposure in FH management.

Mechanism Target:

EXACERBATES Chronic Elevation of Plasma LDL Cholesterol — Dietary fat intake adds to the circulating LDL burden already produced by the inherited receptor-degradation defect.

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."

GeneReviews lists high saturated and trans fat intake among the exposures to avoid in FH, acting at the lipid level itself.

Tobacco Smoking

Smoking is a modifiable cardiovascular risk factor in FH. Its contribution is not assumed to be independent of every lipid measure.

Show evidence (1 reference)

PMID:34433300 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The FH-Risk-Score incorporates 7 clinical variables: sex, age, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hypertension, smoking, and lipoprotein (a) (Lp(a)) with a Harrell C-index for 10-year ASCVD event of 0.75"

Smoking is retained as one of only seven predictors in a 10-year ASCVD risk score derived prospectively in 3881 heterozygous FH patients. That is the quantitative basis for curating smoking as a modifiable exposure acting on the vascular arm rather than on the lipid node.

Mechanism Target:

EXACERBATES Subendothelial Retention of ApoB-Containing Lipoproteins — Smoking can aggravate vascular risk; GeneReviews supports avoidance but does not experimentally isolate the arterial-retention step in PCSK9 carriers.

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."

GeneReviews lists smoking first among the exposures to avoid in FH.

Sedentary Lifestyle

Physical inactivity is a modifiable FH risk factor. An observational composite of diet, exercise, smoking and weight cannot estimate the effect of changing exercise alone.

Show evidence (1 reference)

PMID:35294538 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Among carriers, a favorable lifestyle conferred 86% lower risk of CAD compared with an unfavorable lifestyle (hazard ratio, 0.14 [95% CI, 0.04-0.41])."

An observational association with a composite healthy-lifestyle score; not an isolated exercise intervention or proof that inactivity alone accounts for this effect.

Mechanism Target:

EXACERBATES Subendothelial Retention of ApoB-Containing Lipoproteins — Physical activity is part of cardiovascular prevention. The specific intermediate connecting inactivity to arterial retention is inferred from general vascular biology.

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."

GeneReviews lists sedentary lifestyle among the exposures to avoid in FH.

🔬

Biochemical Markers

2

Plasma LDL Cholesterol

Show evidence (1 reference)

PMID:12730697 SUPPORT DIRECT BACKGROUND Human Clinical

"Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels"

The disease is defined by increased LDL cholesterol, distinct from total-cholesterol measurements.

Plasma Lipoprotein(a)

Show evidence (3 references)

PMID:27185354 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Our findings suggest that all individuals with familial hypercholesterolaemia should have their lipoprotein(a) measured in order to identify those with the highest concentrations, and as a result, the highest risk of myocardial infarction."

Establishes measurement of lipoprotein(a) as part of the FH workup and its role as a risk modifier.

PMID:27185354 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"High lipoprotein(a) cholesterol accounted for a quarter of all individuals diagnosed with clinical familial hypercholesterolaemia"

Supports the confounder role noted above - lipoprotein(a) cholesterol inflates the clinically measured LDL-C used by the phenotypic criteria.

PMID:34433300 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The FH-Risk-Score incorporates 7 clinical variables: sex, age, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hypertension, smoking, and lipoprotein (a) (Lp(a)) with a Harrell C-index for 10-year ASCVD event of 0.75"

Places lipoprotein(a) among the prognostic variables of a validated FH risk score.

🔬

Diagnosis

4

Molecular Genetic Testing of PCSK9

A pathogenic or likely pathogenic PCSK9 gain-of-function variant, or a pathogenic duplication, establishes PCSK9-related FH in the appropriate clinical context. A variant of uncertain significance or a protective loss-of-function allele does not. An FH panel should assess relevant sequence and copy-number variants, with familial testing when a causal finding is established.

Show evidence (3 references)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."

GeneReviews states that molecular identification of a gain-of-function PCSK9 variant establishes the molecular diagnosis.

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Genetic testing is the preferred method for clarifying the diagnosis in at-risk family members, when possible."

GeneReviews states that molecular testing is the preferred route for cascade clarification in relatives, the claim made in this entry's description.

PMID:30269829 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We identified a whole-gene duplication of PCSK9 in 2 unrelated Canadian FH index cases; this PCSK9 CNV was also found to cosegregate with affected status in family members."

Whole-gene duplication provides a distinct dosage mechanism in two families.

Lipid Surveillance from Early Childhood

Early lipid assessment and family cascade screening identify affected children before clinical vascular disease. Follow-up evaluates LDL-C, treatment response and modifiable cardiovascular risks; the schedule and treatment thresholds depend on age and clinical context.

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Surveillance: Monitor lipid levels from age two years; consider noninvasive imaging modalities in adults; identify modifiable risk factors (e.g., smoking, sedentary behavior, hypertension, diabetes, obesity)."

GeneReviews surveillance recommendation for FH.

Clinical Diagnostic Criteria for Familial Hypercholesterolemia

DLCN, Simon Broome and MEDPED are FH-wide clinical frameworks with different criteria. DLCN incorporates LDL-C, clinical findings and history; MEDPED uses age- and family-relationship-specific cholesterol thresholds rather than a xanthoma score. They do not establish PCSK9 causation, and adult proband scores should not be substituted for pediatric or familial cascade criteria.

Clinical and molecular assessment are complementary. Elevated Lp(a), treatment, age and referral selection can affect phenotypic classification.

Show evidence (2 references)

PMID:29408959 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Prediction of a mutation for the DLCN and SB definite and MEDPED criteria (ORs 9.4, 11.7, and 10.5, respectively) was higher than with the AHA criteria (OR 4.67)."

In 885 lipid-clinic referrals, the three frameworks differed in how well they predicted an FH-causing mutation in any FH gene. This supports treating them as distinct FH-wide criteria, not as tests for PCSK9 causation. The abstract does not list each framework's components.

PMID:29408959 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The DLCN, SB, and MEDPED criteria are valid predictors of an FH-causing mutation in patients referred to a lipid clinic, but concordance between these phenotypic criteria is only moderate."

Supports the criteria as valid predictors while recording their limitation in the same sentence - concordance between them is only moderate - which is why this entry keeps molecular testing as the diagnostic step.

Assessment for Secondary Hypercholesterolemia

Evaluate acquired causes of elevated LDL-C, including hypothyroidism, kidney disease, obstructive liver disease and medications, before attributing the entire phenotype to inherited FH.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK174884/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Hypercholesterolemia secondary to acquired conditions including obesity, diabetes mellitus, obstructive liver disease, hypothyroidism, drugs (e.g., steroids), or kidney disease can also be associated with laboratory findings similar to those of FH"

GeneReviews identifies important secondary causes that can mimic or modify FH.

🩻

Imaging Findings

2

Coronary atherosclerotic plaque burden on coronary CT angiography

Coronary CT angiography measures plaque burden and tissue categories in broader FH cohorts. The cited observational study relates plaque burden to subsequent events but does not provide a PCSK9-specific estimate.

Ct Multifocal

Coronary artery atherosclerosis HP:0001677 coronary artery UBERON:0001621

General FH imaging evidence. ARCHITECT treatment-associated CT changes are described under alirocumab; CT tissue categories are not histological cap measurements.

Show evidence (2 references)

PMID:33261814 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Median plaque burden was 25.0% (19.0-29.0), non-calcified plaque burden 22.83% (17.94-26.88), calcified plaque-burden 1.12% (0.31-2.86) and CCS 8.9 (0-93)."

Quantifies the coronary plaque burden measurable by CT angiography in 259 asymptomatic molecularly diagnosed FH patients.

PMID:33261814 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Plaque burden was significantly related to event-free survival during follow-up (HR:1.11; 95%CI:1.05-1.18; p < 0.001)."

Establishes that the imaging measurement is prognostic, not only descriptive, over 3.9 years of follow-up.

Coronary artery calcification

Coronary calcium is an imaging component of atherosclerotic burden. It does not establish PCSK9 causation or directly measure all noncalcified plaque.

Ct

Coronary artery calcification HP:0001717 coronary artery UBERON:0001621

FH-wide finding; no PCSK9-specific distribution is inferred. IAS guidance advises against using coronary calcium scores to monitor lipid-lowering treatment effectiveness.

Show evidence (2 references)

PMID:33261814 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Five-year risk was independently related to plaque burden, non-calcified plaque burden, calcified plaque burden and coronary calcium score"

Shows calcified plaque burden and coronary calcium score are each independently related to estimated cardiovascular risk in FH.

PMID:37322181 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"CACS should not be used to monitor the effectiveness of cholesterol-lowering treatment"

Calcium scores have a different role from monitoring treatment response.

📈

Progression

3

Presymptomatic (birth to childhood)

LDL cholesterol elevation can be recognized in childhood, whereas visible cholesterol deposits and clinical atherosclerotic events are variably expressed later. Treatment and allele-specific severity modify the course.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK174884/ SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Individuals with FH have elevated LDL-C levels starting soon after birth."

FH-wide natural history supports early biochemical expression, without assigning a fixed age at which a cholesterol threshold necessarily causes coronary disease.

Cholesterol deposition and clinical presentation (young adulthood)

In the long-term British D374Y series, carriers presented about a decade earlier than severe LDLR-mutation heterozygotes, at a mean age of about 21 years, with markedly higher pretreatment cholesterol.

Show evidence (1 reference)

PMID:16224054 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8+/-14.7 versus 30.2+/-15.7 years; P=0.003)"

Quantifies the age at presentation in a PCSK9 gain-of-function cohort.

Premature atherosclerotic cardiovascular disease (adulthood)

In the selected British D374Y families, clinical coronary disease appeared earlier than in the comparator LDLR group. This small family-based estimate does not specify onset for all PCSK9 alleles.

Show evidence (1 reference)

PMID:16224054 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"

Quantifies the age at onset of premature coronary disease in this genotype.

📊

Prevalence

1

Molecularly characterised familial hypercholesterolemia cohorts

Unknown Unknown

No population prevalence specific to PCSK9-related FH is established by the cited selected cohorts. The proportion of PCSK9 findings among LDLR/APOB-negative referrals is not an upper bound on the contribution to unselected FH. GeneReviews describes PCSK9 as accounting for less than 1% of FH, with ascertainment and variant interpretation affecting the estimate.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Hypercholesterolemia 3:

Familial hypercholesterolemia due to LDLR variants

Overlapping Features The most common dominant FH form. Clinically indistinguishable from ADH3 at the bedside; distinguished by molecular testing. Mechanistically the receptor itself is defective, rather than being degraded prematurely by a normal-but-overactive regulator.

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."

GeneReviews lists LDLR alongside PCSK9 as an alternative molecular cause of the same clinical picture, which is what makes it a differential.

Familial defective apolipoprotein B-100 (APOB)

Overlapping Features Dominant FH caused by APOB variants that impair binding of LDL to the LDL receptor. The receptor and its regulation are intact; the ligand is defective.

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."

GeneReviews specifies the APOB mechanism (impaired binding of LDL-C to the receptor) that distinguishes it from PCSK9 gain of function.

Autosomal recessive hypercholesterolemia (LDLRAP1)

Overlapping Features Caused by biallelic LDLRAP1 variants affecting the adaptor required for receptor endocytosis; recessive rather than dominant inheritance.

Show evidence (1 reference)

PMID:24404629 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"LDLRAP1-related FH is caused by biallelic pathogenic variants and is inherited in an autosomal recessive manner."

GeneReviews states the recessive inheritance that separates this entity from dominant ADH3.

Polygenic hypercholesterolemia

Overlapping Features Elevated LDL cholesterol from the aggregate effect of many common small-effect alleles rather than a single dominant variant; the commonest explanation for a clinical FH phenotype without an identified monogenic cause.

Sterol storage disorders presenting with tendon xanthomas

Overlapping Features Sitosterolemia (ABCG5/ABCG8) and cerebrotendinous xanthomatosis (CYP27A1) both produce tendon xanthomas indistinguishable on inspection from those of FH, and lysosomal acid lipase deficiency likewise causes dyslipidaemia with lipid deposition. They are separated from ADH3 not by the xanthomas but by the sterol profile and by inheritance - both are recessive, and in cerebrotendinous xanthomatosis cholesterol may be normal while cholestanol accumulates. This matters here because tendon xanthomatosis is a curated phenotype of this entry and is one of the strongest predictors in the clinical FH criteria above, so a xanthoma phenocopy can score as clinical FH while carrying no PCSK9 variant.

Show evidence (1 reference)

PMID:27678445 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Tendon xanthoma are most commonly associated with Familial Hypercholesterolemia, but the differential diagnosis includes sitosterolemia and cerebrotendinous xanthomatosis (CTX)."

Names the two sterol storage disorders that phenocopy the tendon-xanthoma sign of FH.

📊

Related Datasets

1

Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia geo:GSE75545

GSE75545 contains ten expression arrays comparing urine-derived progenitor cells with reprogrammed iPSCs from a control donor and an S127R carrier: two progenitor samples per donor and three iPSC clones per donor. It does not contain hepatocyte-like-cell treatment arrays or the loss-of-function donor arrays described elsewhere in the publication.

human MICROARRAY

PMID:26586530

Sample-level GEO design was checked against the publication Methods and Figure 2. The GEO series summary reproduces the broader study abstract, whose hepatocyte and drug experiments extend beyond this deposited microarray series.

Show evidence (1 reference)

PMID:26586530 SUPPORT DIRECT PRIMARY RESULT In Vitro

"A transcriptomic analysis was performed and confirmed the global gene-expression profile modification between two control Ucell lines, two PCSK9-S127R Ucell lines and three clones of each UhiPSC line generated"

The full-text reprogramming analysis defines the deposited expression experiment; clone counts do not represent independent patients.

🔬

Clinical Trials

6

NCT01763918 PHASE_III COMPLETED

RUTHERFORD-2: randomised, double-blind, placebo-controlled trial of evolocumab in adults with heterozygous familial hypercholesterolemia on stable lipid-lowering therapy.

Target Phenotypes: Increased LDL cholesterol concentration HP:0003141

Show evidence (1 reference)

clinicaltrials:NCT01763918 SUPPORT INDIRECT BACKGROUND Human Clinical

"The primary objective was to evaluate the effect of 12 weeks of evolocumab subcutaneously once every 2 weeks (Q2W) and once monthly (QM), compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in adults with heterozygous familial hypercholesterolemia (HeFH)."

Registration record establishing the trial's population (heterozygous FH) and LDL-C endpoint.

NCT05398029 PHASE_I COMPLETED

VERVE-101: completed early-phase, open-label hepatic PCSK9 base-editing study in HeFH with ASCVD. Registry status checked September 2026. The registered design establishes an investigational intervention, not proven efficacy in PCSK9 gain-of-function disease.

Target Phenotypes: Increased LDL cholesterol concentration HP:0003141

Show evidence (1 reference)

clinicaltrials:NCT05398029 SUPPORT INDIRECT BACKGROUND Human Clinical

"VERVE-101 uses base-editing technology designed to disrupt the expression of the PCSK9 gene in the liver and lower circulating PCSK9 and LDL-C in patients with established ASCVD due to HeFH."

Registration record establishing that the intervention acts on hepatic PCSK9 expression, the mechanism node of this entry.

NCT03397121 PHASE_III COMPLETED

ORION-9: placebo-controlled, double-blind, randomised trial of twice-yearly inclisiran sodium in adults with heterozygous familial hypercholesterolemia and elevated LDL cholesterol.

Target Phenotypes: Increased LDL cholesterol concentration HP:0003141

Show evidence (1 reference)

clinicaltrials:NCT03397121 SUPPORT INDIRECT BACKGROUND Human Clinical

"This is a Phase III, placebo-controlled, double-blind, randomized study in participants with HeFH and elevated LDL-C to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) injection(s) of inclisiran."

Registration record establishing the trial's population and the intervention relevant to this disease.

NCT05465278 PHASE_IV COMPLETED

ARCHITECT: completed open-label, single-arm alirocumab study with serial coronary CT angiography in molecularly determined FH without clinical ASCVD. No PCSK9-stratified effect or randomized plaque comparison was reported.

Target Phenotypes: Coronary artery atherosclerosis HP:0001677

Show evidence (3 references)

clinicaltrials:NCT05465278 SUPPORT INDIRECT BACKGROUND Human Clinical

"clinical trial to evaluate the effect of alirocumab on the volume, architecture and composition of atherosclerotic plaque in patients with Familial hypercholesterolemia from the SAFEHEART Registry"

Registration record establishing the intervention, the plaque endpoint, and the registry-based FH cohort.

PMID:37009731 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"in subjects with molecularly determined FH without clinical ASCVD enrolled in the SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study)"

The results publication states the cohort is molecularly determined, which the registration record did not.

PMID:37009731 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Treatment with alirocumab in addition to high-intensity statin therapy resulted in significant regression of coronary plaque burden and plaque stabilization on coronary computed tomographic angiography over 78 weeks"

The publication reports within-person CT changes over 78 weeks; absence of a control group limits causal attribution.

NCT01604824 PHASE_II COMPLETED

Randomized placebo-phase alirocumab study in genetic hypercholesterolemia. The PCSK9 publication reports 13 adults carrying four variants, with a two-week primary randomized LDL-C comparison and later pooled on-treatment follow-up. The registry total includes a separate APOB cohort and must not be substituted for the PCSK9 sample size.

Target Phenotypes: Increased LDL cholesterol concentration HP:0003141

Show evidence (2 references)

PMID:26374825 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline and 53.7% compared with control PCSK9 GOF mutation patients treated with placebo for 2 weeks (P=0.0009; primary end point)."

The primary randomized contrast was a 53.7-percentage-point difference at week 2 in 13 adults carrying four PCSK9 variants; the 62.5% figure is a within-group change. This was not an event-outcome trial.

clinicaltrials:NCT01604824 SUPPORT INDIRECT BACKGROUND Human Clinical

"The primary objective of the study is to assess the pharmacodynamic (PD) effect of alirocumab on serum low density lipoprotein cholesterol (LDL-C)"

The registration defines an LDL-C pharmacodynamic study; the PCSK9 subgroup results are supported separately by the primary publication.

NCT03705234 PHASE_III ACTIVE_NOT_RECRUITING

ORION-4 evaluates inclisiran versus placebo for cardiovascular outcomes in established ASCVD. Registry status was active, not recruiting in September 2026; the trial population is broader than PCSK9-related FH.

Show evidence (1 reference)

clinicaltrials:NCT03705234 SUPPORT INDIRECT BACKGROUND Human Clinical

"The study aims to find out if a new cholesterol-lowering injection (inclisiran) safely lowers the risk of heart attacks and strokes in people who have already had one of these conditions, or who have had an operation or procedure to treat blocked arteries."

The registry describes an outcome-study aim, not an available positive result, in a population defined by established atherosclerotic disease rather than by FH or PCSK9 genotype.

🧫

Experimental Models

1

Urine-derived iPSC hepatocyte-like cells from a PCSK9 S127R carrier (HLC-S127R) IPSC_DERIVED_MODEL

Urine-derived cells from one S127R carrier were reprogrammed into iPSCs and differentiated into hepatocyte-like cells. One healthy donor supplied the comparator; multiple clones are not independent patients. The nonisogenic comparison supports a patient-cell phenotype without isolating the variant from donor background.

Organism

human NCBITaxon:9606

Cell source

Patient-derived (urine somatic cells reprogrammed to iPSC)

Culture

Two-dimensional hepatocyte-like cell differentiation

Publication

PMID:26586530

Pathograph links

Reduced Hepatic Clearance of Circulating LDL Particles recapitulates fidelity: moderate Hepatocyte-like cells carrying the patient's S127R allele take up 71% less LDL than control cells, the cellular readout of this node.

Limitations: Hepatocyte-like cells derived from iPSC are immature relative to adult hepatocytes; the comparison is between individuals rather than between isogenic corrected and uncorrected lines, so donor background is not controlled.

Readouts

LDL uptake by hepatocyte-like cells

Direction: DECREASED

Interpretation: A cellular LDL-uptake measurement supporting, but not directly measuring, whole-body hepatic clearance.

Show evidence (1 reference)

PMID:26586530 SUPPORT DIRECT PRIMARY RESULT In Vitro

"cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake"

Reports the LDL-uptake measurement grounding this readout.

Show evidence (1 reference)

PMID:26586530 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We aimed to validate urine-sample-derived human induced pluripotent stem cells (UhiPSCs) as an appropriate tool to model PCSK9-mediated ADH and FHBL."

States the model's purpose as a model of PCSK9-mediated autosomal dominant hypercholesterolemia.

Pravastatin enhanced LDL uptake in culture; a separate uncontrolled clinical observation involved five S127R carriers. The cell response does not validate individual clinical prediction or universal statin sensitivity.

Show evidence (1 reference)

PMID:26586530 SUPPORT DIRECT PRIMARY RESULT In Vitro

"urine samples provide an attractive and convenient source of somatic cells for reprogramming and hepatocyte differentiation, but also a powerful tool to further decipher PCSK9 mutations and function."

The authors' conclusion on the model's utility for studying PCSK9 variant function.

🐁

Animal Models

2

AAV-hPCSK9(D374Y) mouse

Liver-directed AAV expression of human D374Y PCSK9 in mice produces hyperlipidemia and, under the studied high-fat feeding conditions, aortic lesions with macrophages and fibrous caps. Somatic overexpression does not reproduce endogenous germline regulation or lifelong human exposure.

Species

Mouse

Genotype

Liver-directed AAV transfer of human PCSK9 p.Asp374Tyr into wild-type mice

Background

C57BL/6J, 129/SvPasCrlf, or FVB/NCrl

Genes

PCSK9 hgnc:20001

Publication

PMID:25341796

Pathograph links

Chronic Elevation of Plasma LDL Cholesterol recapitulates fidelity: moderate Liver expression of human PCSK9 D374Y produces long-term elevation of serum LDL in three mouse backgrounds.

Limitations: Expression is achieved by somatic AAV transfer in adult animals rather than by a germline heterozygous allele from conception, so the lifelong "cholesterol-years" exposure central to the human disease is not reproduced; lesion development was studied with high-fat feeding; necessity of that diet is not established here.

Readouts

Serum low-density lipoprotein

Direction: INCREASED

Interpretation: Direct biochemical correlate of the human LDL-C elevation node.

Show evidence (1 reference)

PMID:25341796 SUPPORT DIRECT PRIMARY RESULT Model Organism

"mice in the C57BL/6J, 129/SvPasCrlf, or FVB/NCrl backgrounds developed long-term hyperlipidemia with a strong increase in serum low-density lipoprotein."

Reports the LDL measurement grounding this readout.

Show evidence (1 reference)

PMID:25341796 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We aimed to stably express the pathological human D374Y gain-of-function mutant form of PCSK9 (PCSK9(DY)) in adult wild-type mice to generate a hyperlipidemic and proatherogenic animal model, achieved with a single systemic injection with adeno-associated virus (AAV)."

States that the model expresses the human ADH3 disease allele to reproduce the hyperlipidaemic, proatherogenic state.

Atherosclerotic Plaque Formation partially recapitulates fidelity: moderate High-fat-fed AAV-PCSK9(D374Y) mice develop aortic atherosclerotic lesions that progress to macrophage-infiltrated, fibrous-capped plaques.

Limitations: Mouse atherosclerosis reproduces lesion initiation and fibrous-cap formation but not the late human complications of plaque rupture and thrombosis; lesions are aortic rather than coronary, and lesions were studied under high-fat feeding.

Readouts

Aortic atherosclerotic lesion burden and fibrous cap formation

Direction: INCREASED

Interpretation: Histological correlate of the fibrofatty plaque node.

Show evidence (1 reference)

PMID:25341796 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Advanced lesions in these high-fat-diet-fed mice also showed evidence of macrophage infiltration and fibrous cap formation."

Reports the histological lesion features grounding this readout.

Show evidence (1 reference)

PMID:25341796 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Macroscopic and histological analysis showed atherosclerotic lesions in the aortas of AAV-PCSK9(DY) mice fed a high-fat-diet."

Establishes that the model develops atherosclerotic lesions attributable to the PCSK9 D374Y allele.

Show evidence (1 reference)

PMID:25341796 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Single intravenous AAV-PCSK9(DY) injection is a fast, easy, and cost-effective approach, resulting in rapid and long-term sustained hyperlipidemia and atherosclerosis."

The authors' summary of what the model produces, supporting its use as a model of PCSK9 gain-of-function hypercholesterolemia and atherosclerosis.

