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Familial hypercholesterolemia: is it time to separate monogenic from polygenic familial hypercholesterolemia?
Julia Brandts1,2, Kanika I Dharmayat1, Kausik K Ray1
1Imperial Centre for Cardiovascular Disease Prevention (ICCP), Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, UK.
Insights
Identifying familial hypercholesterolemia as monogenic versus polygenic impacts clinical practice. Monogenic familial hypercholesterolemia requires different screening and risk assessment strategies compared to polygenic forms.
Area of Science:
- Genetics
- Cardiology
- Clinical Practice
Background:
- Familial hypercholesterolemia (FH) presents a spectrum of genetic etiologies.
- Distinguishing between monogenic and polygenic forms is crucial for effective management.
Purpose of the Study:
- To explore the concepts of monogenic and polygenic FH.
- To delineate the clinical implications of differentiating monogenic FH from polygenic primary hypercholesterolemia.
Main Methods:
- Review of genetic testing findings in FH cases.
- Analysis of inheritance patterns and cascade screening efficacy.
- Evaluation of cardiovascular risk stratification based on genetic status.
Main Results:
- Genetic testing identifies mutations in 60-80% of clinically diagnosed FH.
- Monogenic FH shows higher relative risk in relatives (50%) compared to polygenic forms (30%).
- Monogenic mutations correlate with highest cardiovascular risk, independent of LDL-C, and may improve treatment adherence.
Conclusions:
- Genetic status (monogenic vs. polygenic) in FH provides critical insights for risk evaluation.
- Understanding genetic basis informs disease management and optimizes screening strategies.
- Clinical practice benefits from precise differentiation of FH subtypes for personalized patient care.
Purpose Of Review:
This review explores the concepts of monogenic and the so-called polygenic familial hypercholesterolemia and how the identification of familial hypercholesterolemia as a monogenic condition and its separation from polygenic primary hypercholesterolemia may have implications for clinical practice.
Recent Findings:
Through genetic testing, a mutation in any of the three known autosomal dominant familial hypercholesterolemia-causing genes is found in 60-80% of cases with a clinical diagnosis of definite familial hypercholesterolemia. As individuals with a polygenic basis for their hypercholesterolemia do not follow the same inheritance pattern observed in monogenic familial hypercholesterolemia, the use of family-based cascade screening in individuals with a polygenic origin is not recommend, as only 30% of relatives have an elevated LDL-C compared to the 50% in monogenic families. The presence of a causative monogenic mutation associates the highest cardiovascular risk vs. not having a mutation or having a polygenic background, providing prognostic information independent of LDL-C. It may also help assess intensity of interventions. Treatment adherence also seems to be higher after monogenic confirmation of hypercholesterolemia.
Summary:
Knowledge about the genetic status of an individual with clinical familial hypercholesterolemia (monogenic vs. polygenic) can provide a more informed understanding to evaluating risk, managing disease and opportunities for screening strategies.
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