Beyond the Classic Genes: Rare Variants, Phenocopies, and Polygenic Architecture in Familial Hypercholesterolemia

Q: What is the clinical evidence from this study?

Study design: Review. Population: Familial hypercholesterolemia. Intervention: Rare genetic variants and polygenic architecture (LIPA, ABCG5/ABCG8, APOE, LDLRAP1, STAP1) vs. Classical monogenic FH variants (LDLR, APOB, PCSK9) accounting for 60-80% of diagnosed cases. Primary outcome: Contribution to mutation-negative familial hypercholesterolemia phenotypes.

Q: What does this research mean for the field?

Classical variants in LDLR, APOB, and PCSK9 account for 60-80% of familial hypercholesterolemia cases, while the remaining mutation-negative phenotypes largely result from polygenic hypercholesterolemia and rare phenocopy-associated gene variants. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.NEUTRAL.

Kristina Zubielienė; Simona Bėrontaitė; Diana Zaliaduonyte; Ieva Aleknaitė; Vytautas Zabiela

doi:10.33678/cor.2026.055

October 20, 2026Cor et VasaOpen Access

Beyond the Classic Genes: Rare Variants, Phenocopies, and Polygenic Architecture in Familial Hypercholesterolemia

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Key result

Rare phenocopies in LIPA, ABCG5/8, and APOE explain up to ~3% of mutation-negative familial hypercholesterolemia.

Why the study?

A substantial proportion of patients meeting clinical diagnostic criteria for familial hypercholesterolemia lack pathogenic variants in the classic LDLR, APOB, or PCSK9 genes, pointing to a more complex genetic architecture involving rare variants, phenocopies, and polygenic contributions.

Key Points

To review the contribution of rare genetic variants, phenocopies, and polygenic architecture to the clinical presentation and diagnosis of familial hypercholesterolemia.
Narrative review synthesizing published molecular and clinical literature on the genetic heterogeneity of familial hypercholesterolemia.
Evaluation of classical genes, rare variants (STAP1, LIPA, ABCG5/ABCG8, APOE, LDLRAP1), and polygenic risk assessment via next-generation sequencing.
Pathogenic variants in the canonical genes LDLR, APOB, and PCSK9 account for approximately 60–80% of molecularly diagnosed familial hypercholesterolemia cases.
In mutation-negative patients, elevated LDL-C is frequently driven by polygenic hypercholesterolemia from multiple common variants or phenocopies in genes including LIPA, ABCG5/ABCG8, APOE, and LDLRAP1.
Evidence suggests STAP1 is unlikely to represent a causal gene for familial hypercholesterolemia due to a lack of consistent cosegregation in family studies.

Structured PICO

P

Population

Patients fulfilling clinical diagnostic criteria for familial hypercholesterolemia (FH), particularly those who do not carry pathogenic variants in the classical FH genes (LDLR, APOB, or PCSK9).

E

Exposure

Expanded next-generation sequencing (NGS) panels (including rare genes and phenocopy genes such as LIPA, ABCG5/ABCG8, APOE, and LDLRAP1) and polygenic risk score (PRS) assessment.

Expanding genetic testing panels to include phenocopy genes (LIPA, ABCG5/ABCG8, APOE, LDLRAP1), excluding non-causal genes like STAP1, and integrating polygenic risk scores can improve diagnostic accuracy and guide personalized therapy in mutation-negative familial hypercholesterolemia patients.

Limitations

Narrative review without original pooled quantitative analysis
Conflicting evidence regarding the role of STAP1 variants as a causal gene

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Implication

Supports expanded FH genetic panels; leaves open prospective validation of polygenic risk integration.

Abstract

Familirn hypercholesterolemie (FH) je ast ddin porucha metabolismu lipid, pro ni jsou charakteristick vrazn zven hodnoty cholesterolu lipoprotein o nzk hustot (low-density lipoprotein cholesterol, LDL-C) a zven riziko pedasnho rozvoje aterosklerotick kardiovaskulrn nemoci. Familirn hypercholesterolemie se tradin povauje za monogenn poruchu zpsobenou patogennmi variantami v klasickch genech LDLR, APOB nebo PCSK9, kter naru drhu receptor pro LDL a odstraovn stic LDL v jtrech. U znanho procenta pacient splujcch klinick diagnostick kritria FH vak patogenn varianty uvedench gen nejsou ptomny, co ukazuje na sloitj genetickou architekturu. Pokrok zaznamenan v posledn dob v oblasti sekvenovn nov generace (next-generation sequencing, NGS) a stanoven polygennho rizika rozil poznn genetiky FH. U pacient bez mutac mohou bt zven hodnoty LDL-C dsledkem polygenn hypercholesterolemie, kdy kumulativn inek nkolika astch variant pispv k vslednmu fenotypu. Krom toho me nkolik vzcnch gen vytvoit FH-like fenotyp nebo psobit jako fenokopie. Do tto skupiny pat LIPA, ABCG5/ABCG8, APOE a LDLRAP1, kter ovlivuj metabolismus lipid prostednictvm rznch molekulrnch mechanism. loha STAP1 je i nadle sporn, piem souasn dkazy napovdaj, e pravdpodobn nepedstavuje kauzln gen pro FH. Tento pehled shrnuje podl vzcnch variant, fenokopi a polygenn architektury na klinickch projevech FH. Rozen panel pro genetick testovn a stanoven skre polygennho rizika me zvit diagnostickou pesnost a zajistit individualizovanj lbu pacient s tkou hypercholesterolemi a pi o n.

Discussion

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Cite This Study

Zubielienė et al. (2026) conducted a review in Familial hypercholesterolemia. Rare genetic variants and polygenic architecture (LIPA, ABCG5/ABCG8, APOE, LDLRAP1, STAP1) vs. Classical monogenic FH variants (LDLR, APOB, PCSK9) accounting for 60-80% of diagnosed cases was evaluated on Contribution to mutation-negative familial hypercholesterolemia phenotypes. Classical LDLR, APOB, and PCSK9 variants explain 60-80% of familial hypercholesterolemia, while rare variants in LIPA, ABCG5/ABCG8, and APOE explain mutation-negative cases.

synapsesocial.com/papers/6af8f7b3016f830a1d017466 https://doi.org/10.33678/cor.2026.055

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Beyond the Classic Genes: Rare Variants, Phenocopies, and Polygenic Architecture in Familial Hypercholesterolemia

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Beyond the Classic Genes: Rare Variants, Phenocopies, and Polygenic Architecture in Familial Hypercholesterolemia

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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