D374Y-PCSK9 transgenic Yucatan minipig

Cloned Yucatan minipigs expressing human D374Y-PCSK9 in liver show reduced hepatic LDL receptor levels, impaired LDL clearance, severe hypercholesterolaemia, and spontaneous progressive atherosclerosis at a body size that permits intravascular imaging. The model covers the ADH3 chain from hepatic receptor loss through to arterial lesion formation; the late human events of plaque rupture and atherothrombosis are not demonstrated in it.

Species

Pig

Genotype

Liver-specific expression of human PCSK9 p.Asp374Tyr (Sleeping Beauty transposition, somatic cell nuclear transfer)

Background

Yucatan minipig

Genes

PCSK9 hgnc:20001

Publication

PMID:23283366

Pathograph links

Reduced Hepatic Clearance of Circulating LDL Particles recapitulates fidelity: moderate Transgenic pigs show the receptor-depletion-to-clearance-failure step directly, with both hepatic LDL receptor level and LDL clearance measured in the same animals.

Limitations: The human allele is expressed from a transgene under a liver-specific promoter rather than from the endogenous porcine locus, so expression level and regulation need not match a human heterozygote.

Readouts

Hepatic LDL receptor level

Direction: DECREASED

Interpretation: Reduced total hepatic LDLR protein provides indirect support for the linked hepatic-clearance defect; it does not directly localize receptor degradation or quantify surface LDLR.

Show evidence (1 reference)

PMID:23283366 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."

Reports the receptor-level and clearance measurements grounding this readout.

Hepatic LDL clearance

Direction: DECREASED

Interpretation: Impaired LDL clearance is the measured functional readout corresponding to this mechanism.

Show evidence (1 reference)

PMID:23283366 SUPPORT DIRECT PRIMARY RESULT Model Organism

"D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."

The cited experiment directly reports impaired LDL clearance in the transgenic pigs.

Show evidence (1 reference)

PMID:23283366 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9."

Describes the construction of the model on the human ADH3 allele.

Atherosclerotic Plaque Formation recapitulates fidelity: moderate Transgenic pigs developed progressive atherosclerotic lesions measurable by imaging. The cited abstract does not establish diet independence or superiority to mouse models.

Limitations: Even in this model the late human events of plaque rupture and atherothrombosis are not established; lesion progression, not acute coronary syndrome, is what is demonstrated.

Readouts

Progressive atherosclerotic lesion development on noninvasive imaging

Direction: INCREASED

Interpretation: Imaging correlate of arterial plaque formation driven by the PCSK9 gain-of-function allele.

Show evidence (1 reference)

PMID:23283366 SUPPORT DIRECT PRIMARY RESULT Model Organism

"spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."

Reports the imaging readout of lesion progression.

Show evidence (1 reference)

PMID:23283366 SUPPORT DIRECT PRIMARY RESULT Model Organism

"spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."

Reports the imaging readout of lesion progression.

Show evidence (1 reference)

PMID:23283366 SUPPORT DIRECT PRIMARY RESULT Model Organism

"D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."

Reports the findings the model description lists: reduced hepatic LDL receptor, impaired LDL clearance, severe hypercholesterolemia and progressive lesions on imaging. Rupture and atherothrombosis are not reported.

