The link between elevated serum cholesterol, triglyceride, and lipoprotein levels and increased atherosclerotic cardiovascular disease (ASCVD) risk is well established.¹ Patients with significantly elevated lipoprotein or triglyceride levels, or a family history of premature ASCVD, may warrant additional testing to screen for genetically inherited dyslipidemias, such as familial hypercholesterolemia (FH).

Recently, a consensus statement was published to guide the utilization of genetic testing for people with suspected FH.² Additionally, with expanding use of novel lipid lowering therapies, such as proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), genetic testing is becoming part of routine evaluation for dyslipidemia management.

This review summarizes The National Lipid Association's (NLA) recent statement, which discusses the role for genetic testing for inherited lipid disorders, provides an overview of available tests, proposes an algorithm to select appropriate patients for testing, and offers guidance to interpret the results.³

Monogenic and polygenic dyslipidemias

Genetically inherited dyslipidemias can be classified as monogenic or polygenic.³ Monogenic disorders often have a large phenotypic effect and display Mendelian inheritance. Approximately 25 monogenic dyslipidemias have been defined with their inheritance and causal mutations.⁴

The most common monogenic dyslipidemia is heterozygous FH with a prevalence estimated at 1 in 250 persons in the US.⁵ FH often results from defects in the low-density lipoprotein receptor (LDL-R), PCSK9, or apolipoprotein B.⁶ Homozygotes typically have LDL levels >500 and develop premature, severe atherosclerosis, while heterozygotes typically develop atherosclerosis by middle age if left untreated.⁷

Up to 5% of myocardial infarctions under age 60 may be related to FH.⁶ Less than 10% of cases are diagnosed worldwide, underscoring the importance of disseminating information about genetic screening and utilizing risk scores to identify patients that may have FH (Table 1).^2,7

Table 1: Comparison of diagnostic criteria for Familial Hypercholesterolemia

Dutch Lipid Clinic Network Diagnostic Criteria for FH	Simon Broome Diagnostic Criteria for FH	MEDPED Diagnostic Criteria for FH
Family History
First degree relative with LDL >95th percentile for age and gender (1)	Family history of elevated total cholesterol >290 mg/dL in an adult first or second-degree relative (5)
First degree relative with tendon xanthomas and/or arcus cornealis (2)	Family history of elevated total cholesterol >260 in a child, brother, or sister 16 years or younger (5)
Children <18 years old with LDL >95th percentile (2)
Clinical History
Patients with premature coronary artery disease (2)
Patients with premature cerebral or peripheral vascular disease (1)
Physical Exam
Tendon xanthomas (6)	Tendon xanthomas in the patient OR a first or second degree relative (2)
Arcus cornealis before age <45-year-old (4)
Lipids
LDL >330 mg/dL (8)	Total cholesterol levels >290 mg/dL or LDL-C >190 mg/dL in adults (1)	Age (years)	1st degree relative with FH	2nd degree relative with FH	3rd degree relative with FH	General population
LDL 250-329 mg/dL (5)
LDL 190-249 mg/dL (3)	Total cholesterol levels >260 mg/dL or LDL-C >155 mg/dL (1)	<20	220	230	240	270
		20-29	240	250	260	290
LDL 155-189 mg/dL (1)		30-39	270	280	290	340
		≥40	290	300	310	360
DNA Analysis
Functional mutation of LDL-R, ApoB or PCSK9 gene (8)	DNA-based evidence of an LDL-R mutation, familial defective apo B-100, or a PCSK9 mutation (3)
Diagnosis
Definite Familial Hyperlipidemia (>8)	Definite familial hypercholesterolemia (1+2 or 3)	FH diagnosed if total cholesterol exceeds above cut points in mg/dL
Probable Familial Hyperlipidemia (6-8)
Possible Familial Hyperlipidemia (3-5)	Possible familial hypercholesterolemia (1+4 or 5)
Unlikely Familial Hyperlipidemia (<3)

In contrast, polygenic dyslipidemias occur from the aggregate effect of multiple genetic variants; each variant has a small individual effect, but together they confer a significantly increased risk. Polygenic dyslipidemias do not display Mendelian patterns of inheritance. "Polygenic scores" estimate the combined effect of these variants on ASCVD risk; however, there are no established reference values, as different laboratories often develop their own algorithms. More data and standardization are needed to determine their role in clinical use.