{ }

Source YAML

click to show

name: Autosomal Dominant Hypercholesterolemia 3
creation_date: "2026-08-18T00:00:00Z"
description: >-
  PCSK9-related familial hypercholesterolemia is an autosomal dominant disorder caused
  by gain-of-function
  sequence variants or, rarely, whole-gene duplication. Allele-specific effects increase
  PCSK9-mediated
  loss of hepatic LDL receptors, reducing LDL removal and raising lifelong LDL cholesterol
  exposure. Increased
  apoB-containing lipoprotein production has also been measured in two S127R carriers.
  Coronary atherosclerosis,
  angina, myocardial infarction and cholesterol deposits can develop, but severity
  varies with the allele,
  age, treatment and other risk factors. PCSK9 loss-of-function variants cause a different,
  low-LDL phenotype.
  Care follows familial-hypercholesterolemia guidance; a small randomized alirocumab
  study provides direct
  short-term LDL-lowering evidence in carriers of four PCSK9 gain-of-function variants.
category: Mendelian
disease_term:
  preferred_term: Autosomal Dominant Hypercholesterolemia 3
  term:
    id: MONDO:0011369
    label: hypercholesterolemia, autosomal dominant, 3
synonyms:
- HCHOLA3
- FH3
- hypercholesterolemia, autosomal dominant, type 3
- hypercholesterolemia, familial, 3
- PCSK9 familial hypercholesterolemia
- familial hypercholesterolemia caused by mutation in PCSK9
parents:
- Familial Hypercholesterolemia
references:
- reference: PMID:24404629
  title: "Familial Hypercholesterolemia."
  tags:
  - GeneReviews
notes: >-
  This entry covers PCSK9-related hypercholesterolemia (MONDO:0011369; OMIM:603776;
  HGNC:20001), within
  the broader familial-hypercholesterolemia spectrum. Gene identity does not establish
  that an individual
  variant is pathogenic or gain-of-function. Acquired and polygenic hypercholesterolemia,
  LDLR/APOB disorders
  and protective PCSK9 loss-of-function alleles remain distinct. General FH care and
  downstream atherosclerosis
  biology are explicitly identified as broader evidence.
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    evidence:
    - reference: PMID:12730697
      reference_title: "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis."
      explanation: >-
        Places the causal gene, and so the disease, in hepatic cholesterol
        homeostasis - the lipoprotein-metabolism material of Harrison's
        Endocrinology and Metabolism Part.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
    notes: >-
      Harrison's Parts follow the sibling FH entries
      (kb/disorders/LDLR-Related_Familial_Hypercholesterolemia.yaml,
      kb/disorders/Familial_Defective_Apolipoprotein_B-100.yaml), which place
      the dominant hypercholesterolemias in the metabolism Part plus the
      Mendelian genetics Part. CARDIOVASCULAR is deliberately not assigned:
      premature atherosclerotic disease is the dominant clinical outcome here,
      but it is modelled as the downstream pathograph branch and as phenotypes
      rather than as a second nosological home, and assigning it would put this
      entry out of step with the rest of the FH family for no mechanistic gain.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:12730697
      reference_title: "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH."
      explanation: >-
        Establishes ADH3 as a Mendelian disorder segregating at a single mapped
        locus with a named causal gene.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  icimd_category:
  - classification_value: hypercholesterolemias
    evidence:
    - reference: PMID:12730697
      reference_title: "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels"
      explanation: >-
        Defines the entity by elevated LDL cholesterol, placing it among the
        inherited hypercholesterolemias.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Hypercholesterolemias"
      under category "Disorders of lipoprotein metabolism". Same group as the
      LDLR- and APOB-related sibling entries in this knowledge base.
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous PCSK9 gain-of-function variants segregate as an autosomal
    dominant trait, as first shown by linkage of the HCHOLA3 locus at 1p32 in
    French ADH pedigrees.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APOB-, LDLR-, and PCSK9-related FH are inherited in an autosomal dominant manner."
    explanation: GeneReviews states the mode of inheritance for PCSK9-related FH explicitly.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each child of an individual with a heterozygous pathogenic variant in APOB, LDLR, or PCSK9 has a 50% chance of inheriting the pathogenic variant and having FH."
    explanation: >-
      GeneReviews states the 50% transmission risk for a heterozygous PCSK9
      variant, the recurrence figure used in genetic counselling.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:12730697
    reference_title: "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH."
    explanation: >-
      The founding report identifies PCSK9 as the third autosomal dominant
      hypercholesterolemia locus, establishing the disease entity curated here.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
prevalence:
- population: Molecularly characterised familial hypercholesterolemia cohorts
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    No population prevalence specific to PCSK9-related FH is established by the cited
    selected cohorts.
    The proportion of PCSK9 findings among LDLR/APOB-negative referrals is not an
    upper bound on the contribution
    to unselected FH. GeneReviews describes PCSK9 as accounting for less than 1% of
    FH, with ascertainment
    and variant interpretation affecting the estimate.
progression:
- phase: Presymptomatic (birth to childhood)
  notes: >-
    LDL cholesterol elevation can be recognized in childhood, whereas visible cholesterol
    deposits and
    clinical atherosclerotic events are variably expressed later. Treatment and allele-specific
    severity
    modify the course.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK174884/
    reference_title: Familial Hypercholesterolemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals with FH have elevated LDL-C levels starting soon after birth.
    explanation: FH-wide natural history supports early biochemical expression, without assigning a fixed age at which a cholesterol threshold necessarily causes coronary disease.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
- phase: Cholesterol deposition and clinical presentation (young adulthood)
  notes: >-
    In the long-term British D374Y series, carriers presented about a decade
    earlier than severe LDLR-mutation heterozygotes, at a mean age of about 21
    years, with markedly higher pretreatment cholesterol.
  evidence:
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8+/-14.7 versus 30.2+/-15.7 years; P=0.003)"
    explanation: Quantifies the age at presentation in a PCSK9 gain-of-function cohort.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- phase: Premature atherosclerotic cardiovascular disease (adulthood)
  notes: >-
    In the selected British D374Y families, clinical coronary disease appeared earlier
    than in the comparator
    LDLR group. This small family-based estimate does not specify onset for all PCSK9
    alleles.
  evidence:
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"
    explanation: Quantifies the age at onset of premature coronary disease in this genotype.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
pathophysiology:
- name: Pathogenic PCSK9 Sequence Variant or Duplication
  description: Pathogenic heterozygous sequence variants and rare whole-gene duplication cause PCSK9-related FH. Their biochemical effects differ; altered processing alone does not distinguish gain from loss of function. Candidate reporter variants are not equated with clinically established alleles.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:12730697
    reference_title: "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH."
    explanation: >-
      The founding report identifies PCSK9 as the third autosomal dominant
      hypercholesterolemia locus, establishing the disease entity curated here.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - &id012
    reference: PMID:30269829
    reference_title: Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a whole-gene duplication of PCSK9 in 2 unrelated Canadian FH index cases; this PCSK9 CNV was also found to cosegregate with affected status in family members.
    explanation: Whole-gene duplication provides a distinct dosage mechanism in two families.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  role: trigger
  genes:
  - &id013
    preferred_term: PCSK9
    term:
      id: hgnc:20001
      label: PCSK9
  downstream:
  - target: Production of Disease-Associated PCSK9
    description: The causal allele is expressed; dosage and sequence variants need not increase secretion in the same way.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12730697
      reference_title: Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.
      explanation: The discovery study establishes hepatic expression; expression of disease-associated alleles is the upstream context, not evidence that all variants increase synthesis.
      directness: DIRECT
      quote_role: BACKGROUND
    - reference: PMID:30269829
      reference_title: Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We identified a whole-gene duplication of PCSK9 in 2 unrelated Canadian FH index cases; this PCSK9 CNV was also found to cosegregate with affected status in family members.
      explanation: Whole-gene duplication provides a distinct dosage mechanism in two families.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
  genetic_context:
    gene:
      preferred_term: PCSK9
      term:
        id: hgnc:20001
        label: PCSK9
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Established heterozygous PCSK9 gain-of-function sequence variants or dosage
      increase from whole-gene
      duplication. Variant-specific biochemical activity must be distinguished from
      increased abundance
      of otherwise wild-type protein.
- name: Production of Disease-Associated PCSK9
  description: 'Hepatic expression supplies variant PCSK9 or additional wild-type protein after gene duplication. This is the synthesis step targeted by RNA silencing. It does not assert increased synthesis or secretion for every allele: S127R hepatocyte-like cells secreted less protein despite impaired LDL uptake. Intracellular and extracellular actions need not share a secretion requirement.'
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:12730697
    reference_title: Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.
    explanation: The discovery study establishes hepatic expression; expression of disease-associated alleles is the upstream context, not evidence that all variants increase synthesis.
    directness: DIRECT
    quote_role: BACKGROUND
  - &id004
    reference: PMID:26586530
    reference_title: Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake
    explanation: A patient-derived hepatocyte-like line had reduced uptake despite lower secretion; nonisogenic donor background limits allele attribution.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  cell_types: &id001
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations: &id002
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  downstream:
  - target: Increased Circulating PCSK9 Abundance
    description: The duplication branch can increase circulating abundance; processing and secretion intervene.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30269829
      reference_title: Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Features in affected individuals included severely elevated LDL cholesterol levels that were refractory to intensive statin therapy, pronounced clinical stigmata, premature cardiovascular events, and a plasma PCSK9 of approximately 5000 ng/mL in 1 index case.
      explanation: Very high circulating PCSK9 was measured in one duplication index case; this is not a universal concentration in ADH3.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
  - target: Reduced PCSK9 Association with LDL Particles
    description: Selected expressed variants impair LDL-particle association.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36187800
      reference_title: Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Herein, we identify additional GOF mutations that inhibit LDL association, localized either within CM1 or a surface-exposed region in the PCSK9 prodomain.
      explanation: Purified-protein and cell experiments establish impaired association with LDL particles for selected variants; this differs from LDL-receptor binding.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
  - target: PCSK9 Binding to the LDL Receptor EGF-A Domain
    description: Secreted protein can bind LDLR; D374Y increases activity in the tested extracellular assays.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17452316
      reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR."
      explanation: Localises the PCSK9 binding site on the LDL receptor to the EGF-A repeat.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
    - reference: PMID:17080197
      reference_title: Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: This activity was approximately 10-fold greater for a gain-of-function mutant, PCSK9(D374Y), that causes hypercholesterolemia.
      explanation: D374Y has greater LDLR-depleting activity in the tested exogenous-protein assay, not a uniform tenfold effect of all alleles.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
  - target: Increased Production of ApoB-Containing Lipoproteins
    description: S127R expression is associated with increased apoB production; the intervening human molecular mechanism remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15166014
      reference_title: Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: PCSK9 mutation dramatically increased the production rate of apolipoprotein B100 (3-fold) compared with controls or LDL-R mutated subjects, related to direct overproduction of VLDL (3-fold), IDL (3-fold), and LDL (5-fold).
      explanation: Stable-isotope compartmental modelling in two S127R carriers supports increased apoB production, not a mechanism demonstrated in every allele.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
- name: Increased Circulating PCSK9 Abundance
  description: Whole-gene duplication can increase circulating PCSK9 abundance. A concentration near 5000 ng/mL was reported in one index case. This dosage branch must not be generalized to sequence variants with normal or reduced secretion.
  biological_scale: ORGANISM
  evidence:
  - &id014
    reference: PMID:30269829
    reference_title: Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Features in affected individuals included severely elevated LDL cholesterol levels that were refractory to intensive statin therapy, pronounced clinical stigmata, premature cardiovascular events, and a plasma PCSK9 of approximately 5000 ng/mL in 1 index case.
    explanation: Very high circulating PCSK9 was measured in one duplication index case; this is not a universal concentration in ADH3.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  downstream:
  - target: PCSK9 Binding to the LDL Receptor EGF-A Domain
    description: Greater extracellular exposure can increase receptor engagement; the one duplication measurement does not establish a quantitative dose-response.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30269829
      reference_title: Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Features in affected individuals included severely elevated LDL cholesterol levels that were refractory to intensive statin therapy, pronounced clinical stigmata, premature cardiovascular events, and a plasma PCSK9 of approximately 5000 ng/mL in 1 index case.
      explanation: Very high circulating PCSK9 was measured in one duplication index case; this is not a universal concentration in ADH3.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
    - reference: PMID:17080197
      reference_title: Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We show that purified PCSK9 added to the medium of HepG2 cells reduces the number of cell-surface LDLRs in a dose- and time-dependent manner.
      explanation: More extracellular PCSK9 removed more surface LDLR in cultured hepatoma cells, which supports an abundance-driven route to receptor engagement. The same paper's tenfold D374Y comparison is a per-molecule potency difference, not an abundance effect, so it is not cited for this edge.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
- name: Reduced PCSK9 Association with LDL Particles
  description: Selected prodomain and C-terminal variants impair PCSK9 association with LDL particles in vitro. LDL can inhibit extracellular receptor-depleting activity in the tested systems. How much this regulatory association contributes to each human phenotype remains unresolved; reduced particle binding is not increased binding to LDLR.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:36187800
    reference_title: Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Herein, we identify additional GOF mutations that inhibit LDL association, localized either within CM1 or a surface-exposed region in the PCSK9 prodomain.
    explanation: Purified-protein and cell experiments establish impaired association with LDL particles for selected variants; this differs from LDL-receptor binding.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Increased Lysosomal LDL Receptor Degradation
    description: Loss of LDL-particle inhibition may increase receptor-depleting activity, but human mediation is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36187800
      reference_title: Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Herein, we identify additional GOF mutations that inhibit LDL association, localized either within CM1 or a surface-exposed region in the PCSK9 prodomain.
      explanation: Purified-protein and cell experiments establish impaired association with LDL particles for selected variants; this differs from LDL-receptor binding.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
- name: PCSK9 Binding to the LDL Receptor EGF-A Domain
  description: Extracellular PCSK9 binds the LDL receptor EGF-A domain in calcium- and pH-dependent assays. D374Y has enhanced binding and receptor-depleting activity in the tested systems. This branch describes an experimentally supported extracellular route; neither universal secretion necessity nor equivalent affinity changes across all alleles are established.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:17452316
    reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR."
    explanation: Localises the PCSK9 binding site on the LDL receptor to the EGF-A repeat.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:17452316
    reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Binding to EGF-A was calcium-dependent and increased dramatically with reduction in pH from 7 to 5.2."
    explanation: >-
      Establishes the pH dependence that makes the complex persist through
      endocytosis rather than dissociating in the endosome.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:17080197
    reference_title: Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: This activity was approximately 10-fold greater for a gain-of-function mutant, PCSK9(D374Y), that causes hypercholesterolemia.
    explanation: D374Y has greater LDLR-depleting activity in the tested exogenous-protein assay, not a uniform tenfold effect of all alleles.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:36187800
    reference_title: Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "A well-characterized example is the D374Y mutation in the PCSK9 catalytic domain that improves the primary binding interaction with the epidermal growth factor-like repeat A"
    explanation: >-
      Supports INCREASED receptor binding for the D374Y allele. The modifier
      is allele-specific and is not asserted for every ADH3 variant.
  - reference: PMID:26586530
    reference_title: Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Compared to the D374Y GOF mutation, which strengthens the affinity between PCSK9 and LDLR, the S127R mutation does not affect PCSK9 binding to LDLR"
    explanation: >-
      Confirms increased LDLR affinity for D374Y and records that S127R
      leaves receptor binding unchanged, so the INCREASED modifier applies to
      a subset of alleles only.
  cell_types: *id001
  locations: *id002
  genes:
  - preferred_term: PCSK9
    term:
      id: hgnc:20001
      label: PCSK9
  molecular_functions:
  - preferred_term: low-density lipoprotein particle receptor binding
    modifier: INCREASED
    term:
      id: GO:0050750
      label: low-density lipoprotein particle receptor binding
  downstream:
  - target: Reduced LDL Receptor Recycling
    description: PCSK9 binding interferes with receptor recycling; the acid-dependent conformational explanation remains a model.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17452316
      reference_title: Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: These data are consistent with a model in which PCSK9 binding to EGF-A interferes with an acid-dependent conformational change required for receptor recycling.
      explanation: The proposed conformational explanation is inferential; receptor redistribution is measured separately.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
- name: Reduced LDL Receptor Recycling
  description: PCSK9 association reduces the return of internalized LDL receptor to the cell surface. Interference with an acid-dependent receptor conformational change is a proposed explanation rather than a directly resolved molecular intermediate in the cited study.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:17452316
    reference_title: Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These data are consistent with a model in which PCSK9 binding to EGF-A interferes with an acid-dependent conformational change required for receptor recycling.
    explanation: The proposed conformational explanation is inferential; receptor redistribution is measured separately.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  cell_types: *id001
  locations: *id002
  biological_processes:
  - preferred_term: receptor recycling
    term:
      id: GO:0001881
      label: receptor recycling
    modifier: DECREASED
  downstream:
  - target: Increased Lysosomal LDL Receptor Degradation
    description: Failure to recycle favors lysosomal receptor loss through the experimentally observed rerouting process.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17452316
      reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The addition of PCSK9, but not heat-inactivated PCSK9, to the medium of cultured hepatocytes resulted in redistribution of the receptor from the plasma membrane to lysosomes."
      explanation: Demonstrates the plasma-membrane-to-lysosome rerouting that defines this node.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
- name: Increased Lysosomal LDL Receptor Degradation
  description: PCSK9 promotes receptor delivery to lysosomes and loss of LDLR protein. PCSK9 is not asserted to proteolytically cleave LDLR itself. The cited route depends on cell context; uptake into mouse embryonic fibroblasts did not produce the same receptor loss.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:17452316
    reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The addition of PCSK9, but not heat-inactivated PCSK9, to the medium of cultured hepatocytes resulted in redistribution of the receptor from the plasma membrane to lysosomes."
    explanation: Demonstrates the plasma-membrane-to-lysosome rerouting that defines this node.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - &id003
    reference: PMID:16571601
    reference_title: "Effect of mutations in the PCSK9 gene on the cell surface LDL receptors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The two gain-of-function mutations had a 23% decreased level of cell surface LDLR and a 38% decreased level of internalization of LDL as compared with WT-PCSK9."
    explanation: >-
      Reduced surface LDLR in transfected HepG2 cells corroborates receptor loss but
      does not itself localize
      degradation to lysosomes.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  role: central_effector
  cell_types: *id001
  locations: *id002
  biological_processes:
  - preferred_term: low-density lipoprotein particle receptor catabolic process
    term:
      id: GO:0032802
      label: low-density lipoprotein particle receptor catabolic process
    modifier: INCREASED
  downstream:
  - target: Reduced Hepatocyte Surface LDL Receptor Abundance
    description: Receptor degradation reduces the available surface pool.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16571601
      reference_title: "Effect of mutations in the PCSK9 gene on the cell surface LDL receptors."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The two gain-of-function mutations had a 23% decreased level of cell surface LDLR and a 38% decreased level of internalization of LDL as compared with WT-PCSK9."
      explanation: >-
        Quantifies the fall in hepatocyte surface LDL receptor caused specifically
        by the S127R and D374Y gain-of-function alleles.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
- name: Reduced Hepatocyte Surface LDL Receptor Abundance
  description: Enhanced receptor loss decreases the surface LDLR pool. Surface abundance is a separate readout from lysosomal location, LDLR transcription and whole-body LDL clearance.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:16571601
    reference_title: "Effect of mutations in the PCSK9 gene on the cell surface LDL receptors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The two gain-of-function mutations had a 23% decreased level of cell surface LDLR and a 38% decreased level of internalization of LDL as compared with WT-PCSK9."
    explanation: >-
      Directly measures the reduced cell-surface LDLR level in HepG2 cells
      expressing the two gain-of-function alleles relative to wild-type PCSK9,
      which is this node's claim.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  cell_types: *id001
  locations: *id002
  downstream:
  - target: Reduced Hepatic Clearance of Circulating LDL Particles
    description: Fewer surface receptors reduce receptor-mediated LDL uptake.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16571601
      reference_title: "Effect of mutations in the PCSK9 gene on the cell surface LDL receptors."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The two gain-of-function mutations had a 23% decreased level of cell surface LDLR and a 38% decreased level of internalization of LDL as compared with WT-PCSK9."
      explanation: >-
        Quantifies the fall in hepatocyte surface LDL receptor caused specifically
        by the S127R and D374Y gain-of-function alleles.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
    - reference: PMID:26586530
      reference_title: Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake
      explanation: A patient-derived hepatocyte-like line had reduced uptake despite lower secretion; nonisogenic donor background limits allele attribution.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
- name: Reduced Hepatic Clearance of Circulating LDL Particles
  description: Reduced receptor availability impairs hepatocyte LDL uptake. Patient-derived cell uptake and human isotope-derived LDL catabolic rates support related but distinct aspects of this route; neither assay alone measures all liver flux.
  biological_scale: TISSUE
  evidence:
  - *id004
  - &id005
    reference: PMID:15166014
    reference_title: Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: LDL fractional catabolic rate was slightly decreased (by 30%) compared with controls but still higher than LDL-R-mutated subjects.
    explanation: This human kinetic comparison supports impaired removal in two S127R carriers, without conflating hepatic cell uptake with a whole-body rate.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  cell_types: *id001
  locations: *id002
  biological_processes:
  - preferred_term: low-density lipoprotein particle clearance
    term:
      id: GO:0034383
      label: low-density lipoprotein particle clearance
    modifier: DECREASED
  downstream:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    description: Reduced removal contributes to circulating LDL accumulation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15166014
      reference_title: Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: LDL fractional catabolic rate was slightly decreased (by 30%) compared with controls but still higher than LDL-R-mutated subjects.
      explanation: This human kinetic comparison supports impaired removal in two S127R carriers, without conflating hepatic cell uptake with a whole-body rate.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
    - reference: PMID:12730697
      reference_title: Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels
      explanation: The disease is defined by increased LDL cholesterol, distinct from total-cholesterol measurements.
      directness: DIRECT
      quote_role: BACKGROUND
- name: Increased Production of ApoB-Containing Lipoproteins
  description: A parallel contribution is supported by compartmental tracer kinetics in two S127R carriers and secretion experiments in rat hepatoma cells. The human model estimated increased apoB production in VLDL, IDL and LDL fractions. The route is allele- and assay-limited and is not placed downstream of secreted PCSK9 or LDLR loss as a proven dependency.
  biological_scale: CELLULAR
  evidence:
  - &id009
    reference: PMID:15166014
    reference_title: Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PCSK9 mutation dramatically increased the production rate of apolipoprotein B100 (3-fold) compared with controls or LDL-R mutated subjects, related to direct overproduction of VLDL (3-fold), IDL (3-fold), and LDL (5-fold).
    explanation: Stable-isotope compartmental modelling in two S127R carriers supports increased apoB production, not a mechanism demonstrated in every allele.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:15772090
    reference_title: "Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This suggests that the variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers."
    explanation: >-
      The authors' own statement of the alternative mechanism this node
      represents.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  cell_types: *id001
  locations: *id002
  downstream:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    description: Greater apoB-particle production can add to LDL burden; VLDL/IDL metabolism and clearance intervene.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15166014
      reference_title: Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: PCSK9 mutation dramatically increased the production rate of apolipoprotein B100 (3-fold) compared with controls or LDL-R mutated subjects, related to direct overproduction of VLDL (3-fold), IDL (3-fold), and LDL (5-fold).
      explanation: Stable-isotope compartmental modelling in two S127R carriers supports increased apoB production, not a mechanism demonstrated in every allele.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
- name: Chronic Elevation of Plasma LDL Cholesterol
  description: Increased LDL cholesterol exposure reflects impaired removal and, in some studied carriers, altered production of apoB lipoproteins. Severity varies across alleles and individuals. The British D374Y series reported total cholesterol, which is not substituted for LDL-C here.
  biological_scale: ORGANISM
  evidence:
  - &id011
    reference: PMID:12730697
    reference_title: Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels
    explanation: The disease is defined by increased LDL cholesterol, distinct from total-cholesterol measurements.
    directness: DIRECT
    quote_role: BACKGROUND
  - *id005
  biological_processes:
  - preferred_term: cholesterol homeostasis
    term:
      id: GO:0042632
      label: cholesterol homeostasis
    modifier: DYSREGULATED
  downstream:
  - target: Extra-Arterial Cholesterol Deposition
    description: Prolonged cholesterol excess supports tissue deposition.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels."
      explanation: GeneReviews describes tendon xanthomas as an FH cholesterol-deposition sign.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids."
      explanation: GeneReviews describes xanthelasma as an FH cholesterol-deposition sign.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH."
      explanation: GeneReviews describes early corneal arcus as an FH cholesterol-deposition sign.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  - target: Subendothelial Retention of ApoB-Containing Lipoproteins
    description: Greater circulating particle exposure contributes to arterial retention.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Indeed, infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis.
      explanation: General atherosclerosis synthesis supports the retention step downstream of the ADH3 LDL burden, not an allele-specific arterial experiment.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  - target: Hypercholesterolemia
    description: This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16224054
      reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications."
      explanation: >-
        Documents severe hypercholesterolemia as the defining clinical phenotype
        of PCSK9 D374Y carriers.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
  - target: Elevated LDL Cholesterol
    description: This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A clinical diagnosis of FH can be established in a proband with characteristic clinical features and significantly elevated LDL-C levels (typically >190 mg/dL in adults and >160 mg/dL in children)."
      explanation: >-
        GeneReviews sets the elevated-LDL-C threshold that defines the biochemical
        phenotype in PCSK9-related FH as in the other FH genes.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
- name: Extra-Arterial Cholesterol Deposition
  description: Sustained cholesterol excess can produce deposits in tendons, periocular skin and the corneal margin. The sites are distinct clinical expressions of cholesterol deposition and are variably present.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels."
    explanation: GeneReviews describes tendon xanthomas as an FH cholesterol-deposition sign.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids."
    explanation: GeneReviews describes xanthelasma as an FH cholesterol-deposition sign.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH."
    explanation: GeneReviews describes early corneal arcus as an FH cholesterol-deposition sign.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Tendon Xanthomas
    description: This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels."
      explanation: GeneReviews describes tendon xanthomas as an FH cholesterol-deposition sign.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  - target: Xanthelasma
    description: This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids."
      explanation: GeneReviews describes xanthelasma as an FH cholesterol-deposition sign.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  - target: Corneal Arcus
    description: This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH."
      explanation: GeneReviews describes early corneal arcus as an FH cholesterol-deposition sign.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
- name: Subendothelial Retention of ApoB-Containing Lipoproteins
  description: ApoB particles entering susceptible arterial regions can be retained in the intima. Endothelial state, particle modification and inflammation influence subsequent lesion development; retention alone does not imply an immediate symptomatic stenosis.
  biological_scale: TISSUE
  evidence:
  - &id006
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Indeed, infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis.
    explanation: General atherosclerosis synthesis supports the retention step downstream of the ADH3 LDL burden, not an allele-specific arterial experiment.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  locations:
  - preferred_term: tunica intima
    term:
      id: UBERON:0002523
      label: tunica intima
  downstream:
  - target: Macrophage Foam Cell Formation
    description: Particle modification, immune-cell recruitment and uptake connect retained lipoproteins to foam cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis.
      explanation: General lipoprotein uptake biology supports macrophage foam-cell formation.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  conforms_to: "atherogenesis#Endothelial Dysfunction and Subendothelial LDL Retention"
- name: Macrophage Foam Cell Formation
  description: Intimal macrophages accumulate lipoprotein-derived cholesterol and form foam cells. Modified or aggregated lipoproteins and several uptake pathways contribute; the process is not identical to LDLR-mediated hepatic clearance.
  biological_scale: CELLULAR
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis.
    explanation: General lipoprotein uptake biology supports macrophage foam-cell formation.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: foam cell differentiation
    term:
      id: GO:0090077
      label: foam cell differentiation
    modifier: INCREASED
  downstream:
  - target: Vascular Smooth Muscle Cell Proliferation
    description: Inflammatory mediators can stimulate smooth-muscle proliferation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Macrophage inflammatory chemoattractants stimulate infiltration and proliferation of smooth muscle cells.
      explanation: General plaque biology supplies the smooth-muscle response; this is not a PCSK9-specific cell assay.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  conforms_to: "atherogenesis#Monocyte Recruitment and Macrophage Foam Cell Formation"
- name: Vascular Smooth Muscle Cell Proliferation
  description: Plaque-associated mediators can stimulate smooth-muscle-cell proliferation. This is a conserved atherosclerosis process inferred downstream of lipid accumulation, not a directly measured response to every PCSK9 allele.
  biological_scale: CELLULAR
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Macrophage inflammatory chemoattractants stimulate infiltration and proliferation of smooth muscle cells.
    explanation: General plaque biology supplies the smooth-muscle response; this is not a PCSK9-specific cell assay.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  cell_types:
  - preferred_term: smooth muscle cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  biological_processes:
  - preferred_term: positive regulation of smooth muscle cell proliferation
    term:
      id: GO:0048661
      label: positive regulation of smooth muscle cell proliferation
    modifier: INCREASED
  downstream:
  - target: Arterial Extracellular Matrix Deposition
    description: Smooth-muscle expansion contributes to matrix production; this is not its only determinant.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets.
      explanation: Matrix deposition contributes to fibrous plaque structure and can be stabilizing.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
- name: Arterial Extracellular Matrix Deposition
  description: Smooth muscle cells produce collagen, proteoglycans and elastin within the developing plaque. A fibrous cap can stabilize the lesion; matrix accumulation is not equated with cap degradation.
  biological_scale: TISSUE
  evidence:
  - &id007
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets.
    explanation: Matrix deposition contributes to fibrous plaque structure and can be stabilizing.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  downstream:
  - target: Atherosclerotic Plaque Formation
    description: Matrix adds to the accumulating cellular and lipid components of plaque.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets.
      explanation: Matrix deposition contributes to fibrous plaque structure and can be stabilizing.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
- name: Atherosclerotic Plaque Formation
  description: Lipid-laden cells and extracellular material form arterial plaques. General lesion biology connects the cellular branches to plaque structure; clinical PCSK9 series establish atherosclerotic disease without resolving every histological intermediate.
  biological_scale: TISSUE
  evidence:
  - *id006
  - *id007
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"
    explanation: >-
      Quantifies the earlier onset of premature coronary artery disease in
      PCSK9 D374Y carriers relative to LDLR-mutation heterozygotes.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Arterial Luminal Narrowing
    description: Plaque growth can narrow the lumen despite compensatory remodeling.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Indeed, infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis.
      explanation: General atherosclerosis synthesis supports the retention step downstream of the ADH3 LDL burden, not an allele-specific arterial experiment.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  - target: Fibrous Cap Thinning
    description: Unresolved inflammation and cell death can lead to cap matrix loss.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Unresolved inflammation results in formation of vulnerable plaques characterized by enhanced macrophage apoptosis and defective efferocytosis of apoptotic cells resulting in necrotic cell death leading to increased smooth muscle cell death, decreased extracellular matrix production, and collagen degradation by macrophage proteases.
      explanation: Several known inflammatory and cell-death processes can weaken the cap; the edge does not assert that every plaque progresses to rupture.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  - target: Premature Coronary Artery Disease
    description: This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16224054
      reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"
      explanation: >-
        Quantifies the earlier onset of premature coronary artery disease in
        PCSK9 D374Y carriers relative to LDLR-mutation heterozygotes.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
- name: Arterial Luminal Narrowing
  description: Enlarging plaques can narrow arteries and impair perfusion. Compensatory remodeling and nonobstructive plaques mean that plaque burden is not identical to stenosis. This chronic flow-limiting branch is separate from acute rupture and thrombosis.
  biological_scale: TISSUE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: As the intimal volume enlarges due to accumulating cells, there is vascular remodeling to lessen protrusion of the lesion into the lumen
    explanation: General synthesis explains why plaque growth and luminal obstruction are distinct.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:27444203
    reference_title: "Coronary Heart Disease, Peripheral Arterial Disease, and Stroke in Familial Hypercholesterolaemia: Insights From the SAFEHEART Registry (Spanish Familial Hypercholesterolaemia Cohort Study)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coronary artery-related manifestations and peripheral artery disease were more prevalent in FH patients than in controls, but no significant differences were found for cerebrovascular events."
    explanation: >-
      Broader FH clinical peripheral arterial disease supports a downstream vascular
      consequence, not
      direct measurement of luminal narrowing in PCSK9 carriers.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Angina Pectoris
    description: This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely."
      explanation: GeneReviews lists angina among the premature cardiovascular events of FH.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  - target: Peripheral Arterial Disease
    description: This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30085243
      reference_title: "Familial Hypercholesterolemia and Risk of Peripheral Arterial Disease and Chronic Kidney Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Compared with individuals with unlikely FH, multivariable adjusted ORs (95% CIs) of PAD were 1.84 (1.70 to 2.00) in those with possible FH and 1.36 (1.00 to 1.84) in individuals with probable/definite FH."
      explanation: >-
        Quantifies elevated peripheral arterial disease risk in a general-population
        FH cohort of 106,172 individuals.
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
- name: Fibrous Cap Thinning
  description: In some advanced plaques, unresolved inflammation, matrix degradation and smooth-muscle-cell loss weaken the fibrous cap. These known intervening processes are summarized in the edge; no ADH3-specific histological progression series is claimed.
  biological_scale: TISSUE
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Unresolved inflammation results in formation of vulnerable plaques characterized by enhanced macrophage apoptosis and defective efferocytosis of apoptotic cells resulting in necrotic cell death leading to increased smooth muscle cell death, decreased extracellular matrix production, and collagen degradation by macrophage proteases.
    explanation: Several known inflammatory and cell-death processes can weaken the cap; the edge does not assert that every plaque progresses to rupture.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DECREASED
  downstream:
  - target: Atherosclerotic Plaque Rupture
    description: Weakened caps are susceptible to rupture.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Unresolved inflammation results in formation of vulnerable plaques characterized by enhanced macrophage apoptosis and defective efferocytosis of apoptotic cells resulting in necrotic cell death leading to increased smooth muscle cell death, decreased extracellular matrix production, and collagen degradation by macrophage proteases.
      explanation: Several known inflammatory and cell-death processes can weaken the cap; the edge does not assert that every plaque progresses to rupture.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The thick fibrous cap of the stable plaque provides an effective barrier preventing plaque rupture and exposure of lesion prothrombotic factors to blood, thereby limiting thrombus formation and clinical events.
      explanation: General plaque biology in which an intact thick cap is what prevents rupture; the edge's claim that a weakened cap is susceptible to rupture is the converse inference. Not PCSK9-specific.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
- name: Atherosclerotic Plaque Rupture
  description: A weakened fibrous cap can rupture and expose thrombogenic plaque components. Rupture is one acute complication and is not required for stable angina, chronic peripheral stenosis or every atherothrombotic event.
  biological_scale: TISSUE
  evidence:
  - &id008
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Plaque rupture leads to acute exposure of procoagulant and prothrombotic factors from the necrotic core of the lesion to platelets and procoagulant factors in the lumen, thereby causing thrombus formation
    explanation: General plaque biology connects rupture to thrombosis, not every stable coronary symptom to rupture.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Arterial Thrombus Formation
    description: Exposure of plaque procoagulants activates platelet/coagulation responses.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK343489/
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis - Endotext - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Plaque rupture leads to acute exposure of procoagulant and prothrombotic factors from the necrotic core of the lesion to platelets and procoagulant factors in the lumen, thereby causing thrombus formation
      explanation: General plaque biology connects rupture to thrombosis, not every stable coronary symptom to rupture.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
- name: Arterial Thrombus Formation
  description: Exposure of thrombogenic plaque material can trigger platelet and coagulation responses producing luminal thrombus. Acute coronary occlusion can cause infarction. The graph depicts the rupture pathway without excluding erosion or other routes.
  biological_scale: TISSUE
  evidence:
  - *id008
  downstream:
  - target: Myocardial Infarction
    description: This tissue or biochemical process contributes to the corresponding clinical finding; severity and occurrence vary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely."
      explanation: >-
        GeneReviews lists myocardial infarction among the premature cardiovascular
        events of FH, of which PCSK9-related FH is one molecular form.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
discussions:
- evidence:
  - *id004
  - *id009
  - reference: PMID:17080197
    reference_title: Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Considered together, the available data now suggest that PCSK9 can function both extra- and intracellularly, but we do not know which pathway predominates under normal and/or pathologic conditions.
    explanation: The authors distinguish pathway sufficiency from unresolved physiological predominance.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  discussion_id: adh3_allele_specific_routes
  prompt: How do allele-specific intracellular and extracellular routes contribute to the human LDL phenotype?
  rationale: The extracellular pathway is experimentally sufficient, but no universal secretion requirement follows from the high-expression parabiosis experiment. S127R cells can show reduced secretion with impaired LDL uptake, and two S127R carriers had increased apoB production by tracer modelling. These observations support heterogeneous, potentially parallel contributions rather than a single obligatory biochemical sequence.
  kind: KNOWLEDGE_GAP
  status: OPEN
- evidence:
  - reference: PMID:40225943
    reference_title: Functional Analysis of 3'UTR Variants at the LDLR and PCSK9 Genes in Patients with Familial Hypercholesterolemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The luciferase expression of the c.∗171C > T and c.∗950C > T variants was 18% and 41% higher than that of PCSK9 WT (p < 0.006 and p < 0.0018)
    explanation: The measured output is a HepG2 luciferase reporter carrying the untranslated region. This does not directly measure endogenous PCSK9 expression, LDLR turnover, LDL uptake, or segregation.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  discussion_id: adh3_candidate_regulatory_variants
  prompt: Do candidate PCSK9 untranslated-region variants cause clinically meaningful gain of function?
  rationale: A 2025 selected FH study found altered HepG2 reporter activity for several PCSK9 untranslated-region variants. Increased reporter output for c.*950C>T does not measure endogenous protein, receptor turnover or LDL uptake, and segregation and miRNA mediation remain unresolved. These findings are kept as candidate regulatory observations rather than an established additional ADH3 subtype.
  kind: KNOWLEDGE_GAP
  status: OPEN
- discussion_id: adh3_cerebrovascular_risk
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Does lifelong LDL-cholesterol elevation in familial hypercholesterolemia,
    and in PCSK9 gain-of-function carriers specifically, raise the risk of
    ischemic stroke and other cerebrovascular disease?
  attaches_to:
  - "phenotypes#"
  - "pathophysiology#Arterial Thrombus Formation"
  rationale: >-
    Stroke occurrence is documented in a selected PCSK9 carrier series (6/98 assessed;
    PMID:26374825 Table
    1), and GeneReviews includes stroke among FH manifestations. Whether PCSK9-related
    FH confers excess
    stroke risk remains unresolved. Broader molecularly defined FH cohorts reported
    no excess cerebrovascular
    risk, unlike their coronary risk. These designs do not establish an allele-specific
    effect or absence
    of stroke; no population frequency is inferred from selected carriers.
  evidence:
  - reference: PMID:30580708
    reference_title: "Risk of Ischemic Stroke and Total Cerebrovascular Disease in Familial Hypercholesterolemia: A Register Study From Norway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whether FH increases the risk of cerebrovascular disease, including ischemic stroke, is debated."
    explanation: >-
      States the controversy directly, in the background of the study that then
      reports a null result - establishing that this is a live disagreement in
      the field and not an artefact of this entry's reading.
    quote_role: BACKGROUND
    directness: DIRECT
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely."
    explanation: >-
      GeneReviews keeps stroke on the FH manifestation list while calling it
      rarer than the coronary events. Cited for the listing, not as a claim of
      excess risk - the clause itself is closer to the registry findings than
      to a positive association.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:30580708
    reference_title: "Risk of Ischemic Stroke and Total Cerebrovascular Disease in Familial Hypercholesterolemia: A Register Study From Norway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a large cohort of genetically verified FH, risks of cerebrovascular disease and ischemic stroke were not increased compared with the total Norwegian population."
    explanation: >-
      Supports the opposing position, in 3144 genetically verified FH patients
      linked to a nationwide hospitalisation database.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:27444203
    reference_title: "Coronary Heart Disease, Peripheral Arterial Disease, and Stroke in Familial Hypercholesterolaemia: Insights From the SAFEHEART Registry (Spanish Familial Hypercholesterolaemia Cohort Study)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coronary artery-related manifestations and peripheral artery disease were more prevalent in FH patients than in controls, but no significant differences were found for cerebrovascular events."
    explanation: >-
      Independent replication of the null cerebrovascular result in a second
      molecularly defined FH registry, alongside a positive coronary and
      peripheral result in the same comparison.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - &id010
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK174884/
    reference_title: Familial Hypercholesterolemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely.
    explanation: GeneReviews includes stroke among FH manifestations; occurrence does not establish a PCSK9-specific excess relative to controls.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    Stroke occurrence is curated as a phenotype, with a PCSK9-carrier count from PMID:26374825 Table 1
    and broader FH synthesis. Excess risk and an allele-specific causal route remain unresolved; occurrence
    alone does not establish either.
phenotypes:
- category: Biochemical
  name: Hypercholesterolemia
  description: >-
    Elevated total cholesterol accompanies the LDL-predominant biochemical phenotype.
    Thirteen selected
    D374Y carriers from four British families had particularly severe hypercholesterolemia;
    the authors
    cautioned that this might be a cohort-specific phenotype.
  phenotype_term:
    preferred_term: Hypercholesterolemia
    term:
      id: HP:0003124
      label: Hypercholesterolemia
    temporality: CHRONIC
  evidence:
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications."
    explanation: >-
      Documents severe hypercholesterolemia as the defining clinical phenotype
      of PCSK9 D374Y carriers.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:19191301
    reference_title: "Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Several PCSK9 variants have been identified, some of them are gain-of-function mutations causing hypercholesterolemia by a reduction of low-density lipoprotein (LDL) receptor levels; while others are loss-of-function variants associated with a reduction of LDL-cholesterol (LDL-C) levels and a decreased risk of CHD."
    explanation: Attributes hypercholesterolemia to the gain-of-function PCSK9 alleles.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
- category: Biochemical
  name: Elevated LDL Cholesterol
  description: >-
    Elevated plasma LDL cholesterol concentration is the measured abnormality
    used both for diagnosis and for monitoring treatment response.
  phenotype_term:
    preferred_term: Increased LDL cholesterol concentration
    term:
      id: HP:0003141
      label: Increased LDL cholesterol concentration
    temporality: CHRONIC
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A clinical diagnosis of FH can be established in a proband with characteristic clinical features and significantly elevated LDL-C levels (typically >190 mg/dL in adults and >160 mg/dL in children)."
    explanation: >-
      GeneReviews sets the elevated-LDL-C threshold that defines the biochemical
      phenotype in PCSK9-related FH as in the other FH genes.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- category: Cardiovascular
  name: Premature Coronary Artery Disease
  description: >-
    Premature coronary atherosclerosis is an important complication. The more-than-ten-year
    difference
    from selected LDLR carriers was observed in the small British D374Y cohort and
    is not a universal
    age-of-onset difference for PCSK9 variants.
  phenotype_term:
    preferred_term: Coronary artery atherosclerosis
    term:
      id: HP:0001677
      label: Coronary artery atherosclerosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"
    explanation: >-
      Quantifies the earlier onset of premature coronary artery disease in
      PCSK9 D374Y carriers relative to LDLR-mutation heterozygotes.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:17452316
    reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gain-of-function mutations in PCSK9 cause hypercholesterolemia and premature atherosclerosis, whereas loss-of-function mutations result in hypocholesterolemia and protection from heart disease."
    explanation: >-
      Background summary of prior human genetics, used as secondary corroboration of the PCSK9-carrier
      cohort above; this sentence is not an experimental result of the cited in-vitro study.
    quote_role: BACKGROUND
    directness: INDIRECT
- category: Cardiovascular
  name: Myocardial Infarction
  description: >-
    Myocardial infarction is the archetypal premature cardiovascular event of
    familial hypercholesterolemia, including its PCSK9-related form.
  phenotype_term:
    preferred_term: Myocardial infarction
    term:
      id: HP:0001658
      label: Myocardial infarction
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely."
    explanation: >-
      GeneReviews lists myocardial infarction among the premature cardiovascular
      events of FH, of which PCSK9-related FH is one molecular form.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- category: Cardiovascular
  name: Angina Pectoris
  description: Exertional angina as a manifestation of premature coronary atherosclerosis.
  phenotype_term:
    preferred_term: Angina pectoris
    term:
      id: HP:0001681
      label: Angina pectoris
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely."
    explanation: GeneReviews lists angina among the premature cardiovascular events of FH.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- category: Cardiovascular
  name: Peripheral Arterial Disease
  description: >-
    Peripheral arterial stenosis can occur. It was recorded in 2 of 96 assessed carriers
    in a selected
    multicentre PCSK9 cohort. Broader FH studies also show increased peripheral arterial
    disease; these
    observations do not establish a population frequency for ADH3.
  phenotype_term:
    preferred_term: Peripheral arterial disease
    term:
      id: HP:0004950
      label: Peripheral arterial stenosis
  evidence:
  - reference: PMID:30085243
    reference_title: "Familial Hypercholesterolemia and Risk of Peripheral Arterial Disease and Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with individuals with unlikely FH, multivariable adjusted ORs (95% CIs) of PAD were 1.84 (1.70 to 2.00) in those with possible FH and 1.36 (1.00 to 1.84) in individuals with probable/definite FH."
    explanation: >-
      Quantifies elevated peripheral arterial disease risk in a general-population
      FH cohort of 106,172 individuals.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:27444203
    reference_title: "Coronary Heart Disease, Peripheral Arterial Disease, and Stroke in Familial Hypercholesterolaemia: Insights From the SAFEHEART Registry (Spanish Familial Hypercholesterolaemia Cohort Study)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coronary artery-related manifestations and peripheral artery disease were more prevalent in FH patients than in controls, but no significant differences were found for cerebrovascular events."
    explanation: >-
      Independent replication in a molecularly defined FH registry, and the
      cleanest statement that the excess arterial disease in FH is coronary and
      peripheral rather than cerebrovascular.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: >-
    The 164-carrier source includes PCSK9/LDLR double heterozygotes, and outcome-specific
    denominators
    are incomplete. No frequency band is inferred.
- category: Dermatologic
  name: Tendon Xanthomas
  description: >-
    Cholesterol deposits in tendons, classically the Achilles tendon and the
    extensor tendons of the hands, worsening with age.
  phenotype_term:
    preferred_term: Tendon xanthomatosis
    term:
      id: HP:0010874
      label: Tendon xanthomatosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels."
    explanation: GeneReviews describes tendon xanthomas as an FH cholesterol-deposition sign.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- category: Dermatologic
  name: Xanthelasma
  description: Yellowish waxy cholesterol deposits around the eyelids.
  phenotype_term:
    preferred_term: Xanthelasma
    term:
      id: HP:0001114
      label: Xanthelasma
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids."
    explanation: GeneReviews describes xanthelasma as an FH cholesterol-deposition sign.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- category: Ophthalmologic
  name: Corneal Arcus
  description: >-
    Opaque ring at the corneal margin from cholesterol deposition, appearing at
    a younger age than in the general population.
  phenotype_term:
    preferred_term: Corneal arcus
    term:
      id: HP:0001084
      label: Corneal arcus
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH."
    explanation: GeneReviews describes early corneal arcus as an FH cholesterol-deposition sign.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- name: Stroke
  category: Cardiovascular
  phenotype_term:
    preferred_term: Stroke
    term:
      id: HP:0001297
      label: Stroke
  description: Stroke can occur in FH. A selected multicentre PCSK9 carrier cohort recorded stroke in 6 of 98 assessed individuals; incomplete ascertainment, mixed ages and inclusion of double heterozygotes prevent a population frequency estimate.
  evidence:
  - *id010
  notes: 'Deliberately left unconnected in the causal graph: the selected PCSK9 cohort documents occurrence, but does not establish stroke subtype or a PCSK9-specific atherothrombotic route. The FH registry findings do not show excess cerebrovascular risk. The 6/98 count comes from Table 1 of PMID:26374825, inspected in the original table image; it is not a population-frequency estimate.'
imaging_findings:
- name: Coronary atherosclerotic plaque burden on coronary CT angiography
  modality: CT
  imaging_finding_term:
    preferred_term: Coronary artery atherosclerosis
    term:
      id: HP:0001677
      label: Coronary artery atherosclerosis
  located_in:
    preferred_term: coronary artery
    term:
      id: UBERON:0001621
      label: coronary artery
  spatial_extent: MULTIFOCAL
  description: >-
    Coronary CT angiography measures plaque burden and tissue categories in broader
    FH cohorts. The cited
    observational study relates plaque burden to subsequent events but does not provide
    a PCSK9-specific
    estimate.
  diagnostic: false
  evidence:
  - reference: PMID:33261814
    reference_title: "Coronary plaque burden, plaque characterization and their prognostic implications in familial hypercholesterolemia: A computed tomographic angiography study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median plaque burden was 25.0% (19.0-29.0), non-calcified plaque burden 22.83% (17.94-26.88), calcified plaque-burden 1.12% (0.31-2.86) and CCS 8.9 (0-93)."
    explanation: >-
      Quantifies the coronary plaque burden measurable by CT angiography in 259
      asymptomatic molecularly diagnosed FH patients.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:33261814
    reference_title: "Coronary plaque burden, plaque characterization and their prognostic implications in familial hypercholesterolemia: A computed tomographic angiography study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plaque burden was significantly related to event-free survival during follow-up (HR:1.11; 95%CI:1.05-1.18; p < 0.001)."
    explanation: >-
      Establishes that the imaging measurement is prognostic, not only
      descriptive, over 3.9 years of follow-up.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: >-
    General FH imaging evidence. ARCHITECT treatment-associated CT changes are described
    under alirocumab;
    CT tissue categories are not histological cap measurements.
- name: Coronary artery calcification
  modality: CT
  imaging_finding_term:
    preferred_term: Coronary artery calcification
    term:
      id: HP:0001717
      label: Coronary artery calcification
  located_in:
    preferred_term: coronary artery
    term:
      id: UBERON:0001621
      label: coronary artery
  description: >-
    Coronary calcium is an imaging component of atherosclerotic burden. It does not
    establish PCSK9 causation
    or directly measure all noncalcified plaque.
  diagnostic: false
  evidence:
  - reference: PMID:33261814
    reference_title: "Coronary plaque burden, plaque characterization and their prognostic implications in familial hypercholesterolemia: A computed tomographic angiography study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five-year risk was independently related to plaque burden, non-calcified plaque burden, calcified plaque burden and coronary calcium score"
    explanation: >-
      Shows calcified plaque burden and coronary calcium score are each
      independently related to estimated cardiovascular risk in FH.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:37322181
    reference_title: International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CACS should not be used to monitor the effectiveness of cholesterol-lowering treatment
    explanation: Calcium scores have a different role from monitoring treatment response.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    FH-wide finding; no PCSK9-specific distribution is inferred. IAS guidance advises
    against using coronary
    calcium scores to monitor lipid-lowering treatment effectiveness.
biochemical:
- name: Plasma LDL Cholesterol
  notes: >-
    LDL-C is distinct from total cholesterol. The British D374Y mean of 13.6 mmol/L
    was total serum cholesterol
    and is not used as an LDL-C value.
  biomarker_term:
    preferred_term: Increased LDL cholesterol concentration
    term:
      id: HP:0003141
      label: Increased LDL cholesterol concentration
  evidence:
  - *id011
- name: Plasma Lipoprotein(a)
  notes: >-
    Lp(a) is an additional risk marker considered in FH assessment; it is not categorically
    unaffected
    by PCSK9-directed therapy. Lp(a) can modify cardiovascular risk in FH. A value
    or association in a
    clinically defined FH cohort does not establish increased Lp(a) as a universal
    PCSK9 phenotype. The
    small carrier trial had no significant randomized Lp(a) difference at week 2,
    despite a later pooled
    decrease.
  biomarker_term:
    preferred_term: Elevated circulating lipoprotein(a) concentration
    term:
      id: HP:6000521
      label: Elevated circulating lipoprotein(a) concentration
  evidence:
  - reference: PMID:27185354
    reference_title: "High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings suggest that all individuals with familial hypercholesterolaemia should have their lipoprotein(a) measured in order to identify those with the highest concentrations, and as a result, the highest risk of myocardial infarction."
    explanation: >-
      Establishes measurement of lipoprotein(a) as part of the FH workup and
      its role as a risk modifier.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:27185354
    reference_title: "High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High lipoprotein(a) cholesterol accounted for a quarter of all individuals diagnosed with clinical familial hypercholesterolaemia"
    explanation: >-
      Supports the confounder role noted above - lipoprotein(a) cholesterol
      inflates the clinically measured LDL-C used by the phenotypic criteria.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:34433300
    reference_title: "Familial Hypercholesterolemia-Risk-Score: A New Score Predicting Cardiovascular Events and Cardiovascular Mortality in Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The FH-Risk-Score incorporates 7 clinical variables: sex, age, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hypertension, smoking, and lipoprotein (a) (Lp(a)) with a Harrell C-index for 10-year ASCVD event of 0.75"
    explanation: >-
      Places lipoprotein(a) among the prognostic variables of a validated FH
      risk score.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
genetic:
- name: PCSK9
  gene_term:
    preferred_term: PCSK9
    term:
      id: hgnc:20001
      label: PCSK9
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_bf710ddc-c189-419f-ab70-25300b067db2-2018-11-14T170000.000Z
    evidence:
    - reference: CGGV:assertion_bf710ddc-c189-419f-ab70-25300b067db2-2018-11-14T170000.000Z
      reference_title: "PCSK9 / hypercholesterolemia, autosomal dominant, 3 (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PCSK9 | HGNC:20001 | hypercholesterolemia, autosomal dominant, 3 | MONDO:0011369 | AD | Definitive"
      explanation: >-
        The ClinGen General Gene Curation Expert Panel classifies the
        autosomal dominant PCSK9-hypercholesterolemia 3 relationship
        (MONDO:0011369, this entry's disease term) as Definitive.
    - reference: CGGV:assertion_bf710ddc-c189-419f-ab70-25300b067db2-2018-11-14T170000.000Z
      reference_title: "PCSK9 / hypercholesterolemia, autosomal dominant, 3 (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "The mechanism for disease is heterozygous gain of function (Maxwell et al., 2005; PMID: 16577715), while heterozygous loss of function variants are associated with low levels of LDL cholesterol"
      explanation: >-
        ClinGen names heterozygous gain of function as the disease mechanism,
        and separates the loss-of-function low-LDL phenotype from this entry.
  notes: >-
    PCSK9 gain-of-function sequence variants and rare whole-gene duplication cause
    autosomal dominant
    hypercholesterolemia. Allele-specific binding, processing, secretion and receptor-depleting
    effects
    must be distinguished. The tenfold potency comparison is a D374Y culture result,
    not a universal clinical
    effect size. Biochemical penetrance and clinical event risk differ. GeneReviews
    summarizes approximately
    90% penetrance for S127R and high penetrance for D374Y; estimates for many other
    alleles are unknown.
    Incomplete segregation and intrafamilial variability were reported for other variants.
    PCSK9 loss-of-function
    variants are a separate low-LDL phenotype, not ADH3.
  evidence:
  - reference: PMID:12730697
    reference_title: "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH."
    explanation: Establishes PCSK9 as the causal gene at the HCHOLA3 locus.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:16211558
    reference_title: "Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Segregation with hypercholesterolemia is incomplete in one pedigree. Type and severity of hyperlipidemia and of cardiovascular disease could vary among subjects from the same family."
    explanation: >-
      Documents incomplete segregation and within-family variability in
      severity for PCSK9 alleles, the observation behind the expressivity
      statement in this entry's notes.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:15358785
    reference_title: "NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The S127R and D374Y mutations result in approximately 50-60% and > or =98% decrease in zymogen processing, respectively."
    explanation: >-
      Supports the allele-level heterogeneity noted above: S127R and D374Y
      differ markedly from each other in their effect on zymogen processing.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:16554528
    reference_title: "Sequence variations in PCSK9, low LDL, and protection against coronary heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD"
    explanation: >-
      The reciprocal, loss-of-function arm of the same gene: nonsense PCSK9
      alleles lower LDL-C and coronary risk lifelong. This is not evidence that
      PCSK9 causes ADH3. It supports the notes' statement that loss-of-function
      alleles give a separate low-LDL phenotype, and supports the
      gain-of-function mechanism only by inference from the opposite direction
      of effect.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
  - *id012
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK174884/
    reference_title: Familial Hypercholesterolemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Penetrance is approximately 90% in persons
    explanation: GeneReviews identifies S127R heterozygotes in the surrounding sentence; this estimate is allele-specific and is not the penetrance of clinical ASCVD.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  case_fractions:
  - population: >-
      130 adult and paediatric autosomal dominant hypercholesterolemia patients
      already screened negative for LDLR and APOB mutations
    case_fraction_percent: 2.3
    cohort_size: 130
    notes: >-
      The authors reported approximately 2.3% in 130 selected LDLR/APOB-negative referrals.
      This is not
      population prevalence or an upper bound for unselected FH; incomplete segregation
      and modifiers
      complicate interpretation.
    evidence:
    - reference: PMID:16211558
      reference_title: "Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These observations suggest that variations in PCSK9 are a rare cause of non LDLR/non APOB ADH (approximately 2.3%) and that additional environmental or genetic factors may contribute to the phenotype caused by PCSK9 missense mutations in humans."
      explanation: >-
        States the 2.3% share directly, together with the authors' own caveat
        that additional factors shape the phenotype.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
    - reference: PMID:16211558
      reference_title: "Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we analysed the PCSK9 coding region and intronic junctions in 130 adult or pediatric patients with ADH, previously found as being non LDLR/non APOB mutation carriers."
      explanation: Establishes the cohort size and the LDLR/APOB-negative denominator.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  variants:
  - name: PCSK9 p.Ser127Arg
    description: >-
      One of the two founding ADH3 alleles. Markedly impairs autocatalytic
      zymogen processing and reduces cell-surface LDL receptor in patient
      lymphoblasts.
    gene:
      preferred_term: PCSK9
      term:
        id: hgnc:20001
        label: PCSK9
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:15358785
      reference_title: "NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The cell surface LDL receptor (LDLR) levels are reduced by 35% in lymphoblasts of S127R patients."
      explanation: Functional consequence of S127R measured in patient-derived cells.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - name: PCSK9 p.Phe216Leu
    description: >-
      The second founding ADH3 allele, reported alongside S127R in the original
      French pedigrees. Zymogen processing is normal, so its gain of function is
      not explained by the processing defect seen with S127R.
    gene:
      preferred_term: PCSK9
      term:
        id: hgnc:20001
        label: PCSK9
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:15358785
      reference_title: "NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "F216L, and R218S natural mutants resulted in normal zymogen processing."
      explanation: Documents that F216L retains normal zymogen processing.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - name: PCSK9 p.Asp374Tyr
    description: >-
      D374Y increases LDLR-depleting activity in the tested extracellular-protein
      assays. Small selected
      British families had unusually severe cholesterol elevation and early coronary
      disease; the clinical
      difference is not generalized to every PCSK9 variant.
    gene:
      preferred_term: PCSK9
      term:
        id: hgnc:20001
        label: PCSK9
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:17080197
      reference_title: "Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This activity was approximately 10-fold greater for a gain-of-function mutant, PCSK9(D374Y), that causes hypercholesterolemia."
      explanation: Quantifies the increased receptor-degrading potency of D374Y.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
    - reference: PMID:15772090
      reference_title: "Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We have identified the D374Y mutant of PCSK9 in three FH families of English origin; all 12 affected individuals have unusually severe hypercholesterolaemia and require more stringent treatment than typical FH patients, who are heterozygous for defects in the LDL receptor."
      explanation: Documents the severe clinical phenotype of D374Y carriers.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - name: PCSK9 p.Arg496Trp
    description: >-
      R496W was reported as a C-terminal gain-of-function variant with impaired LDL-particle
      association
      in prior in-vitro work summarized by the 2022 study. The contribution of this
      association to human
      receptor turnover remains inferred.
    gene:
      preferred_term: PCSK9
      term:
        id: hgnc:20001
        label: PCSK9
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:36187800
      reference_title: "Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We previously reported that an R496W GOF mutation in a region of PCSK9 known as cysteine-histidine-rich domain module 1 (CM1) prevents LDL binding in vitro"
      explanation: >-
        Identifies R496W as a CM1-domain gain-of-function allele acting through
        loss of LDL binding.
      quote_role: BACKGROUND
      directness: DIRECT
    - reference: PMID:36187800
      reference_title: "Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Herein, we identify additional GOF mutations that inhibit LDL association, localized either within CM1 or a surface-exposed region in the PCSK9 prodomain."
      explanation: >-
        Establishes loss of LDL association as a shared mechanism spanning two
        distinct PCSK9 domains, which is what makes this a separate variant
        class from S127R/F216L/D374Y as classically described.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - name: PCSK9 whole-gene duplication
    description: Rare copy-number mechanism reported in two unrelated index cases with cosegregation in affected relatives. Very high plasma PCSK9 was measured in one index case; treatment resistance is not a universal prediction.
    gene: *id013
    type: duplication
    clinical_significance: PATHOGENIC
    evidence:
    - *id012
    - *id014
environmental:
- name: High Saturated and Trans Fat Intake
  description: >-
    High saturated and trans fat intake can add to LDL exposure. Dietary improvement
    complements pharmacological
    treatment in FH.
  exposure_term:
    preferred_term: high dietary saturated and trans fat exposure
    modifier: INCREASED
    term:
      id: ECTO:0090010
      label: exposure to lipid in food
  influences_mechanisms:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Dietary fat intake adds to the circulating LDL burden already produced by
      the inherited receptor-degradation defect.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."
      explanation: >-
        GeneReviews lists high saturated and trans fat intake among the
        exposures to avoid in FH, acting at the lipid level itself.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevention of primary manifestations: Heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day); increased physical activity; no smoking."
    explanation: >-
      The corresponding dietary recommendation, establishing this as a
      modifiable exposure in FH management.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- name: Tobacco Smoking
  description: >-
    Smoking is a modifiable cardiovascular risk factor in FH. Its contribution is
    not assumed to be independent
    of every lipid measure.
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  influences_mechanisms:
  - target: Subendothelial Retention of ApoB-Containing Lipoproteins
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Smoking can aggravate vascular risk; GeneReviews supports avoidance but does
      not experimentally
      isolate the arterial-retention step in PCSK9 carriers.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."
      explanation: GeneReviews lists smoking first among the exposures to avoid in FH.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  evidence:
  - reference: PMID:34433300
    reference_title: "Familial Hypercholesterolemia-Risk-Score: A New Score Predicting Cardiovascular Events and Cardiovascular Mortality in Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The FH-Risk-Score incorporates 7 clinical variables: sex, age, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hypertension, smoking, and lipoprotein (a) (Lp(a)) with a Harrell C-index for 10-year ASCVD event of 0.75"
    explanation: >-
      Smoking is retained as one of only seven predictors in a 10-year ASCVD
      risk score derived prospectively in 3881 heterozygous FH patients. That
      is the quantitative basis for curating smoking as a modifiable exposure
      acting on the vascular arm rather than on the lipid node.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Sedentary Lifestyle
  description: >-
    Physical inactivity is a modifiable FH risk factor. An observational composite
    of diet, exercise,
    smoking and weight cannot estimate the effect of changing exercise alone.
  exposure_term:
    preferred_term: exposure to sedentary lifestyle
    term:
      id: ECTO:6000004
      label: exposure to sedentary lifestyle
  influences_mechanisms:
  - target: Subendothelial Retention of ApoB-Containing Lipoproteins
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Physical activity is part of cardiovascular prevention. The specific intermediate
      connecting inactivity
      to arterial retention is inferred from general vascular biology.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."
      explanation: GeneReviews lists sedentary lifestyle among the exposures to avoid in FH.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  evidence:
  - reference: PMID:35294538
    reference_title: "Association of the Interaction Between Familial Hypercholesterolemia Variants and Adherence to a Healthy Lifestyle With Risk of Coronary Artery Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among carriers, a favorable lifestyle conferred 86% lower risk of CAD compared with an unfavorable lifestyle (hazard ratio, 0.14 [95% CI, 0.04-0.41])."
    explanation: >-
      An observational association with a composite healthy-lifestyle score; not an
      isolated exercise
      intervention or proof that inactivity alone accounts for this effect.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
treatments:
- name: Evolocumab
  description: >-
    Fully human monoclonal antibody that binds circulating PCSK9 and prevents it from engaging the hepatocyte
    LDL receptor, restoring receptor recycling and hepatic LDL clearance. In heterozygous familial hypercholesterolemia
    it lowers LDL cholesterol by approximately 60% on top of statin therapy, and in established atherosclerotic
    cardiovascular disease it reduces cardiovascular events. It is the mechanistically direct therapy
    for ADH3: the drug target is PCSK9 itself.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: evolocumab
      term:
        id: NCIT:C174672
        label: Evolocumab
  target_mechanisms:
  - target: PCSK9 Binding to the LDL Receptor EGF-A Domain
    treatment_effect: INHIBITS
    description: >-
      Antibody neutralisation of circulating PCSK9 blocks the EGF-A engagement
      that initiates receptor degradation.
    evidence:
    - reference: PMID:28304224
      reference_title: "Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%."
      explanation: >-
        States the drug's target and its effect on the LDL cholesterol output
        of this pathway. This is the trial's background statement of the
        established drug mechanism, cited for the drug-target identity; the
        trial's own outcome result is cited separately on the treatment.
      quote_role: BACKGROUND
      directness: INDIRECT
  evidence:
  - reference: PMID:25282519
    reference_title: "PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo."
    explanation: >-
      Randomised evidence of efficacy in heterozygous familial
      hypercholesterolemia, the clinical setting of ADH3.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:28304224
    reference_title: "Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events."
    explanation: >-
      Outcome evidence that PCSK9 inhibition reduces cardiovascular events, the
      clinical endpoint this disease threatens.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: >-
    RUTHERFORD-2 studied broader heterozygous FH and FOURIER studied established ASCVD.
    These findings
    are distinct from the small alirocumab trial in PCSK9 gain-of-function carriers.
    No adequately powered
    PCSK9-genotype-specific cardiovascular-event trial is cited.
- name: Alirocumab
  description: >-
    Monoclonal antibody against circulating PCSK9. A randomized placebo-phase study
    in 13 adults carrying
    D374Y, S127R, L108R or R218S demonstrated short-term LDL-C lowering on background
    therapy. Broader
    post-acute-coronary-syndrome trials support cardiovascular-event reduction in
    a different population.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: alirocumab
      term:
        id: NCIT:C174849
        label: Alirocumab
  target_mechanisms:
  - target: PCSK9 Binding to the LDL Receptor EGF-A Domain
    treatment_effect: INHIBITS
    description: >-
      Antibody binding to circulating PCSK9 prevents the receptor engagement
      step.
    evidence:
    - reference: PMID:30403574
      reference_title: "Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy."
      explanation: >-
        Identifies alirocumab's molecular target as PCSK9. This is the trial's
        aim sentence rather than a result; it is cited for the drug-target
        identity only, with the trial's outcome result cited separately on the
        treatment itself.
      quote_role: BACKGROUND
      directness: INDIRECT
  - target: Atherosclerotic Plaque Formation
    treatment_effect: MODULATES
    description: >-
      ARCHITECT observed reduced CT plaque burden and shifts in CT-derived composition
      over 78 weeks on
      added alirocumab. The single-arm study does not isolate drug causality, demonstrate
      histological
      cap restoration, or establish a PCSK9-carrier-specific response.
    evidence:
    - reference: PMID:37009731
      reference_title: "Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "an increase in the proportion of calcified (+0.3%; P<0.001) and mainly fibrous (+6.2%; P<0.001) plaque, accompanied by a decrease in the percentage of fibro-fatty (-3.9%; P<0.001) and necrotic plaque (-0.6%; P<0.001)"
      explanation: >-
        Within-person changes in CT-derived tissue categories in an uncontrolled FH
        study; indirect evidence
        for plaque modification, not direct histological measurement.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  evidence:
  - reference: PMID:30403574
    reference_title: "Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo."
    explanation: Randomised cardiovascular-outcome evidence for PCSK9 antibody therapy, but in patients after acute coronary syndrome rather than in PCSK9 gain-of-function carriers; applying it to this entry is an extrapolation across populations.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
  - reference: PMID:37009731
    reference_title: "Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with alirocumab in addition to high-intensity statin therapy resulted in significant regression of coronary plaque burden and plaque stabilization on coronary computed tomographic angiography over 78 weeks"
    explanation: >-
      The FH-specific alirocumab trial, in a molecularly determined cohort -
      closer to this entry's population than the post-acute-coronary-syndrome
      outcome trial, though still not PCSK9-stratified.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - &id015
    reference: PMID:26374825
    reference_title: Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline and 53.7% compared with control PCSK9 GOF mutation patients treated with placebo for 2 weeks (P=0.0009; primary end point).
    explanation: The primary randomized contrast was a 53.7-percentage-point difference at week 2 in 13 adults carrying four PCSK9 variants; the 62.5% figure is a within-group change. This was not an event-outcome trial.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  notes: >-
    The 13-person trial tested a two-week randomized LDL-C contrast; its pooled eight-week
    73.3% reduction
    had no concurrent placebo comparator. All participants received statins and six
    received ezetimibe.
    It was too small and short for cardiovascular-event or uncommon-safety conclusions.
    ODYSSEY OUTCOMES
    and ARCHITECT provide broader-population evidence; ARCHITECT was open-label and
    single-arm, without
    a reported PCSK9-stratified effect.
- name: Inclisiran
  description: >-
    A small interfering RNA that silences PCSK9 messenger RNA in the
    hepatocyte, suppressing synthesis of the protein rather than neutralising
    it after secretion. Given twice yearly after loading. In heterozygous
    familial hypercholesterolemia it lowered LDL cholesterol by roughly 40%
    versus baseline (about 48 percentage points versus placebo), with
    reductions reported across FH genotypes.
  therapeutic_modality: SIRNA
  oligonucleotide_details:
    oligonucleotide_mechanism: RNAI_KNOCKDOWN
    target_gene:
      preferred_term: PCSK9
      term:
        id: hgnc:20001
        label: PCSK9
    target_transcript: PCSK9 mRNA
    conjugation: GALNAC
    delivery_platform: CONJUGATE
  dosing_interval: once every 6 months
  dosing_interval_days: 182.5
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: inclisiran
      term:
        id: NCIT:C170062
        label: Inclisiran
  target_mechanisms:
  - target: Production of Disease-Associated PCSK9
    treatment_effect: INHIBITS
    description: >-
      RNA interference suppresses hepatic PCSK9 synthesis. The cited LDL-C trial does
      not establish that
      an apoB-production mechanism was specifically reversed in PCSK9 carriers.
    evidence:
    - reference: PMID:32197277
      reference_title: "Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia."
      explanation: >-
        States inclisiran's mechanism as inhibition of hepatic PCSK9 synthesis.
        The sentence reports the earlier phase 2 result rather than this
        trial's own finding, and is cited for the mechanism only; ORION-9's own
        LDL-C result is cited separately on the treatment.
      quote_role: BACKGROUND
      directness: INDIRECT
  evidence:
  - reference: PMID:32197277
    reference_title: "Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile."
    explanation: Randomised evidence of efficacy in heterozygous familial hypercholesterolemia.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:32197277
    reference_title: "Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia."
    explanation: >-
      Reports that the LDL-lowering effect was seen across FH genotypes, the
      closest available evidence that it applies to PCSK9-gene carriers.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: >-
    ORION-9 measured LDL-C in broader heterozygous FH. ORION-4 (NCT03705234) is an
    event-outcome study
    in established ASCVD, listed as active, not recruiting when checked in September
    2026; it does not
    supply completed ADH3-specific cardiovascular-event evidence here.
- name: Statin Therapy
  description: >-
    HMG-CoA reductase inhibition is foundational FH therapy. Response varies: selected
    D374Y carriers
    remained severely hypercholesterolemic despite treatment, while a small S127R
    series had substantial
    LDL-C lowering. These observations do not establish universal PCSK9-related statin
    resistance.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: atorvastatin
      term:
        id: CHEBI:39548
        label: atorvastatin
    - preferred_term: simvastatin
      term:
        id: NCIT:C29454
        label: Simvastatin
  target_mechanisms:
  - target: Reduced Hepatic Clearance of Circulating LDL Particles
    treatment_effect: RESTORES
    description: >-
      Statins promote LDL removal through the established hepatic cholesterol/LDLR
      response. The D374Y
      family series measured serum cholesterol rather than hepatic clearance flux,
      so it provides indirect
      support for this mechanism.
    evidence:
    - reference: PMID:16224054
      reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "had higher pretreatment serum cholesterol levels (13.6+/-2.9 versus 9.6+/-1.6 mmol/L; P=0.004) that remained higher during treatment with simvastatin (10.1+/-3.0 versus 6.5+/-0.9 mmol/L; P=0.006)"
      explanation: >-
        Treatment-associated total-cholesterol change in selected D374Y families,
        not a direct assay of
        hepatic LDL clearance.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adults: pharmacotherapy (statins with additional medications as needed) to reduce lipid levels; referral to a lipid specialist if necessary to reduce LDL-C levels"
    explanation: GeneReviews states statins as first-line pharmacotherapy in FH.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Children: referral to a lipid specialist; diet and lifestyle modifications; statins can be used in children starting around age eight years."
    explanation: >-
      GeneReviews sets the paediatric starting point for statin therapy, which
      matters here because the LDL burden is present from birth.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: url:https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-removal-strongest-warning-against-using-cholesterol-lowering-statins-during-pregnancy
    reference_title: FDA requests removal of strongest warning against using cholesterol-lowering statins during pregnancy; still advises most pregnant patients should stop taking statins | FDA
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Health care professionals should discontinue statin therapy in most pregnant patients. Alternatively, health care professionals should consider the ongoing therapeutic needs of the individual patient
    explanation: FDA guidance replaces an absolute prohibition with usual discontinuation and individualized assessment for exceptional high-risk patients.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:41741298
    reference_title: 'Update on familial hypercholesterolemia: An expert clinical consensus from the National Lipid Association.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A stepwise approach to optimal therapy is outlined, beginning with lifestyle interventions and pharmacotherapy with maximally tolerated statins and ezetimibe.
    explanation: The 2026 NLA consensus supports foundational care across FH. Its cached abstract does not provide detailed genotype-specific thresholds.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    FDA removed the blanket pregnancy contraindication in 2021. Most pregnant patients
    should stop statins;
    selected very-high-risk patients require individualized specialist assessment.
    Patients requiring
    ongoing statins should not breastfeed. The regulatory change does not prove fetal
    safety, and evidence
    about miscarriage remains insufficient. Preconception planning should address
    maternal risk and alternatives.
- name: Ezetimibe
  description: >-
    Intestinal cholesterol-absorption inhibitor used with statins or other agents
    to achieve individualized
    FH LDL-C goals. Intensification depends on baseline LDL-C, ASCVD risk, tolerance
    and response; every
    patient need not follow a rigid sequence.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ezetimibe
      term:
        id: CHEBI:49040
        label: ezetimibe
  target_mechanisms:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    treatment_effect: MODULATES
    description: >-
      Reduced intestinal cholesterol absorption lowers the plasma LDL burden
      downstream of the PCSK9 lesion rather than correcting it.
    evidence:
    - reference: PMID:37322181
      reference_title: International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: PCSK9-targeted therapy (monoclonal antibodies or a small interfering RNA (inclisiran)) should be added if LDL-cholesterol goals are not achieved with diet, maximally tolerated statins, ezetimibe, bempedoic acid and other adjunctive therapies
      explanation: FH-wide guidance supports ezetimibe as part of LDL-lowering care; it is not an isolated drug-mechanism experiment.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  notes: >-
    Curated as background therapy for FH generally. No PCSK9-genotyped
    ezetimibe trial is cited.
- name: Bempedoic Acid
  description: >-
    ATP citrate lyase inhibitor used as an additional LDL-lowering option, including
    in statin intolerance.
    CLEAR Outcomes supports event reduction in statin-intolerant high-risk patients,
    without a PCSK9-specific
    estimate.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: bempedoic acid
      term:
        id: CHEBI:149601
        label: bempedoic acid
  target_mechanisms:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    treatment_effect: MODULATES
    description: >-
      ATP citrate lyase inhibition reduces hepatic cholesterol synthesis and so
      lowers the circulating LDL burden downstream of the PCSK9 lesion, without
      acting on PCSK9 or on LDL receptor degradation.
    evidence:
    - reference: PMID:36876740
      reference_title: "Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events"
      explanation: >-
        States the molecular target and the LDL-lowering effect that place this
        agent on the plasma-LDL node rather than on the PCSK9 node.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  evidence:
  - reference: PMID:36876740
    reference_title: "Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004)"
    explanation: >-
      CLEAR Outcomes provides the cardiovascular outcome evidence that
      justifies curating bempedoic acid alongside ezetimibe and apheresis
      rather than as an investigational option.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: >-
    Curated as background therapy for FH generally, on the same footing as
    ezetimibe. CLEAR Outcomes enrolled statin-intolerant patients at high
    cardiovascular risk, not a PCSK9-genotyped or FH-only cohort, so the
    outcome benefit is not ADH3-specific evidence.
- name: Colesevelam
  description: >-
    Nonabsorbed bile acid sequestrant used as an adjunct for LDL-C reduction. It can
    be considered in
    pregnancy under specialist care; limited pregnancy experience and potential effects
    on fat-soluble
    vitamin absorption require consideration.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: colesevelam
      term:
        id: CHEBI:59594
        label: colesevelam
  target_mechanisms:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    treatment_effect: MODULATES
    description: >-
      Adds LDL-C lowering on top of maximally tolerated statin plus ezetimibe,
      reducing the plasma LDL burden downstream of the PCSK9 lesion without
      correcting it.
    evidence:
    - reference: PMID:23916045
      reference_title: "The efficacy of colesevelam HCl in the treatment of heterozygous familial hypercholesterolemia in pediatric and adult patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In the study in adults with refractory FH, the addition of colesevelam to a maximally tolerated regimen of a statin plus ezetimibe provided a significantly greater reduction from baseline in LDL-C levels compared with placebo."
      explanation: >-
        Establishes an incremental LDL-C reduction on top of the statin plus
        ezetimibe background this entry already curates.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  evidence:
  - reference: PMID:23916045
    reference_title: "The efficacy of colesevelam HCl in the treatment of heterozygous familial hypercholesterolemia in pediatric and adult patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The bile acid sequestrant colesevelam is indicated to reduce elevated LDL-C levels in adults with primary hyperlipidemia and in boys and postmenarchal girls (aged 10-17 years) with heterozygous FH."
    explanation: >-
      States the licensed indications: primary hyperlipidemia in adults, and
      heterozygous FH in the paediatric population this entry's progression
      section starts from.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:38338916
    reference_title: "Unveiling Familial Hypercholesterolemia-Review, Cardiovascular Complications, Lipid-Lowering Treatment and Its Efficacy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bile acid sequestrants bind the bile acids and prevent the reabsorption of cholesterol into the blood. Thus, they increase the metabolism of cholesterol into bile acids and intensify the synthesis of LDLR, which reduces the levels of LDL in the blood"
    explanation: >-
      Sources the class mechanism stated in this treatment's description - the
      LDL receptor upregulation that makes a sequestrant relevant to a
      receptor-degradation disease.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:37322181
    reference_title: International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bile acid sequestrants should be considered to treat hypercholesterolaemia, ideally 3 months before a planned pregnancy, as well as during pregnancy and lactation;
    explanation: FH guidance permits consideration of this class; the recommendation is not a randomized pregnancy-safety result.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    The cited lipid-lowering studies concern broader heterozygous FH, not a PCSK9-specific
    treatment estimate.
    Pregnancy guidance is FH-wide and does not imply proven absence of risk.
- name: LDL Apheresis
  description: >-
    Specialist extracorporeal removal of apoB-containing lipoproteins for selected
    severe FH, particularly
    progressive ASCVD despite intensive combination treatment. The British D374Y series
    documents use
    of apheresis/partial ileal bypass among two intensively treated carriers; the
    abstract does not resolve
    each individual procedure.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: therapeutic apheresis
    term:
      id: NCIT:C173286
      label: Therapeutic Apheresis
  target_mechanisms:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    treatment_effect: MODULATES
    description: >-
      Apheresis removes circulating LDL directly, bypassing the failed hepatic
      receptor route rather than repairing it.
    evidence:
    - reference: PMID:16224054
      reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "or current lipid-lowering therapy, including LDL apheresis and partial ileal bypass in 2 PCSK9 patients (7.0+/-1.6 versus 5.4+/-1.0 mmol/L; P=0.001)"
      explanation: >-
        The family report documents intensive therapy including apheresis and partial
        ileal bypass in
        two patients; procedure-level allocation is not inferred from the abstract.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  evidence:
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications."
    explanation: >-
      Supports escalation to aggressive lipid-lowering management in this
      genotype. The sentence does not name apheresis; apheresis is one of the
      most intensive options, so its application here is an inference.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
  - reference: PMID:37322181
    reference_title: International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Lipoprotein apheresis should be undertaken in adults with phenotypic HeFH and progressive ASCVD who do not achieve LDL-cholesterol goals despite combined treatment with a high-potency statin, ezetimibe and a PCSK9 inhibitor,
    explanation: FH-wide criteria support specialist escalation for selected refractory disease.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
- name: Cardiovascular Risk Factor Modification
  description: >-
    Non-pharmacological management: smoking cessation, reduced saturated and
    trans fat intake, increased soluble fibre, physical activity, weight
    control, and treatment of hypertension and diabetes. These do not address
    the PCSK9 lesion but reduce the atherogenic burden it acts upon.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: lifestyle and risk-factor therapy
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  target_mechanisms:
  - target: Subendothelial Retention of ApoB-Containing Lipoproteins
    treatment_effect: MODULATES
    description: >-
      Lifestyle and risk-factor care can reduce cardiovascular risk through several
      lipid and vascular
      processes. The GeneReviews recommendation does not isolate a measured effect
      on intimal retention.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."
      explanation: GeneReviews names the modifiable exposures that aggravate atherosclerotic risk in FH.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevention of primary manifestations: Heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day); increased physical activity; no smoking."
    explanation: GeneReviews management recommendation for primary prevention in FH.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- name: Age- and Risk-Adapted Pediatric Lipid-Lowering Care
  description: Treatment decisions use repeated lipid measurements, age, family history and other risks. IAS 2023 guidance recommends offering medication at ages 8–10 for persistent LDL-C above 190 mg/dL, with lower thresholds considered when additional risk is present. Drug selection follows local pediatric approvals and specialist assessment; these are broader FH recommendations, not PCSK9-specific trial thresholds.
  notes: Long-term evidence for newer agents in children remains limited. Growth, adherence and adverse effects require follow-up. The cited age threshold is explicitly the 2023 IAS recommendation, not a universal regulatory label.
  evidence:
  - reference: PMID:37322181
    reference_title: International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pharmacological treatment should be offered at age 8–10 years with an LDL-cholesterol concentration >4.9 mmol/l (>190 mg/dl), recorded on two occasions with a fasting lipid profile
    explanation: Age and repeat LDL-C measurements qualify the pediatric FH recommendation.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:37322181
    reference_title: International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Use of a PCSK9 inhibitor may be considered according to clinical indications and regulatory approvals, with the caveat of limited evidence of long-term safety in children and adolescents
    explanation: Pediatric use remains conditional on indication and approval; no uniform age label is inferred.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
experimental_models:
- name: Urine-derived iPSC hepatocyte-like cells from a PCSK9 S127R carrier (HLC-S127R)
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Urine-derived cells from one S127R carrier were reprogrammed into iPSCs and differentiated
    into hepatocyte-like
    cells. One healthy donor supplied the comparator; multiple clones are not independent
    patients. The
    nonisogenic comparison supports a patient-cell phenotype without isolating the
    variant from donor
    background.
  cell_source: Patient-derived (urine somatic cells reprogrammed to iPSC)
  culture_system: Two-dimensional hepatocyte-like cell differentiation
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: hepatocyte-like cell
    term:
      id: CL:0000182
      label: hepatocyte
  publication: PMID:26586530
  modeled_mechanisms:
  - target: Reduced Hepatic Clearance of Circulating LDL Particles
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Hepatocyte-like cells carrying the patient's S127R allele take up 71% less
      LDL than control cells, the cellular readout of this node.
    limitations: >-
      Hepatocyte-like cells derived from iPSC are immature relative to adult
      hepatocytes; the comparison is between individuals rather than between
      isogenic corrected and uncorrected lines, so donor background is not
      controlled.
    readouts:
    - name: LDL uptake by hepatocyte-like cells
      target: Reduced Hepatic Clearance of Circulating LDL Particles
      direction: DECREASED
      interpretation: >-
        A cellular LDL-uptake measurement supporting, but not directly measuring,
        whole-body hepatic clearance.
      evidence:
      - reference: PMID:26586530
        reference_title: "Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake"
        explanation: Reports the LDL-uptake measurement grounding this readout.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:26586530
      reference_title: "Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We aimed to validate urine-sample-derived human induced pluripotent stem cells (UhiPSCs) as an appropriate tool to model PCSK9-mediated ADH and FHBL."
      explanation: >-
        States the model's purpose as a model of PCSK9-mediated autosomal
        dominant hypercholesterolemia.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  evidence:
  - reference: PMID:26586530
    reference_title: "Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "urine samples provide an attractive and convenient source of somatic cells for reprogramming and hepatocyte differentiation, but also a powerful tool to further decipher PCSK9 mutations and function."
    explanation: The authors' conclusion on the model's utility for studying PCSK9 variant function.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: >-
    Pravastatin enhanced LDL uptake in culture; a separate uncontrolled clinical observation
    involved
    five S127R carriers. The cell response does not validate individual clinical prediction
    or universal
    statin sensitivity.
datasets:
- accession: geo:GSE75545
  title: >-
    Urine-sample-derived human induced pluripotent stem cells as a model to
    study PCSK9-mediated autosomal dominant hypercholesterolemia
  description: >-
    GSE75545 contains ten expression arrays comparing urine-derived progenitor cells
    with reprogrammed
    iPSCs from a control donor and an S127R carrier: two progenitor samples per donor
    and three iPSC clones
    per donor. It does not contain hepatocyte-like-cell treatment arrays or the loss-of-function
    donor
    arrays described elsewhere in the publication.
  data_type: MICROARRAY
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:26586530
  evidence:
  - reference: PMID:26586530
    reference_title: Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: A transcriptomic analysis was performed and confirmed the global gene-expression profile modification between two control Ucell lines, two PCSK9-S127R Ucell lines and three clones of each UhiPSC line generated
    explanation: The full-text reprogramming analysis defines the deposited expression experiment; clone counts do not represent independent patients.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  notes: >-
    Sample-level GEO design was checked against the publication Methods and Figure
    2. The GEO series summary
    reproduces the broader study abstract, whose hepatocyte and drug experiments extend
    beyond this deposited
    microarray series.
animal_models:
- name: AAV-hPCSK9(D374Y) mouse
  species: Mouse
  genotype: Liver-directed AAV transfer of human PCSK9 p.Asp374Tyr into wild-type mice
  background: C57BL/6J, 129/SvPasCrlf, or FVB/NCrl
  publication: PMID:25341796
  description: >-
    Liver-directed AAV expression of human D374Y PCSK9 in mice produces hyperlipidemia
    and, under the
    studied high-fat feeding conditions, aortic lesions with macrophages and fibrous
    caps. Somatic overexpression
    does not reproduce endogenous germline regulation or lifelong human exposure.
  genes:
  - preferred_term: PCSK9
    term:
      id: hgnc:20001
      label: PCSK9
  evidence:
  - reference: PMID:25341796
    reference_title: "Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Single intravenous AAV-PCSK9(DY) injection is a fast, easy, and cost-effective approach, resulting in rapid and long-term sustained hyperlipidemia and atherosclerosis."
    explanation: >-
      The authors' summary of what the model produces, supporting its use as a
      model of PCSK9 gain-of-function hypercholesterolemia and atherosclerosis.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  modeled_mechanisms:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Liver expression of human PCSK9 D374Y produces long-term elevation of
      serum LDL in three mouse backgrounds.
    limitations: >-
      Expression is achieved by somatic AAV transfer in adult animals rather than
      by a germline heterozygous
      allele from conception, so the lifelong "cholesterol-years" exposure central
      to the human disease
      is not reproduced; lesion development was studied with high-fat feeding; necessity
      of that diet
      is not established here.
    readouts:
    - name: Serum low-density lipoprotein
      target: Chronic Elevation of Plasma LDL Cholesterol
      direction: INCREASED
      interpretation: Direct biochemical correlate of the human LDL-C elevation node.
      evidence:
      - reference: PMID:25341796
        reference_title: "Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "mice in the C57BL/6J, 129/SvPasCrlf, or FVB/NCrl backgrounds developed long-term hyperlipidemia with a strong increase in serum low-density lipoprotein."
        explanation: Reports the LDL measurement grounding this readout.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:25341796
      reference_title: "Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We aimed to stably express the pathological human D374Y gain-of-function mutant form of PCSK9 (PCSK9(DY)) in adult wild-type mice to generate a hyperlipidemic and proatherogenic animal model, achieved with a single systemic injection with adeno-associated virus (AAV)."
      explanation: >-
        States that the model expresses the human ADH3 disease allele to
        reproduce the hyperlipidaemic, proatherogenic state.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Atherosclerotic Plaque Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      High-fat-fed AAV-PCSK9(D374Y) mice develop aortic atherosclerotic lesions
      that progress to macrophage-infiltrated, fibrous-capped plaques.
    limitations: >-
      Mouse atherosclerosis reproduces lesion initiation and fibrous-cap formation
      but not the late human
      complications of plaque rupture and thrombosis; lesions are aortic rather than
      coronary, and lesions
      were studied under high-fat feeding.
    readouts:
    - name: Aortic atherosclerotic lesion burden and fibrous cap formation
      target: Atherosclerotic Plaque Formation
      direction: INCREASED
      interpretation: Histological correlate of the fibrofatty plaque node.
      evidence:
      - reference: PMID:25341796
        reference_title: "Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Advanced lesions in these high-fat-diet-fed mice also showed evidence of macrophage infiltration and fibrous cap formation."
        explanation: Reports the histological lesion features grounding this readout.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:25341796
      reference_title: "Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Macroscopic and histological analysis showed atherosclerotic lesions in the aortas of AAV-PCSK9(DY) mice fed a high-fat-diet."
      explanation: Establishes that the model develops atherosclerotic lesions attributable to the PCSK9 D374Y allele.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
- name: D374Y-PCSK9 transgenic Yucatan minipig
  species: Pig
  genotype: Liver-specific expression of human PCSK9 p.Asp374Tyr (Sleeping Beauty transposition, somatic cell nuclear transfer)
  background: Yucatan minipig
  publication: PMID:23283366
  description: >-
    Cloned Yucatan minipigs expressing human D374Y-PCSK9 in liver show reduced
    hepatic LDL receptor levels, impaired LDL clearance, severe
    hypercholesterolaemia, and spontaneous progressive atherosclerosis at a
    body size that permits intravascular imaging. The model covers the ADH3
    chain from hepatic receptor loss through to arterial lesion formation; the
    late human events of plaque rupture and atherothrombosis are not
    demonstrated in it.
  genes:
  - preferred_term: PCSK9
    term:
      id: hgnc:20001
      label: PCSK9
  evidence:
  - reference: PMID:23283366
    reference_title: "Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."
    explanation: >-
      Reports the findings the model description lists: reduced hepatic LDL
      receptor, impaired LDL clearance, severe hypercholesterolemia and
      progressive lesions on imaging. Rupture and atherothrombosis are not
      reported.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  modeled_mechanisms:
  - target: Reduced Hepatic Clearance of Circulating LDL Particles
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Transgenic pigs show the receptor-depletion-to-clearance-failure step
      directly, with both hepatic LDL receptor level and LDL clearance measured
      in the same animals.
    limitations: >-
      The human allele is expressed from a transgene under a liver-specific promoter
      rather than from
      the endogenous porcine locus, so expression level and regulation need not match
      a human heterozygote.
    readouts:
    - name: Hepatic LDL receptor level
      target: Reduced Hepatic Clearance of Circulating LDL Particles
      direction: DECREASED
      interpretation: Reduced total hepatic LDLR protein provides indirect support for the linked hepatic-clearance defect; it does not directly localize receptor degradation or quantify surface LDLR.
      evidence:
      - reference: PMID:23283366
        reference_title: "Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."
        explanation: Reports the receptor-level and clearance measurements grounding this readout.
        quote_role: PRIMARY_RESULT
        directness: INDIRECT
    - name: Hepatic LDL clearance
      target: Reduced Hepatic Clearance of Circulating LDL Particles
      direction: DECREASED
      interpretation: Impaired LDL clearance is the measured functional readout corresponding to this mechanism.
      evidence:
      - reference: PMID:23283366
        reference_title: "Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."
        explanation: The cited experiment directly reports impaired LDL clearance in the transgenic pigs.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:23283366
      reference_title: "Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9."
      explanation: Describes the construction of the model on the human ADH3 allele.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Atherosclerotic Plaque Formation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Transgenic pigs developed progressive atherosclerotic lesions measurable by
      imaging. The cited abstract
      does not establish diet independence or superiority to mouse models.
    limitations: >-
      Even in this model the late human events of plaque rupture and atherothrombosis
      are not established;
      lesion progression, not acute coronary syndrome, is what is demonstrated.
    readouts:
    - name: Progressive atherosclerotic lesion development on noninvasive imaging
      target: Atherosclerotic Plaque Formation
      direction: INCREASED
      interpretation: Imaging correlate of arterial plaque formation driven by the PCSK9 gain-of-function allele.
      evidence:
      - reference: PMID:23283366
        reference_title: "Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."
        explanation: Reports the imaging readout of lesion progression.
        quote_role: PRIMARY_RESULT
        directness: DIRECT
    evidence:
    - reference: PMID:23283366
      reference_title: "Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."
      explanation: Reports the imaging readout of lesion progression.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
clinical_trials:
- name: NCT01763918
  phase: PHASE_III
  status: COMPLETED
  description: >-
    RUTHERFORD-2: randomised, double-blind, placebo-controlled trial of
    evolocumab in adults with heterozygous familial hypercholesterolemia on
    stable lipid-lowering therapy.
  target_phenotypes:
  - preferred_term: Increased LDL cholesterol concentration
    term:
      id: HP:0003141
      label: Increased LDL cholesterol concentration
  evidence:
  - reference: clinicaltrials:NCT01763918
    reference_title: "A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 on LDL-C in Subjects With Heterozygous Familial Hypercholesterolemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary objective was to evaluate the effect of 12 weeks of evolocumab subcutaneously once every 2 weeks (Q2W) and once monthly (QM), compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in adults with heterozygous familial hypercholesterolemia (HeFH)."
    explanation: >-
      Registration record establishing the trial's population (heterozygous FH)
      and LDL-C endpoint.
    quote_role: BACKGROUND
    directness: INDIRECT
- name: NCT05398029
  phase: PHASE_I
  status: COMPLETED
  description: >-
    VERVE-101: completed early-phase, open-label hepatic PCSK9 base-editing study
    in HeFH with ASCVD.
    Registry status checked September 2026. The registered design establishes an investigational
    intervention,
    not proven efficacy in PCSK9 gain-of-function disease.
  target_phenotypes:
  - preferred_term: Increased LDL cholesterol concentration
    term:
      id: HP:0003141
      label: Increased LDL cholesterol concentration
  evidence:
  - reference: clinicaltrials:NCT05398029
    reference_title: "Open-label, Phase 1b, Single-ascending Dose and Optional re Dosing Study to Evaluate the Safety of VERVE-101 Administered to Patients With Heterozygous Familial Hypercholesterolemia, Atherosclerotic Cardiovascular Disease, and Uncontrolled Hypercholesterolemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "VERVE-101 uses base-editing technology designed to disrupt the expression of the PCSK9 gene in the liver and lower circulating PCSK9 and LDL-C in patients with established ASCVD due to HeFH."
    explanation: >-
      Registration record establishing that the intervention acts on hepatic
      PCSK9 expression, the mechanism node of this entry.
    quote_role: BACKGROUND
    directness: INDIRECT
- name: NCT03397121
  phase: PHASE_III
  status: COMPLETED
  description: >-
    ORION-9: placebo-controlled, double-blind, randomised trial of twice-yearly
    inclisiran sodium in adults with heterozygous familial hypercholesterolemia
    and elevated LDL cholesterol.
  target_phenotypes:
  - preferred_term: Increased LDL cholesterol concentration
    term:
      id: HP:0003141
      label: Increased LDL cholesterol concentration
  evidence:
  - reference: clinicaltrials:NCT03397121
    reference_title: "Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect of 300 mg of Inclisiran Sodium Given as Subcutaneous Injections in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH) and Elevated Low-Density Lipoprotein Cholesterol (LDL-C)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a Phase III, placebo-controlled, double-blind, randomized study in participants with HeFH and elevated LDL-C to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) injection(s) of inclisiran."
    explanation: >-
      Registration record establishing the trial's population and the
      intervention relevant to this disease.
    quote_role: BACKGROUND
    directness: INDIRECT
- name: NCT05465278
  phase: PHASE_IV
  status: COMPLETED
  description: >-
    ARCHITECT: completed open-label, single-arm alirocumab study with serial coronary
    CT angiography in
    molecularly determined FH without clinical ASCVD. No PCSK9-stratified effect or
    randomized plaque
    comparison was reported.
  target_phenotypes:
  - preferred_term: Coronary artery atherosclerosis
    term:
      id: HP:0001677
      label: Coronary artery atherosclerosis
  evidence:
  - reference: clinicaltrials:NCT05465278
    reference_title: "Clinical Trial to Evaluate the Effect of Alirocumab on the Volume, Architecture and Composition of Atherosclerotic Plaque in Patients With Familial Hypercholesterolemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical trial to evaluate the effect of alirocumab on the volume, architecture and composition of atherosclerotic plaque in patients with Familial hypercholesterolemia from the SAFEHEART Registry"
    explanation: >-
      Registration record establishing the intervention, the plaque endpoint,
      and the registry-based FH cohort.
    quote_role: BACKGROUND
    directness: INDIRECT
  - reference: PMID:37009731
    reference_title: "Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in subjects with molecularly determined FH without clinical ASCVD enrolled in the SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study)"
    explanation: >-
      The results publication states the cohort is molecularly determined,
      which the registration record did not.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:37009731
    reference_title: "Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with alirocumab in addition to high-intensity statin therapy resulted in significant regression of coronary plaque burden and plaque stabilization on coronary computed tomographic angiography over 78 weeks"
    explanation: >-
      The publication reports within-person CT changes over 78 weeks; absence of a
      control group limits
      causal attribution.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: >-
    Genetic confirmation encompassed the broader FH population. Imaging changes cannot
    establish a treatment-specific
    histological mechanism.
- name: NCT01604824
  phase: PHASE_II
  status: COMPLETED
  description: Randomized placebo-phase alirocumab study in genetic hypercholesterolemia. The PCSK9 publication reports 13 adults carrying four variants, with a two-week primary randomized LDL-C comparison and later pooled on-treatment follow-up. The registry total includes a separate APOB cohort and must not be substituted for the PCSK9 sample size.
  target_phenotypes:
  - preferred_term: Increased LDL cholesterol concentration
    term:
      id: HP:0003141
      label: Increased LDL cholesterol concentration
  evidence:
  - *id015
  - reference: clinicaltrials:NCT01604824
    reference_title: A Phase 2 Pilot Study With a Randomized Double-Blind Treatment Phase to Evaluate the Pharmacodynamics and Safety of Alirocumab in Patients With Autosomal Dominant Hypercholesterolemia and Gain-of-Function Mutations in 1 or Both Alleles of the PCSK9 Gene or Loss-of-Function Mutations in 1 or More Alleles of the Loss-of-Function Mutations B Gene
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The primary objective of the study is to assess the pharmacodynamic (PD) effect of alirocumab on serum low density lipoprotein cholesterol (LDL-C)
    explanation: The registration defines an LDL-C pharmacodynamic study; the PCSK9 subgroup results are supported separately by the primary publication.
    quote_role: BACKGROUND
    directness: INDIRECT
- name: NCT03705234
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: ORION-4 evaluates inclisiran versus placebo for cardiovascular outcomes in established ASCVD. Registry status was active, not recruiting in September 2026; the trial population is broader than PCSK9-related FH.
  evidence:
  - reference: clinicaltrials:NCT03705234
    reference_title: 'HPS-4/TIMI 65/ORION-4: A Double-blind Randomized Placebo-controlled Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Atherosclerotic Cardiovascular Disease'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The study aims to find out if a new cholesterol-lowering injection (inclisiran) safely lowers the risk of heart attacks and strokes in people who have already had one of these conditions, or who have had an operation or procedure to treat blocked arteries.
    explanation: The registry describes an outcome-study aim, not an available positive result, in a population defined by established atherosclerotic disease rather than by FH or PCSK9 genotype.
    quote_role: BACKGROUND
    directness: INDIRECT
diagnosis:
- name: Molecular Genetic Testing of PCSK9
  description: >-
    A pathogenic or likely pathogenic PCSK9 gain-of-function variant, or a pathogenic
    duplication, establishes
    PCSK9-related FH in the appropriate clinical context. A variant of uncertain significance
    or a protective
    loss-of-function allele does not. An FH panel should assess relevant sequence
    and copy-number variants,
    with familial testing when a causal finding is established.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."
    explanation: >-
      GeneReviews states that molecular identification of a gain-of-function
      PCSK9 variant establishes the molecular diagnosis.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing is the preferred method for clarifying the diagnosis in at-risk family members, when possible."
    explanation: >-
      GeneReviews states that molecular testing is the preferred route for
      cascade clarification in relatives, the claim made in this entry's
      description.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - *id012
- name: Lipid Surveillance from Early Childhood
  description: >-
    Early lipid assessment and family cascade screening identify affected children
    before clinical vascular
    disease. Follow-up evaluates LDL-C, treatment response and modifiable cardiovascular
    risks; the schedule
    and treatment thresholds depend on age and clinical context.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: Monitor lipid levels from age two years; consider noninvasive imaging modalities in adults; identify modifiable risk factors (e.g., smoking, sedentary behavior, hypertension, diabetes, obesity)."
    explanation: GeneReviews surveillance recommendation for FH.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- name: Clinical Diagnostic Criteria for Familial Hypercholesterolemia
  description: >-
    DLCN, Simon Broome and MEDPED are FH-wide clinical frameworks with different criteria.
    DLCN incorporates
    LDL-C, clinical findings and history; MEDPED uses age- and family-relationship-specific
    cholesterol
    thresholds rather than a xanthoma score. They do not establish PCSK9 causation,
    and adult proband
    scores should not be substituted for pediatric or familial cascade criteria.
  evidence:
  - reference: PMID:29408959
    reference_title: "A Comparative Analysis of Phenotypic Predictors of Mutations in Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prediction of a mutation for the DLCN and SB definite and MEDPED criteria (ORs 9.4, 11.7, and 10.5, respectively) was higher than with the AHA criteria (OR 4.67)."
    explanation: >-
      In 885 lipid-clinic referrals, the three frameworks differed in how well
      they predicted an FH-causing mutation in any FH gene. This supports
      treating them as distinct FH-wide criteria, not as tests for PCSK9
      causation. The abstract does not list each framework's components.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
  - reference: PMID:29408959
    reference_title: "A Comparative Analysis of Phenotypic Predictors of Mutations in Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The DLCN, SB, and MEDPED criteria are valid predictors of an FH-causing mutation in patients referred to a lipid clinic, but concordance between these phenotypic criteria is only moderate."
    explanation: >-
      Supports the criteria as valid predictors while recording their
      limitation in the same sentence - concordance between them is only
      moderate - which is why this entry keeps molecular testing as the
      diagnostic step.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: >-
    Clinical and molecular assessment are complementary. Elevated Lp(a), treatment,
    age and referral selection
    can affect phenotypic classification.
- name: Assessment for Secondary Hypercholesterolemia
  description: Evaluate acquired causes of elevated LDL-C, including hypothyroidism, kidney disease, obstructive liver disease and medications, before attributing the entire phenotype to inherited FH.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK174884/
    reference_title: Familial Hypercholesterolemia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypercholesterolemia secondary to acquired conditions including obesity, diabetes mellitus, obstructive liver disease, hypothyroidism, drugs (e.g., steroids), or kidney disease can also be associated with laboratory findings similar to those of FH
    explanation: GeneReviews identifies important secondary causes that can mimic or modify FH.
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
differential_diagnoses:
- name: Familial hypercholesterolemia due to LDLR variants
  description: >-
    The most common dominant FH form. Clinically indistinguishable from ADH3 at
    the bedside; distinguished by molecular testing. Mechanistically the
    receptor itself is defective, rather than being degraded prematurely by a
    normal-but-overactive regulator.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."
    explanation: >-
      GeneReviews lists LDLR alongside PCSK9 as an alternative molecular cause
      of the same clinical picture, which is what makes it a differential.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- name: Familial defective apolipoprotein B-100 (APOB)
  description: >-
    Dominant FH caused by APOB variants that impair binding of LDL to the LDL
    receptor. The receptor and its regulation are intact; the ligand is
    defective.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."
    explanation: >-
      GeneReviews specifies the APOB mechanism (impaired binding of LDL-C to the
      receptor) that distinguishes it from PCSK9 gain of function.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- name: Autosomal recessive hypercholesterolemia (LDLRAP1)
  description: >-
    Caused by biallelic LDLRAP1 variants affecting the adaptor required for
    receptor endocytosis; recessive rather than dominant inheritance.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LDLRAP1-related FH is caused by biallelic pathogenic variants and is inherited in an autosomal recessive manner."
    explanation: >-
      GeneReviews states the recessive inheritance that separates this entity
      from dominant ADH3.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
- name: Polygenic hypercholesterolemia
  description: >-
    Elevated LDL cholesterol from the aggregate effect of many common
    small-effect alleles rather than a single dominant variant; the commonest
    explanation for a clinical FH phenotype without an identified monogenic
    cause.
- name: Sterol storage disorders presenting with tendon xanthomas
  description: >-
    Sitosterolemia (ABCG5/ABCG8) and cerebrotendinous xanthomatosis (CYP27A1)
    both produce tendon xanthomas indistinguishable on inspection from those of
    FH, and lysosomal acid lipase deficiency likewise causes dyslipidaemia with
    lipid deposition. They are separated from ADH3 not by the xanthomas but by
    the sterol profile and by inheritance - both are recessive, and in
    cerebrotendinous xanthomatosis cholesterol may be normal while cholestanol
    accumulates. This matters here because tendon xanthomatosis is a curated
    phenotype of this entry and is one of the strongest predictors in the
    clinical FH criteria above, so a xanthoma phenocopy can score as clinical FH
    while carrying no PCSK9 variant.
  evidence:
  - reference: PMID:27678445
    reference_title: "Tendon xanthomas: Not always familial hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tendon xanthoma are most commonly associated with Familial Hypercholesterolemia, but the differential diagnosis includes sitosterolemia and cerebrotendinous xanthomatosis (CTX)."
    explanation: >-
      Names the two sterol storage disorders that phenocopy the tendon-xanthoma
      sign of FH.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
updated_date: '2026-09-23T00:00:00Z'

📚

References & Deep Research

References

1

PMID:24404629

Familial Hypercholesterolemia.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Review PCSK9-related familial hypercholesterolemia against full-text mechanisms, clinical evidence and dataset design · 2026-09-23T03:18:59Z · View source

Reviewed the entire entry, the matching Falcon deep-research narrative and citation artifact, and recovered source audits. The entity is inherited PCSK9-related FH, eligible under the resumed scope excluding infectious/environmental diseases and poisonings. No prior REVIEW event or overlapping open PR was present at eligibility checks. Rebuilt the causal graph around allele-specific processes: sequence effects versus gene dosage, LDL-particle versus LDLR binding, receptor recycling/degradation/surface abundance and LDL clearance, with an independent apoB-production contribution measured in two S127R humans. Extracellular PCSK9 sufficiency is not universal secretion necessity. Separated chronic plaque/stenosis from cap disruption/thrombosis so stable angina and peripheral disease do not require rupture. Retained useful genetic context and the two compatible early atherogenesis module bindings; the remaining former module bindings bundled processes now represented separately. Corrected total-cholesterol versus LDL-C measurements, selected-cohort prevalence/severity claims, stroke occurrence versus excess risk, allele-specific penetrance, and rare whole-gene duplication. Kept untranslated-region reporter findings as unresolved candidate regulatory observations rather than established pathogenic variants. Added the 13-person/four-variant alirocumab study, distinguishing its two-week randomized contrast from pooled eight-week LDL change and from broader cardiovascular outcome trials. Corrected pregnancy guidance using FDA, qualified pediatric and adult FH care, refreshed trial statuses from the official registry, corrected model diet/readout claims and nonisogenic donor limitations, and replaced the incorrect GSE75545 hepatocyte/drug/LOF-array description with the actual ten-sample progenitor-to-iPSC experiment. Full-text consumption: PMID26374825 Methods, Results, Discussion and all four original image tables; PMID26586530 and PMID36187800 complete scientific bodies, methods and figure/table content; recovered complete PMID17080197 PDF audit including methods, assay doses, parabiosis and Table 1; full PMID35294538, PMID37009731 and PMID38338916 scientific source audits; complete GeneReviews clinical/genetics/counseling body, Endotext atherosclerosis chapter, IAS2023 diagnosis/risk/care recommendations and tables, and FDA pregnancy communication/data summary. Regenerated two existing caches to recover full text/tables. Read primary abstracts for PMID15166014 and PMID30269829 where full text was unavailable. PMID40225943 full-text reporter methods/results constrain regulatory interpretation. The 2026 NLA cached abstract supports only the broad care statement quoted; inaccessible current guideline detail was not reconstructed into a cache. GEO sample-level text and ClinicalTrials.gov API records were inspected independently of their narrative summaries. No frozen dataset-accession blob was accessed. Deep-research completeness: phenotype coverage adequate after adding stroke with no inferred frequency; subtypes adequate (alleles/dosage, no invented clinical subtypes); central mechanism coverage adequate including human apoB kinetics; treatment/trial coverage adequate after gene-specific trial and ORION-4 context; genetics adequate with penetrance/dosage/candidate-regulatory distinctions; biomarkers/diagnostics adequate with secondary causes and clinical-score limitations; high-value references consumed, with original articles overriding erroneous report absence claims; overall scope adequate. Speculative epigenetic/extrahepatic mechanisms and unsupported proposed gene-specific outcome benefits remain nonblocking research questions. Validation: schema, ontology terms and cached snippets passed before final formatting; entity references, graph targets, qualifier labels, duplicate keys and repository evidence hygiene were checked. Final validation counts and PR link are recorded with the published review. Independent review follow-up: aligned pig-model readout targets and separated measured LDL clearance from its indirect receptor-protein correlate; corrected background/review quote roles; reconciled stroke notes and documented why its causal route remains unconnected; generalized evolocumab target wording to include whole-gene duplication. Added the published PR link. Final validation verifies 200/200 snippets and model readout/link consistency.

Augment: classifications, imaging findings, cerebrovascular controversy, colesevelam, PCSK9 case fractions · 2026-09-06T14:45:06Z · View source

Third session on this entry, an augmentation of the existing ADH3 curation (created in PR #8884). No new disease scope; the entry, its MONDO anchor and its pathograph are unchanged. DEEP RESEARCH. A fresh falcon (Edison) run was executed rather than reusing the August report: `just research-disorder falcon Autosomal_Dominant_Hypercholesterolemia_3`, 674s, 34 citations. Its own validation sections are clean - reference validation 13/13 resolved, 0 unresolved, 0 off topic; term validation 12/13 resolved, 0 unresolved, 0 obsolete, 1 unverifiable. The recipe again failed to pass the MONDO ID through (frontmatter records `mondo_id: ''` despite `disease_term.term.id: MONDO:0011369` being present in the file), so `just preflight-dr <report> MONDO:0011369` was run separately: verdict WARN, PCSK9 dominant at 69 mentions against LDLR=34 and APOB=7, with the flagged rival "FH" again the disease abbreviation misread as the fumarate hydratase gene symbol. The preflight also reported that the report cites OMIM 143890 and 607786 while MONDO:0011369 xrefs OMIM 603776 - i.e. the report does mix in the sibling FH entities - so its LDLR- and APOB-specific passages were excluded and only PCSK9-anchored content was used. Falcon reports cite by author-year key with no PMIDs, so the report's DOIs were swept out of the body and resolved to PMIDs through the PMC ID converter before use. WHAT WAS ADDED. (1) A `classifications:` block - harrisons_chapter ENDOCRINOLOGY_METABOLISM and GENETICS_ENVIRONMENT_DISEASE plus icimd_category `hypercholesterolemias`, each evidenced from the Abifadel 2003 abstract (PMID:12730697). Values deliberately match the sibling LDLR-Related_Familial_Hypercholesterolemia and Familial_Defective_Apolipoprotein_B-100 entries; CARDIOVASCULAR was considered and declined, with the reason recorded in the assignment's `notes:` rather than left implicit. (2) An `imaging_findings:` block, the first in this entry: coronary plaque burden on CT angiography and coronary artery calcification (PMID:33261814, 259 asymptomatic molecularly diagnosed FH patients), and regression of plaque burden under PCSK9 inhibition (PMID:37009731, ARCHITECT). (3) A CONTROVERSY discussion, `adh3_cerebrovascular_risk`, recording why no cerebrovascular phenotype is curated here: GeneReviews lists stroke among FH manifestations, while the Norwegian genetically verified FH register (PMID:30580708) and SAFEHEART (PMID:27444203) both report no excess cerebrovascular risk. Recorded, not resolved. (4) Colesevelam as a treatment - bile acid sequestrant, `therapeutic_modality: OTHER` with the reason stated (a non-absorbed polymeric resin is not a small molecule and no other enum value fits), NCIT:C15986 plus CHEBI:59594, `target_mechanisms` MODULATES on the LDL-C node, evidenced from PMID:23916045 and the GeneReviews pregnancy guidance. (5) `case_fractions` on the PCSK9 genetic entry: 2.3% of a 130-patient LDLR/APOB-negative ADH cohort (PMID:16211558), with `notes:` stating explicitly that the denominator is already enriched and the figure is an upper bound on the PCSK9 share of unselected FH. (6) Evidence for incomplete segregation and within-family variability in severity from the same paper, which converts the entry's expressivity statement from an inference about an absent estimate into an observed property. (7) The cumulative-LDL-burden threshold age (about 12.5 years in FH versus about 55 without) on the presymptomatic progression phase, from PMID:38338916. (8) `evidence:` on the geo:GSE75545 dataset record, quoting the cached GEO summary - legitimate here because the record is hand-curated rather than bulk-generated, and the `notes:` was rewritten to say so instead of citing the no-evidence SOP. WHAT WAS CORRECTED. The ARCHITECT trial (NCT05465278) carried a `notes:` saying the registry record does not establish that participants are molecularly diagnosed; the results publication (PMID:37009731) does say so, so it was added as evidence and the note rewritten. The Peripheral Arterial Disease phenotype gained SAFEHEART as a second, molecularly defined source. Three `explanation:`/`notes:` strings still argued for the retired `supports: PARTIAL` enum value (dismech#7439, and the prose-rot problem #10003 records) and were rewritten to say what they meant without naming a value the schema no longer has. The Statin Therapy `notes:` claimed no lipid-lowering option is established in pregnancy; GeneReviews describes bile acid sequestrants as generally considered safe, so that sentence was reconciled with the new Colesevelam entry rather than left to contradict it. SCOPE DISCIPLINE. Most of the added clinical evidence comes from FH-wide cohorts (SAFEHEART, the Norwegian register, the CCTA series, the colesevelam trials), none of them PCSK9-stratified. Every such block carries a `notes:` saying so, following the pattern the existing treatment entries already use. No FH-wide finding is stated as a PCSK9-specific quantity. CLAIMS DROPPED RATHER THAN CURATED. The falcon report attributed an "approximately 1% of FH" figure for the PCSK9 gain-of-function share to a 2024 review (PMID:38338916). That figure could not be located anywhere in the cached full text of that review, so it was not curated; the `case_fractions` notes record the attempt and the failure rather than carrying the number. A draft rationale describing the Norwegian register and SAFEHEART as "the two largest cohort studies" of verified FH was softened to "two large cohort studies" - the superlative was not sourced. The candidate explanations offered in that rationale are explicitly labelled as untested in the cited papers and not curated as evidenced. RED-TEAM REVIEW RESPONSE. A pre-PR adversarial review was run against the change and its findings were addressed in the same session. It verified all evidence snippets as exact substrings independently and found no fabrication. Blocking: the two new GEO evidence items lacked `reference_title` - added. Substantive: (a) the rewritten Statin Therapy pregnancy note said the pregnancy option was "confined to the weakest agent", but the GeneReviews sentence this change itself quotes names two options, sequestrants and LDL apheresis, and this entry already curates LDL apheresis - the note now names both, and the Colesevelam evidence explanation points at the second. (b) The third imaging finding's description claimed to be the imaging counterpart of the entry's treatment `target_mechanisms` edges, but every PCSK9-directed treatment edge targeted only the upstream lesion and none reached an atheroma node - so the claim was false as written. Fixed by closing the pathograph gap rather than by softening the prose: Alirocumab now carries a second `target_mechanisms` edge onto 'Advanced Atheroma with Necrotic Core and Fibrous Cap' with `treatment_effect: MODULATES`, evidenced by the ARCHITECT plaque-composition result, and ARCHITECT was added as treatment-level evidence beside ODYSSEY OUTCOMES with a `notes:` distinguishing the two populations. (c) The cerebrovascular CONTROVERSY had three items on the null side and none genuinely opposing, since the GeneReviews clause cited for the pro-risk side ("stroke occurs more rarely") is closer to the registries than against them. Fixed by citing PMID:30580708's own background sentence, which states the disagreement directly, and PMID:38338916's "milder disease phenotype" characterisation of PCSK9 disease - the latter recorded and explicitly flagged as conflicting with this entry's own D374Y series rather than adopted. The GeneReviews explanation was softened to what its clause actually says. Minor: the colesevelam adult indication was corrected from heterozygous FH to primary hyperlipidemia (the FH half of that label sentence is the paediatric indication); a `phenotype_term` duplicating its own `imaging_finding_term` was dropped as carrying no information; ARCHITECT's >30% baseline plaque-burden entry criterion was recorded as the reason its 34.6% baseline is not comparable with the 25.0% median in the neighbouring finding; "(French cohort)" was removed from a `case_fractions` population because the cited abstract does not state it; and a byte-identical duplicate DOI cache differing only in CURIE casing was deleted. Two review suggestions were not taken: the first GEO snippet is a background sentence rather than a result, which the review itself called defensible as a provenance record and whose explanation already says so; and the point that bile acid sequestrants raise PCSK9 as well as LDLR through the same SREBP-2 response is a real and unusually pointed caveat for this entry, but no quotable source for it was found, so it was left out rather than asserted. PR REVIEW RESPONSE (PR #11274). The automated reviewer approved with no blocking findings and three non-blocking suggestions. Two were acted on. (a) It asked whether modelling a treatment response inside `imaging_findings:` is the intended convention "before it is copied". Checked empirically: of the 119 entries in kb/disorders carrying `imaging_findings:`, none models a treatment response there - the only superficially similar entry, a MELAS acute-episode perfusion finding, is a disease-phase finding. So this entry would have been inventing the convention, not following one. The third imaging finding, 'Regression of coronary plaque burden during PCSK9 inhibition', was therefore removed. Nothing is lost: the identical ARCHITECT evidence already sits on the Alirocumab `target_mechanisms` edge onto 'Advanced Atheroma with Necrotic Core and Fibrous Cap', which is where a treatment response belongs, and the first imaging finding already establishes that coronary CT angiography is the modality that measures plaque burden in this disease. The reasoning is recorded in that finding's `notes:` so the next curator does not re-add it. Snippet count falls 153 -> 151 as a result, which is the two duplicated ARCHITECT quotes going away. (b) The PR description under-reported the change; the body was rewritten before the review landed and now covers the imaging findings, case fractions, the pathograph edge and the corrections, with the GEO dataset evidence added afterwards. (c) Three research-surfaced follow-ons were declined as out of scope for this PR rather than silently dropped: PCSK9 3'UTR regulatory variants (the source report itself cautions these are not established ADH3 alleles without segregation and clinical functional validation), two paediatric FH trials, and large-animal models. They are named here so they are findable. VALIDATION. `just validate` passed (schema, terms and references). `just count-verified-snippets` reported 151/151 snippets verified against cached references, up from 124 at the end of the previous session; every new snippet was checked as an exact substring of its cached source before being written. `just validate-terms` passed, and HP:0001677, HP:0001717 and CHEBI:59594 were added to the enum/term caches by that run. `just check-duplicate-keys`, `just check-entity-refs`, `just check-causal-targets`, `just check-qualifier-terms` and `just check-enum-values` all clean on the file; `just check-title-snippets`, `just check-snippet-length`, `just check-folded-hyphens`, `just check-snippet-grading` and `just check-environmental-evidence` clean KB-wide. `just check-snippet-length` initially failed on a four-word GeneReviews quote ("stroke occurs more rarely") in the new discussion; it was replaced with the full clinical-characteristics sentence whose closing clause carries the claim. Compliance 97.5%, unchanged in rate while the denominator grew by roughly 40 checks. `just validate-disorders` was run over the changed file as the pre-PR sweep. All new references were fetched with `just fetch-reference` (PMID:16211558, 23916045, 27444203, 30580708, 33261814, 37009731, 38338916). PMID:38338916 is additionally cited for the bile-acid-sequestrant class mechanism stated in the Colesevelam description, so that description is not an uncited pharmacology claim. An unrelated metadata-only churn in references_cache/PMID_32197277.md, produced by a refetch attempt during validation, was reverted rather than committed. A red-team review was run against the change before the PR.

Create: Autosomal Dominant Hypercholesterolemia 3 (ADH3, PCSK9 gain-of-function) · 2026-08-19T04:30:26Z · View source

New standalone entry for MONDO:0011369 (OMIM:603776), the PCSK9 gain-of-function form of familial hypercholesterolemia. NEC preflight: the hypercholesterolemia series is a high-NEC-risk numbered/lettered class. Identity was anchored against MONDO before curation via "runoak -i sqlite:obo:mondo info MONDO:0011369 -O obo" - causal gene PCSK9 (RO:0004003 HGNC:20001), OMIM:603776, synonym HCHOLA3. A falcon deep-research report was generated and checked with "just preflight-dr <report> MONDO:0011369": verdict WARN, with PCSK9 dominating at 70 mentions (LDLR=29, APOB=3); the flagged rival "FH" is the FH disease abbreviation being read as the fumarate hydratase gene symbol, a false positive. The report was used only as leads - every PMID was fetched with "just fetch-reference" and every snippet verified against the cached abstract. Scope decision: standalone entry rather than a subtype of Familial_Hypercholesterolemia (MONDO:0005439). The umbrella entry's subtype axis is zygosity (HeFH/HoFH), not gene; MONDO models this as a distinct is_a child defined by causal gene; and the mechanism (accelerated degradation of a structurally normal LDL receptor by an overactive regulator) is distinct from the LDLR and APOB forms and is the direct rationale for PCSK9-inhibitor therapy. Curated content: an eleven-node pathograph running from the PCSK9 gain-of-function variant through EGF-A binding, lysosomal rerouting of the LDL receptor, reduced hepatic LDL clearance and chronic LDL-C elevation, into a three-node atherogenesis branch conforming to "atherogenesis#Endothelial Dysfunction and Subendothelial LDL Retention", "atherogenesis#Monocyte Recruitment and Macrophage Foam Cell Formation" and "atherogenesis#Smooth Muscle Cell Switching and Fibrofatty Plaque Formation", "atherogenesis#Advanced Atheroma with Necrotic Core and Fibrous Cap" and "atherogenesis#Plaque Rupture, Thrombosis, and Ischemic Events". Two mechanistic_hypotheses (CANONICAL receptor-degradation versus ALTERNATIVE apoB-secretion) with a KNOWLEDGE_GAP discussion and two proposed experiments. The variant consequence is recorded on GeneticContext.functional_impact_category (GAIN_OF_FUNCTION), not as a Descriptor modifier. Treatments: evolocumab and alirocumab (MONOCLONAL_ANTIBODY), inclisiran (SIRNA), statin therapy and ezetimibe (SMALL_MOLECULE), LDL apheresis (DEVICE) and lifestyle/risk-factor modification (BEHAVIORAL), each with target_mechanisms into the pathograph. Three PCSK9 variants (S127R, F216L, D374Y), GeneReviews-baselined phenotypes, three clinical trials (RUTHERFORD-2, ORION-9 and the VERVE-101 base-editing phase 1b), two animal models and one patient-derived iPSC hepatocyte-like-cell model with modeled_mechanisms and readouts, plus one relevance-triaged GEO dataset, an environmental block with pathograph links, and a progression timeline. Validation: "just validate" passed (schema, terms and references); "just count-verified-snippets" reported 109/109 snippets verified against cached references; "just validate-terms" passed; "just check-duplicate-keys" and "just check-title-snippets" were clean; "just verify-datasets" resolved geo:GSE75545; compliance 96.5%, with pathograph connectivity at 8/8 phenotypes and 1/1 causal genes wired. A red-team self-review was run before opening the PR and its blocking findings (pathograph connectivity, two mis-tagged evidence_source values, unevidenced OBLIGATE frequencies, an over-claimed binding-affinity statement, and an S127R zymogen-processing framing contradicted by a cited paper) were addressed.

Falcon ▸

Autosomal Dominant Hypercholesterolemia 3: Disease-Characteristics Report

Edison Scientific Literature 34 citations 2026-09-06T14:21:50.782779

Autosomal Dominant Hypercholesterolemia 3: Disease-Characteristics Report

Executive summary and evidence scope

Autosomal dominant hypercholesterolemia 3 (ADH3; FH3/HCHOLA3) is the rare familial-hypercholesterolemia subtype caused by heterozygous germline gain-of-function (GOF) variants in PCSK9. Excess PCSK9 activity decreases hepatocyte-surface LDL receptor (LDLR), causing lifelong elevation of LDL cholesterol (LDL-C), cumulative arterial cholesterol exposure, and premature atherosclerotic cardiovascular disease (ASCVD). The phenotype overlaps LDLR- and APOB-associated familial hypercholesterolemia (FH), so ADH3 is defined molecularly rather than by unique clinical findings. Direct ADH3 evidence is dominated by pedigrees and functional studies; most management and outcome estimates necessarily come from broader heterozygous FH cohorts.

Domain	Evidence scope	Core fact
Disease identity	ADH3-specific	Autosomal dominant hypercholesterolemia 3 (ADH3; FH3/HCHOLA3) is the PCSK9 gain-of-function subtype of familial hypercholesterolemia. The locus was mapped to chromosome 1p32, and the causal relationship was established in 2003 (DOI). (seidah2017thepcsk9revolution pages 3-6, abifadel2003mutationsinpcsk9 pages 2-2)
Causal gene and mechanism	ADH3-specific	Germline gain-of-function variants in PCSK9 enhance loss of hepatic LDL receptors. Secreted PCSK9 binds the LDLR EGF-A domain and directs the complex to late endosomes/lysosomes rather than receptor recycling, reducing hepatic LDL clearance and raising plasma LDL-C. (fularski2024unveilingfamilialhypercholesterolemia—review pages 4-5, mcnutt2010characterizationofthe pages 115-119, weider2017inhibitionofthea pages 152-156)
Inheritance	ADH3-specific	Autosomal dominant; heterozygous variants segregate with hypercholesterolemia, although expressivity and cardiovascular severity vary within and between families. Biallelic PCSK9 gain-of-function disease can produce an exceptionally severe, HoFH-like phenotype but is not the usual ADH3 presentation. (allard2005novelmutationsof pages 3-6, allard2005novelmutationsof pages 1-3, abifadel2003mutationsinpcsk9 pages 2-2)
Hallmark phenotype	ADH3-specific	Lifelong elevation of LDL-C/type IIa hypercholesterolemia, sometimes accompanied by tendon xanthomas, corneal arcus, and premature coronary disease. One p.Arg218Ser proband had untreated LDL-C 293 mg/dL, tendon xanthoma, and corneal arcus at age 45; an original p.Phe216Leu carrier died from myocardial infarction at age 49. (allard2005novelmutationsof pages 3-6, abifadel2003mutationsinpcsk9 pages 2-2)
Key variants	ADH3-specific	Landmark variants include p.Ser127Arg and p.Phe216Leu; reported variants also include p.Asp374Tyr, p.Arg218Ser, p.Arg357His, p.Ala443Thr, and p.Arg469Trp. p.Asp374Tyr increases PCSK9–LDLR affinity by about 10-fold and is associated with severe disease. Variant pathogenicity must be assessed individually because not every rare PCSK9 variant is gain-of-function. (allard2005novelmutationsof pages 3-6, allard2005novelmutationsof pages 1-3, weider2017inhibitionofthe pages 152-156, abifadel2003mutationsinpcsk9 pages 2-2)
Epidemiology caveat	Mixed	ADH3-specific prevalence is not well quantified. PCSK9 gain-of-function variants account for approximately 1% of FH cases in a 2024 review and about 2.3% of LDLR/APOB-negative ADH in one 130-patient series. These selected-cohort figures should not be treated as population prevalence. General FH prevalence is approximately 1:311, affecting more than 34 million people worldwide. (allard2005novelmutationsof pages 1-3, fularski2024unveilingfamilialhypercholesterolemia—review pages 4-5, marquina2024costeffectivenessofscreening pages 1-2)
Diagnosis	General FH framework plus ADH3 confirmation	Diagnose the FH phenotype using repeated untreated LDL-C, premature ASCVD and family history, and physical signs; exclude secondary hypercholesterolemia. Confirm ADH3 through an FH panel including LDLR, APOB, PCSK9, and other validated genes, with segregation and functional/curated evidence for a pathogenic or likely pathogenic PCSK9 gain-of-function variant. A PCSK9 VUS or loss-of-function allele does not establish ADH3. (allard2005novelmutationsof pages 1-3, watts2023internationalatherosclerosissociety pages 7-8, yip2023geneticspectrumand pages 5-6)
Treatment	General FH evidence, mechanistically well matched to ADH3	Begin early intensive LDL lowering: maximally tolerated high-intensity statin, add ezetimibe, then a PCSK9-directed agent if goals are unmet. Ezetimibe lowers LDL-C about 18% alone and provides about 20% additional lowering with statins; alirocumab/evolocumab typically lower LDL-C about 60%. General FH targets are ≥50% reduction and LDL-C below 70 mg/dL in high-risk disease or below 55 mg/dL in very-high-risk disease. (fularski2024unveilingfamilialhypercholesterolemia—review pages 10-12, fularski2024unveilingfamilialhypercholesterolemia—review pages 7-9)
Prevention and screening	General FH evidence applicable to ADH3 families	Primary prevention cannot remove an inherited allele, but diet, exercise, avoidance of smoking, and control of other cardiovascular risks reduce downstream risk. Perform cascade lipid and targeted-variant testing in first-degree relatives; combined cascade and young-age universal screening could identify more than 90% of FH. Cascade screening was cost-effective in 78% of studies and yielded the greatest health benefit per person tested. (marquina2024costeffectivenessofscreening pages 1-2, watts2023internationalatherosclerosissociety pages 1-2, watts2023internationalatherosclerosissociety pages 7-8)
Evidence limitations	ADH3-specific caveat	ADH3 is rare, so most phenotype, prognosis, quality-of-life, and treatment estimates are extrapolated from broader HeFH cohorts rather than PCSK9-genotyped trials. Published evidence is dominated by pedigrees, variant-functional studies, and engineered models; no reliable subtype-specific incidence, penetrance percentage, sex ratio, survival curve, or spontaneous nonhuman disease series was identified. (allard2005novelmutationsof pages 3-6, rochemolina2015inductionofsustained pages 1-2, rochemolina2015inductionofsustained pages 10-10)

Table: This table separates evidence specific to PCSK9 gain-of-function ADH3 from findings extrapolated from familial hypercholesterolemia generally. It summarizes defining genetics, phenotype, diagnosis, management, screening, quantitative findings, and major evidence gaps.

1. Disease information

Definition, names, and identifiers

Preferred name: autosomal dominant hypercholesterolemia 3. Common alternatives are ADH3, familial hypercholesterolemia 3, FH3, HCHOLA3, PCSK9-related familial hypercholesterolemia, and PCSK9 gain-of-function hypercholesterolemia. The original locus was mapped to chromosome 1p32, and the 2003 landmark study identified PCSK9 variants in two linked French families. Its abstract states that the investigators “mapped a third locus associated with ADH, HCHOLA3 at 1p32” and found two causal PCSK9 mutations. DOI: https://doi.org/10.1038/ng1161; publication: June 2003. (seidah2017thepcsk9revolution pages 3-6, abifadel2003mutationsinpcsk9 pages 2-2)

Identifier caution: the retrieved primary literature uses MIM 607786 for the PCSK9-associated hypercholesterolemia phenotype and MIM 607786/603776-related notation in older records; an older article also cites MIM 143890 for the broader ADH phenotype. These historical numbers should be reconciled directly against the current OMIM record before database ingestion. A definitive subtype-specific MONDO identifier was not recovered by the available tools; use the current MONDO familial-hypercholesterolemia parent mapping only after curator verification. Broader coding generally uses familial/pure hypercholesterolemia categories (for example ICD-10-CM E78.01), because ICD and MeSH do not ordinarily distinguish ADH3 by gene. (allard2005novelmutationsof pages 1-3)

Data provenance: the disease definition and variant–phenotype relationships derive from aggregated disease resources, pedigrees, lipid-clinic cohorts, and experimental studies—not individual-level EHR data in this report. Recent implementation studies use aggregated clinical records, but their findings concern FH generally rather than PCSK9-genotyped ADH3.

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

Primary cause

ADH3 is caused by a germline PCSK9 GOF allele. Pathogenicity is mechanism-specific: rare PCSK9 variants can be GOF, loss-of-function (LOF), neutral, or uncertain, so merely finding a rare PCSK9 allele is insufficient. GOF mechanisms include enhanced LDLR binding, altered intracellular trafficking or secretion, resistance to inactivation, increased stability, and reduced inhibitory binding of PCSK9 to LDL particles. A 2024 review estimated that PCSK9 GOF variants cause approximately 1% of FH and listed about 36 pathogenic/probably pathogenic variants, although database totals evolve. (fularski2024unveilingfamilialhypercholesterolemia—review pages 4-5)

Risk factors and modifiers

Genetic: one pathogenic PCSK9 GOF allele, a second pathogenic FH allele, high polygenic LDL-C burden, and other ASCVD-risk alleles can increase severity. A PCSK9 p.Arg469Trp carrier with a coexisting LDLR frameshift had especially severe disease, illustrating additive monogenic effects. Expressivity also varied among p.Arg218Ser relatives. (allard2005novelmutationsof pages 3-6, allard2005novelmutationsof pages 1-3)
Clinical/environmental: smoking, hypertension, diabetes, obesity, inactivity, an atherogenic diet, elevated lipoprotein(a), and delayed or inadequate LDL-lowering do not cause ADH3 but increase downstream ASCVD risk. Lifelong LDL exposure begins at birth; broader FH guidance therefore treats cumulative LDL-C as the dominant causal exposure. (fularski2024unveilingfamilialhypercholesterolemia—review pages 7-9, watts2023internationalatherosclerosissociety pages 1-2, watts2023internationalatherosclerosissociety pages 7-8)
Pregnancy: physiological lipid increases can magnify hypercholesterolemia; markedly high cholesterol during pregnancy was reported in a p.Arg357His carrier. (allard2005novelmutationsof pages 1-3)

Protective factors

PCSK9 LOF alleles lower LDL-C and coronary risk but are not a practical within-patient “protective modifier” once a causal GOF allele is present. Environmental protection consists chiefly of early sustained LDL-C lowering, smoking avoidance, exercise, heart-healthy dietary patterns, normal weight, and control of blood pressure and diabetes. These interventions reduce cardiovascular consequences, not inheritance of ADH3. (fularski2024unveilingfamilialhypercholesterolemia—review pages 4-5, mcnutt2010characterizationofthea pages 115-119)

A gene–treatment interaction is important: statins activate SREBP2 and increase both LDLR and PCSK9 expression. PCSK9 blockade preserves more of the statin-induced LDLR, explaining their mechanistic synergy. (mcnutt2010characterizationofthe pages 115-119, mcnutt2010characterizationofthea pages 115-119)

3. Phenotypes

ADH3-specific phenotype frequencies cannot be estimated reliably from the small published pedigrees. Suggested ontology annotations are therefore qualitative.

Elevated LDL-C / type IIa hyperlipoproteinemia—laboratory abnormality, present from birth, chronic and usually progressive in cumulative impact; severity ranges from mild to very severe. Suggested HPO: Hypercholesterolemia (HP:0003124) and Elevated circulating LDL cholesterol concentration. A p.Arg218Ser proband had untreated total cholesterol 402 mg/dL and LDL-C 293 mg/dL at age 45. (allard2005novelmutationsof pages 3-6)
Tendon xanthoma—physical sign caused by cholesterol deposition, usually appearing after prolonged severe exposure but potentially in childhood in severe FH. Suggested HPO: Tendon xanthomatosis (HP:0000991). The p.Arg218Ser proband had tendinous xanthoma. (allard2005novelmutationsof pages 3-6)
Corneal arcus—bilateral peripheral corneal lipid deposition, particularly informative when premature. Suggested HPO: Corneal arcus (HP:0001084). It was present in the same p.Arg218Ser proband. (allard2005novelmutationsof pages 3-6)
Premature coronary atherosclerosis, angina, myocardial infarction, and cardiovascular death—downstream complications, age-dependent and progressive. Suggested HPO: Premature atherosclerosis (HP:0002621), Coronary artery disease (HP:0001677), and Myocardial infarction (HP:0001658). An original p.Phe216Leu carrier died from myocardial infarction at 49 years; p.Asp374Tyr is associated with particularly severe disease and premature cardiovascular death. (weider2017inhibitionofthe pages 152-156, abifadel2003mutationsinpcsk9 pages 2-2)
Aortic/other arterial atherosclerosis—expected from the FH disease process, but no reliable ADH3-specific frequency was recovered.

Quality of life is usually unaffected by the biochemical phenotype itself until treatment burden, anxiety, xanthomas, angina, or vascular events intervene. No ADH3-specific EQ-5D, SF-36, or PROMIS study was identified. In general FH, childhood treatment is expected to improve quality of life and reduce later mortality. (watts2023internationalatherosclerosissociety pages 1-2)

4. Genetic and molecular information

Causal gene: PCSK9, chromosome 1p32.3; HGNC:20001 (curator should verify current HGNC/Ensembl cross-references). It encodes proprotein convertase subtilisin/kexin type 9, formerly NARC-1. PCSK9 is synthesized as a zymogen and autocatalytically cleaved in the endoplasmic reticulum; cleavage enables ER exit. (seidah2017thepcsk9revolution pages 3-6, abifadel2003mutationsinpcsk9 pages 2-2)

Representative variants

p.Ser127Arg (S127R) and p.Phe216Leu (F216L): original heterozygous variants establishing causality. S127R affects the prodomain/processing region and can inhibit normal LDL binding; F216L lies near catalytic His226. (seidah2017thepcsk9revolution pages 3-6, abifadel2003mutationsinpcsk9 pages 2-2)
p.Asp374Tyr (D374Y): strong GOF missense variant with approximately tenfold greater LDLR affinity, severe hypercholesterolemia, and premature cardiovascular disease. (weider2017inhibitionofthe pages 152-156, rochemolina2015inductionofsustained pages 1-2)
p.Arg218Ser (R218S): heterozygous catalytic-domain variant that cosegregated in four relatives and was absent from 415 diverse controls; functional effect was not demonstrated in the original report, so modern classification should incorporate current ClinVar/ClinGen evidence. (allard2005novelmutationsof pages 3-6)
p.Arg357His, p.Ala443Thr, and p.Arg469Trp: reported in LDLR/APOB-negative ADH screening; original evidence and segregation strength varied. (allard2005novelmutationsof pages 1-3)
Regulatory variation: a 2024 study of 409 suspected-FH patients found rare LDLR/PCSK9 3′UTR variants; PCSK9 c.*950C>T increased reporter expression by 41%. This is emerging FH evidence and should not automatically be labeled definitive ADH3 without segregation and clinical functional validation. DOI: https://doi.org/10.1155/2024/9964734; February 2024. (otero2024functionalanalysisof pages 4-5)

All established disease alleles are germline. Somatic origin is not characteristic. Most reported alleles are missense; the functional endpoint is GOF rather than simple haploinsufficiency. Population frequency should be extremely low for highly penetrant pathogenic alleles, but exact gnomAD frequencies must be entered variant by variant. No recurrent chromosomal abnormality, repeat expansion, mitochondrial defect, or disease-defining structural variant is established.

Modifiers and epigenetics

No validated ADH3-specific modifier gene or epigenetic lesion is established. A 2024 FH study found differential LDLR, PCSK9, and LDLRAP1 methylation associated with clinical manifestations and cardiovascular events in 131 patients, but this remains a potential biomarker in mixed-genotype FH, not a proven cause or modifier of ADH3.

5. Environmental information

No toxin, radiation exposure, occupational agent, or infectious pathogen causes ADH3. Diet, adiposity, inactivity, smoking, diabetes, and hypertension modify LDL-C or vascular consequences. Infectious-agent and zoonotic fields are not applicable. Lifestyle intervention is necessary but is rarely sufficient to normalize genetically elevated LDL-C. General FH evidence shows that cumulative pathogenic LDL exposure can be reached by approximately age 12.5 years versus around 55 years without FH, emphasizing that lifestyle advice must not delay pharmacotherapy. (fularski2024unveilingfamilialhypercholesterolemia—review pages 7-9)

6. Mechanism and pathophysiology

Ordered causal chain

A germline PCSK9 GOF variant leads to increased effective PCSK9 activity through enhanced LDLR affinity, altered trafficking/secretion, increased stability, impaired inactivation, or loss of normal LDL-mediated inhibition.
Increased active PCSK9 leads to greater binding of LDLR’s EGF-A domain at the hepatocyte surface and/or within the secretory pathway.
The PCSK9–LDLR complex results in sorting to late endosomes and lysosomes rather than recycling of LDLR to the plasma membrane.
Accelerated LDLR degradation leads to reduced cell-surface LDLR on hepatocytes.
Reduced receptor abundance results in impaired hepatic uptake of apoB-containing LDL particles and lifelong elevation of plasma LDL-C.
Chronic LDL-C exposure leads to arterial-wall LDL retention and modification.
Retained lipoprotein results in endothelial dysfunction and macrophage uptake/foam-cell formation; direct LDLR-independent PCSK9 inflammatory effects are plausible but remain less firmly demonstrated in human ADH3.
Lipid accumulation, inflammation, smooth-muscle responses, oxidative stress, calcification, and fibrous-cap remodeling lead to progressive atherosclerotic plaque.
Plaque growth or rupture results in coronary disease, myocardial infarction, stroke, and premature death; extravascular cholesterol deposition branches to tendon xanthomas and corneal arcus. (fularski2024unveilingfamilialhypercholesterolemia—review pages 4-5, mcnutt2010characterizationofthe pages 115-119, rochemolina2015inductionofsustained pages 1-2, weider2017inhibitionofthea pages 152-156)

The upstream lesion is variant-specific PCSK9 GOF; LDLR depletion and high LDL-C are central demonstrated intermediates. Arterial inflammation and tissue injury are downstream. D374Y increases PCSK9–LDLR affinity by at least tenfold. S127R/D129G can show abnormal secretion or intracellular activity, demonstrating that not all variants act identically. (rochemolina2015inductionofsustained pages 1-2, matiasperez2021pcsk9geneparticipates pages 2-4)

Suggested GO terms: regulation of receptor-mediated endocytosis; low-density lipoprotein particle receptor catabolic process; cholesterol homeostasis; lipoprotein metabolic process; endosomal transport; lysosomal protein catabolic process; receptor recycling; foam-cell differentiation; inflammatory response; response to oxidative stress.

Suggested Cell Ontology terms: hepatocyte (CL:0000182) as the principal causal cell; enterocyte (CL:0000584), macrophage (CL:0000235), endothelial cell (CL:0000115), vascular smooth-muscle cell, pancreatic beta cell, and adipocyte as secondary/contextual populations.

Molecular profiling is limited. No ADH3-specific clinical single-cell, spatial-transcriptomic, proteomic, or multi-omic atlas was identified. A genome-wide expression analysis of D374Y-expressing cells and newer methylation/3′UTR studies are exploratory rather than diagnostic. PCSK9 is regulated with LDLR by SREBP2 and is expressed mainly in hepatocytes, with lower expression reported in intestine, kidney, pancreatic islets, and cerebellum. (mcnutt2010characterizationofthe pages 115-119, weider2017inhibitionofthea pages 152-156, weider2017inhibitionofthe pages 64-68)

7. Anatomical structures affected

Primary organ/process: liver—hepatocytes regulate circulating LDL clearance. Suggested UBERON: liver (UBERON:0002107).
Primary injured system: cardiovascular system, especially coronary arteries and aorta. Suggested UBERON: aorta (UBERON:0000947), coronary artery, arterial wall/intima, and heart.
Secondary deposition sites: tendons and corneal periphery; usually bilateral/systemic rather than lateralized.
Subcellular compartments: endoplasmic reticulum, Golgi/trans-Golgi network, plasma membrane, endosome, late endosome, and lysosome. Corresponding GO Cellular Component annotations should include ER lumen, Golgi apparatus, cell surface, endosome, and lysosome. PCSK9’s C-terminal domain supports trafficking of the PCSK9–LDLR complex toward late endocytic compartments. (mcnutt2010characterizationofthe pages 115-119, rochemolina2015inductionofsustained pages 1-2, weider2017inhibitionofthea pages 152-156)

8. Temporal development

The biochemical phenotype begins from birth because the causal allele is constitutional. Clinical onset is chronic and insidious. Early-stage disease consists of isolated LDL-C elevation; intermediate disease may include arcus, tendon xanthomas, and subclinical plaque; advanced disease includes symptomatic coronary or other arterial disease. The course is lifelong and cumulative, not episodic or spontaneously remitting. Treatment can normalize or substantially reduce LDL-C and arrest or delay complications but does not eliminate the genotype. Childhood is the critical preventive window. In broader FH cohorts treated from youth, ASCVD occurred in 1% of treated offspring versus 26% of affected parents, and mortality was 0% versus 7%, supporting early intervention even though these figures are not ADH3-specific. (watts2023internationalatherosclerosissociety pages 9-10)

9. Inheritance and population

Inheritance is autosomal dominant; each child of a heterozygous affected individual has a 50% transmission probability. Penetrance for elevated LDL-C is considered high but is age-, variant-, treatment-, and threshold-dependent. Expressivity is variable, as demonstrated within the p.Arg218Ser family. Anticipation is not established. Germline mosaicism is theoretically possible but not a recognized recurrent feature; consanguinity is not required. Biallelic GOF variants or dual molecular diagnoses may cause an HoFH-like extreme phenotype. (allard2005novelmutationsof pages 3-6, watts2023internationalatherosclerosissociety pages 1-2)

Reliable ADH3-specific prevalence, incidence, carrier frequency, sex ratio, and geographic distribution are unavailable. PCSK9 GOF variants account for about 1% of FH in a recent review and 2.3% of LDLR/APOB-negative cases in one selected 130-patient series; these are not population-prevalence estimates. General heterozygous FH prevalence is approximately 1:311, or more than 34 million people worldwide. Males and females inherit ADH3 equally, although sex and conventional risk factors may alter event timing. (allard2005novelmutationsof pages 1-3, fularski2024unveilingfamilialhypercholesterolemia—review pages 4-5, marquina2024costeffectivenessofscreening pages 1-2)

Founder effects may occur for individual alleles, but no single global ADH3 founder variant was established in the retrieved evidence.

10. Diagnostics

Clinical and biochemical assessment

Obtain at least two fasting or nonfasting lipid profiles where feasible, documenting untreated or estimated pretreatment LDL-C. Assess family history of markedly elevated LDL-C and premature ASCVD, tendon xanthomas, corneal arcus, blood pressure, diabetes, smoking, renal/liver/thyroid status, and lipoprotein(a). Use a validated FH framework such as Dutch Lipid Clinic Network, Simon Broome, MEDPED, or a national pediatric criterion. General FH guidelines characterize the triad as hyper-LDL-cholesterolemia, premature coronary disease, and tendon/skin xanthomas. (watts2023internationalatherosclerosissociety pages 7-8, yip2023geneticspectrumand pages 5-6)

Exclude secondary hypercholesterolemia: hypothyroidism, nephrotic syndrome, cholestatic liver disease, chronic kidney disease, uncontrolled diabetes, medications, and severe dietary causes. Molecular differential diagnosis includes LDLR-related FH, APOB-related familial defective apoB, APOE p.Leu167del hypercholesterolemia, LDLRAP1-related recessive hypercholesterolemia, ABCG5/ABCG8 sitosterolemia, polygenic hypercholesterolemia, and elevated lipoprotein(a).

Genetic testing

Use an accredited NGS FH panel including at least LDLR, APOB, PCSK9, and LDLRAP1, with deletion/duplication analysis and additional validated genes where appropriate. A pathogenic/likely pathogenic PCSK9 GOF allele plus a compatible phenotype confirms ADH3. Report VUS separately and do not use one alone for predictive diagnosis. Functional evidence is unusually important because PCSK9 has both GOF and LOF alleles. Family segregation and targeted testing of relatives strengthen interpretation. (allard2005novelmutationsof pages 1-3, watts2023internationalatherosclerosissociety pages 7-8)

Single-gene PCSK9 testing is reasonable when a familial variant is known. WES/WGS may identify deep-intronic, regulatory, or structural variants after a negative panel, but interpretation—not sequencing—is the chief limitation. RNA-seq or reporter assays remain research tools. CMA, karyotype, FISH, mitochondrial sequencing, and repeat-expansion testing are not routine.

Imaging is for complication assessment, not molecular diagnosis: coronary calcium/CT angiography may aid selected adult risk stratification; carotid ultrasound can show plaque. Routine pediatric coronary CT/calcium scoring is discouraged, whereas severe or homozygous-like presentations require specialist cardiovascular imaging. (watts2023internationalatherosclerosissociety pages 9-10)

Screening implementation

Cascade lipid and targeted-variant testing should begin with first-degree relatives and extend through the pedigree. Combined cascade testing and young-age universal screening could identify more than 90% of FH. Yet only about 10% of affected people worldwide are diagnosed, and over 80% of treated patients fail recommended LDL-C goals. (watts2023internationalatherosclerosissociety pages 1-2, watts2023internationalatherosclerosissociety pages 7-8)

11. Outcome and prognosis

Untreated prognosis is governed chiefly by cumulative LDL-C and other cardiovascular risks. General FH carries approximately tenfold higher coronary-heart-disease risk than the general population. ADH3-specific survival curves, five- or ten-year survival, disability rates, and validated prognostic models are unavailable. Severe D374Y disease and the myocardial-infarction death at age 49 in an F216L family illustrate the potential natural history but cannot define average prognosis. (fularski2024unveilingfamilialhypercholesterolemia—review pages 7-9, weider2017inhibitionofthe pages 152-156, abifadel2003mutationsinpcsk9 pages 2-2)

Adverse prognostic factors include higher untreated LDL-C, earlier xanthomas, established ASCVD, smoking, hypertension, diabetes, elevated lipoprotein(a), a second FH allele, and delayed/inadequate treatment. Favorable factors are early diagnosis, sustained LDL-C goal attainment, adherence, and control of all risk factors. Recovery from an established infarction or stroke is incomplete, but plaque progression and future events are preventable.

12. Treatment

ADH3 should be treated as high-risk heterozygous FH, intensified for severe phenotype or established ASCVD.

Lifestyle and risk-factor control: heart-healthy diet, physical activity, weight management, no smoking, and treatment of hypertension/diabetes. Lifestyle is adjunctive, not a substitute for medication.
High-intensity statin: atorvastatin or rosuvastatin unless contraindicated. Suggested NCIT concept: HMG-CoA reductase inhibitor therapy. Statin-associated muscle symptoms occur in roughly 10–15%; rhabdomyolysis is about 1–3 per 100,000 person-years and new-onset diabetes risk rises approximately 9% in broader populations. (fularski2024unveilingfamilialhypercholesterolemia—review pages 10-12)
Add ezetimibe: inhibits NPC1L1 intestinal cholesterol uptake; about 18% LDL-C lowering alone and about 20% additional lowering with a statin. Suggested NCIT: ezetimibe treatment. (fularski2024unveilingfamilialhypercholesterolemia—review pages 10-12)
Add PCSK9-directed treatment: alirocumab or evolocumab antibodies typically lower LDL-C about 60%; inclisiran suppresses hepatic PCSK9 synthesis. These are mechanistically well matched to PCSK9 GOF, although no genotype-specific randomized ADH3 trial was recovered. Injection-site reactions and flu-like symptoms are typical antibody adverse effects. (jeswani2024pcsk9inhibitorsthe pages 1-3, fularski2024unveilingfamilialhypercholesterolemia—review pages 10-12)
Further options: bempedoic acid, bile-acid sequestrants, or specialist combination therapy. Lipoprotein apheresis is reserved for exceptionally severe or refractory disease, especially biallelic/HoFH-like presentations.

ESC/EAS-derived general FH goals are at least a 50% LDL-C reduction and LDL-C below 70 mg/dL (1.8 mmol/L) for high-risk FH without ASCVD/major risk factors, or below 55 mg/dL (1.4 mmol/L) for very-high-risk disease. Children generally begin statins at 8–10 years; one guideline target after age 10 is below 135–140 mg/dL, adjusted to national guidance and risk. (fularski2024unveilingfamilialhypercholesterolemia—review pages 7-9)

Relevant registered studies found by the trial search include ORION-9 inclisiran in HeFH (NCT03397121, phase 3, 482 participants), pediatric evolocumab (NCT02624869, phase 3, 163), pediatric inclisiran (NCT06597019, recruiting phase 3, planned 60), and alirocumab plaque-burden assessment (NCT05465278, phase 4, 104). These enroll phenotypic FH, not specifically ADH3, and should not be presented as genotype-specific trials.

Emerging nucleic-acid and gene-editing approaches aim to silence or permanently disrupt hepatic PCSK9. They are conceptually attractive but experimental for inherited PCSK9 GOF and raise irreversibility, off-target, delivery, and long-term safety issues. DOI for a 2024 review: https://doi.org/10.1161/CIRCULATIONAHA.123.067957; August 2024.

Suggested CHEBI entities include cholesterol, LDL cholesterol/esterified cholesterol, atorvastatin, rosuvastatin, ezetimibe, and bempedoic acid. Suggested NCIT intervention classes include statin therapy, cholesterol-absorption inhibitor therapy, monoclonal-antibody therapy, small-interfering-RNA therapy, and therapeutic apheresis.

13. Prevention

Primary prevention of the genotype is impossible after conception. Reproductive options following counseling include prenatal diagnosis or preimplantation genetic testing for a known familial variant; decisions must remain nondirective.

Secondary prevention is central: childhood lipid screening, molecular confirmation, and cascade testing permit treatment before plaque develops. In a 2024 systematic review of 21 studies and 62 strategies, cascade screening was cost-effective in 78% of studies, opportunistic screening in 85%, systematic screening in 80%, and population-wide screening in 60%; cascade testing produced the greatest health benefit per person tested. DOI: https://doi.org/10.1007/s40273-023-01347-7; January 2024. (marquina2024costeffectivenessofscreening pages 1-2)

Tertiary prevention consists of sustained LDL-C reduction, smoking avoidance, blood-pressure and diabetes control, antiplatelet therapy when otherwise indicated, cardiac rehabilitation after events, and surveillance of established ASCVD. Vaccination and antimicrobial prophylaxis are not disease-specific interventions.

14. Other species and natural disease

No convincing naturally occurring veterinary syndrome caused by orthologous PCSK9 GOF was identified. Therefore, breed, VBO, natural-disease prevalence, zoonotic transmission, and cross-species transmission are not applicable/not established. PCSK9 is evolutionarily conserved across mammals, and engineered mouse, hamster, and pig systems reproduce LDLR depletion and hypercholesterolemia. All such examples should be annotated as experimental, not spontaneous disease. (rochemolina2015inductionofsustained pages 1-2, rochemolina2015inductionofsustained pages 10-10, matiasperez2021pcsk9geneparticipates pages 2-4)

Useful taxa include Mus musculus (NCBI Taxon 10090), Mesocricetus auratus (10036), and Sus scrofa (9823); ortholog identifiers should be drawn directly from current NCBI Gene/Alliance records during database curation.

15. Model organisms and experimental systems

AAV-PCSK9-D374Y mouse: one intravenous AAV dose (3.5×10^10 viral particles) induced sustained LDL elevation in C57BL/6J, 129/Sv, and FVB mice. With high-fat diet, animals developed aortic plaques with macrophages and fibrous caps. In Apoe-null mice, D374Y doubled aortic-lesion extent despite unchanged serum cholesterol, suggesting downstream plaque effects or model interaction. DOI: https://doi.org/10.1161/ATVBAHA.114.303617; January 2015. (rochemolina2015inductionofsustained pages 1-2)
Adenoviral PCSK9 models: murine PCSK9 increased total cholesterol about twofold and non-HDL cholesterol fivefold; human PCSK9 produced approximately ninefold higher LDL-C. Similar profiles in Ldlr-null mice established LDLR dependence. (weider2017inhibitionofthe pages 61-64)
Humanized BAC mice: lines expressing approximately 95–5,000 ng/mL human PCSK9 showed expression-dependent increases in total cholesterol/apoB and reduced hepatic LDLR. (weider2017inhibitionofthe pages 152-156, weider2017inhibitionofthea pages 152-156)
D374Y transgenic/viral models: D374Y increases LDLR affinity around tenfold; some engineered mice expressed about 14 μg/mL active PCSK9. (weider2017inhibitionofthe pages 152-156)
Engineered minipigs: transgenic human PCSK9 GOF minipigs develop FH-like hypercholesterolemia and atherosclerosis, offering more human-like lipoprotein physiology than mice. The model is engineered, not natural disease. (rochemolina2015inductionofsustained pages 10-10, weider2017inhibitionofthe pages 64-68)
Cell systems: HepG2, HuH7, primary hepatocytes, fibroblasts, and fluorescent PCSK9–LDLR trafficking assays test secretion, EGF-A binding, endocytosis, and lysosomal degradation. They are valuable for ACMG functional evidence but may not reproduce lifelong whole-body disease.

Major limitations are that mice lack CETP, viral overexpression may exceed physiological concentrations, liver-restricted vectors omit extrahepatic expression, and high-fat diets introduce environmental effects. BAC and large-animal models improve physiological relevance but remain costly and do not fully reproduce human coronary events. (weider2017inhibitionofthe pages 64-68)

Recent developments and principal evidence gaps

Notable 2023–2024 developments include stronger international emphasis on combined universal/cascade screening, implementation science addressing the evidence-to-practice gap, functional study of PCSK9 3′UTR variants, methylation as a possible FH risk biomarker, wider real-world use of inclisiran and PCSK9 antibodies, and preclinical nucleic-acid/gene-editing approaches. Up to 80–90% of FH remains undiagnosed, while most treated patients remain above goal, making implementation—not merely discovery of additional drugs—a major expert priority. (otero2024functionalanalysisof pages 4-5, marquina2024costeffectivenessofscreening pages 1-2, watts2023internationalatherosclerosissociety pages 1-2)

Critical ADH3-specific gaps are: population prevalence and penetrance; standardized functional classification of rare PCSK9 alleles; variant-specific response to antibodies versus inclisiran; prospective natural history; patient-reported quality of life; pregnancy outcomes; ancestry-diverse cohorts; and long-term safety of permanent PCSK9 editing.

Evidence-quality note

The strongest ADH3 evidence comprises the 2003 discovery pedigrees, later segregation studies, and convergent LDLR-trafficking experiments. Treatment targets and most quantitative outcome estimates are extrapolated from general HeFH because ADH3-specific randomized trials are absent. PMID values were not consistently exposed in the retrieved full texts; DOI URLs and publication dates are therefore supplied where verified rather than inventing PMID mappings.

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(marquina2024costeffectivenessofscreening pages 1-2): Clara Marquina, Jedidiah I Morton, Melanie Lloyd, Dina Abushanab, Yeji Baek, Tamrat Abebe, Adam Livori, Padam Dahal, Gerald F. Watts, and Zanfina Ademi. Cost-effectiveness of screening strategies for familial hypercholesterolaemia: an updated systematic review. Pharmacoeconomics, 42:373-392, Jan 2024. URL: https://doi.org/10.1007/s40273-023-01347-7, doi:10.1007/s40273-023-01347-7. This article has 24 citations and is from a domain leading peer-reviewed journal.
(watts2023internationalatherosclerosissociety pages 7-8): Gerald F. Watts, Samuel S. Gidding, Robert A. Hegele, Frederick J. Raal, Amy C. Sturm, Laney K. Jones, Mitchell N. Sarkies, Khalid Al-Rasadi, Dirk J. Blom, Magdalena Daccord, Sarah D. de Ferranti, Emanuela Folco, Peter Libby, Pedro Mata, Hapizah M. Nawawi, Uma Ramaswami, Kausik K. Ray, Claudia Stefanutti, Shizuya Yamashita, Jing Pang, Gilbert R. Thompson, and Raul D. Santos. International atherosclerosis society guidance for implementing best practice in the care of familial hypercholesterolaemia. Nature Reviews Cardiology, 20:845-869, Jun 2023. URL: https://doi.org/10.1038/s41569-023-00892-0, doi:10.1038/s41569-023-00892-0. This article has 300 citations and is from a domain leading peer-reviewed journal.
(yip2023geneticspectrumand pages 5-6): Man-Kwan Yip, Elaine Kwan, Jenny Leung, Emmy Lau, and Wing-Tat Poon. Genetic spectrum and cascade screening of familial hypercholesterolemia in routine clinical setting in hong kong. Nov 2023. URL: https://doi.org/10.3390/genes14112071, doi:10.3390/genes14112071. This article has 6 citations.
(fularski2024unveilingfamilialhypercholesterolemia—review pages 10-12): 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.
(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.
(watts2023internationalatherosclerosissociety pages 1-2): Gerald F. Watts, Samuel S. Gidding, Robert A. Hegele, Frederick J. Raal, Amy C. Sturm, Laney K. Jones, Mitchell N. Sarkies, Khalid Al-Rasadi, Dirk J. Blom, Magdalena Daccord, Sarah D. de Ferranti, Emanuela Folco, Peter Libby, Pedro Mata, Hapizah M. Nawawi, Uma Ramaswami, Kausik K. Ray, Claudia Stefanutti, Shizuya Yamashita, Jing Pang, Gilbert R. Thompson, and Raul D. Santos. International atherosclerosis society guidance for implementing best practice in the care of familial hypercholesterolaemia. Nature Reviews Cardiology, 20:845-869, Jun 2023. URL: https://doi.org/10.1038/s41569-023-00892-0, doi:10.1038/s41569-023-00892-0. This article has 300 citations and is from a domain leading peer-reviewed journal.
(rochemolina2015inductionofsustained pages 1-2): Marta Roche-Molina, David Sanz-Rosa, Francisco M. Cruz, Jaime García-Prieto, Sergio López, Rocío Abia, Francisco J.G. Muriana, Valentín Fuster, Borja Ibáñez, and Juan A. Bernal. Induction of sustained hypercholesterolemia by single adeno-associated virus–mediated gene transfer of mutant hpcsk9. Arteriosclerosis, Thrombosis, and Vascular Biology, 35:50–59, Jan 2015. URL: https://doi.org/10.1161/atvbaha.114.303617, doi:10.1161/atvbaha.114.303617. This article has 234 citations and is from a domain leading peer-reviewed journal.
(rochemolina2015inductionofsustained pages 10-10): Marta Roche-Molina, David Sanz-Rosa, Francisco M. Cruz, Jaime García-Prieto, Sergio López, Rocío Abia, Francisco J.G. Muriana, Valentín Fuster, Borja Ibáñez, and Juan A. Bernal. Induction of sustained hypercholesterolemia by single adeno-associated virus–mediated gene transfer of mutant hpcsk9. Arteriosclerosis, Thrombosis, and Vascular Biology, 35:50–59, Jan 2015. URL: https://doi.org/10.1161/atvbaha.114.303617, doi:10.1161/atvbaha.114.303617. This article has 234 citations and is from a domain leading peer-reviewed journal.
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(jeswani2024pcsk9inhibitorsthe pages 1-3): Bijay Mukesh Jeswani, Shubhangi Sharma, Sawai Singh Rathore, Abubakar Nazir, Rohit Bhatheja, and Kapil Kapoor. Pcsk9 inhibitors: the evolving future. Health Science Reports, Oct 2024. URL: https://doi.org/10.1002/hsr2.70174, doi:10.1002/hsr2.70174. This article has 44 citations and is from a peer-reviewed journal.
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Artifacts

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Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	13
Resolved	13
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	13
On topic	6
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	13
Resolved	12
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1

12 of 13 terms resolved to a current term; the rest could not be looked up either way.

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Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Imaging Findings

Progression

Prevalence

Differential Diagnoses

Related Datasets

Clinical Trials

Experimental Models

Animal Models

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References & Deep Research

References

Deep Research

Autosomal Dominant Hypercholesterolemia 3: Disease-Characteristics Report

Executive summary and evidence scope

1. Disease information

Definition, names, and identifiers

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

Primary cause

Risk factors and modifiers

Protective factors

3. Phenotypes

4. Genetic and molecular information

Representative variants

Modifiers and epigenetics

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical and biochemical assessment

Genetic testing

Screening implementation

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Recent developments and principal evidence gaps

Evidence-quality note

Artifacts

Reference Validation

Term Validation