The recommendations of NLA's statement apply mostly to screening for monogenic disorders. Polygenic factors, however, influence the phenotype of patients with monogenic disorders. This has been well established in FH; one study found that polygenic scores modulated both LDL levels and ASCVD risk among patients with known monogenic FH.⁸ Another found that up to 80% of patients with a clinical diagnosis of FH did not have classical mutations, suggesting a polygenic component.⁹ Clinicians should bear this in mind and treatment should be guided by the phenotype, rather than the genotype.³

Considerations prior to genetic testing

The most common hint for an underlying genetic dyslipidemia is the characteristic lipid dyscrasia.³ A strong family history of premature ASCVD should raise suspicion. Targeted physical examination should look for characteristic features associated with certain monogenic dyslipidemias, which range from xanthelasmas and xanthomas to hepatosplenomegaly and neurologic abnormalities.

Validated screening tools may be helpful to identify those individuals with FH (Table 1).¹⁰ Notably, the use of genetic testing in addition to these scoring systems may increase the diagnosis of FH by nearly 50%.¹¹ The recent consensus statement can offer guidance regarding which patients warrant testing based on degree of LDL elevation, personal, and family history of coronary artery disease (CAD).²

If there is a concern for a monogenic dyslipidemia, one should have a thorough discussion of the risks, benefits, and cost of genetic testing with the patient prior to testing. Benefits of testing include the ability to initiate targeted therapies such as PCSK9i, provide extra motivation for lifestyle change, and facilitate cascade screening. The risks include potential psychological stress associated with a diagnosis and the implications for family members. Results of genetic testing may also impact family planning and one's ability to obtain life or disability insurance.³ Involvement of a genetic counselor early on during the process is advised.

Current tests typically screen for monogenic dyslipidemias by analyzing a panel of associated genes through sequencing and deletion/duplication analysis. Laboratories that perform clinical genetic tests require certifications to ensure accuracy. Direct-to-consumer tests such as "23andMe" are not regulated and results should be corroborated with clinical testing.³

Interpreting results and initiating therapeutics

Targeted therapeutics exist for certain genetically inherited dyslipidemias. PCSK9i inhibit PCSK9-mediated degradation of LDL-R, thereby enhancing LDL clearance. While effective in individuals with heterozygous FH with a variety of pathogenic variants including in LDLR, APOB and PCSK9 gain-of-function,¹² they are less effective in those with homozygous FH due to LDLR mutations.¹³ In these patients, genotype may help guide management such as possible need for apheresis.³

Monogenic dyslipidemia diagnosis may prompt cascade testing, which can identify affected relatives. One study of patients with inherited cardiomyopathies and primary arrhythmia syndromes found that 98.4% of the relatives who attended genetic counseling proceeded with genetic testing;¹⁴ this highlights the importance of involving genetic counselors in these discussions.

Probands who test negative for a monogenic dyslipidemia may still have a genetically based hyperlipidemia. In one study, a monogenic cause for severe hypertriglyceridemia was identified in only 1% of patients, while a polygenic etiology was considered in 46%.¹⁵ More information is needed to develop standardized panels to screen for these disorders.

Conclusion and areas for future research

Given that most dyslipidemias are managed by primary care physicians who do not specialize in these disorders, the development of streamlined guidelines for genetic testing should be pursued. Research should focus on continued investigation for further monogenic pathogenic variants including reclassification of variants of uncertain significance, and standardizing polygenic risk scores for future use alongside ASCVD and CAC scores to more precisely define individual risk.

References

1. Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993-2000.
2. Sturm AC, Knowles JW, Gidding SS, et al. Clinical genetic testing for familial hypercholesterolemia: JACC scientific expert panel. J Am Coll Cardiol 2018;72:662-80.
3. Brown EE, Sturm AC, Cuchel M, et al. Genetic testing in dyslipidemia: a scientific statement from the National Lipid Association. J Clin Lipidol 2020;14:398-413.
4. Hegele RA, Boren J, Ginsberg HN, et al. Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement. Lancet Diabetes Endocrinol 2020;8:50-67.
5. de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC. Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States national health and nutrition examination surveys (NHANES). Circulation 2016;133:1067-72.
6. Bouhairie VE, Goldberg AC. Familial hypercholesterolemia. Cardiol Clin 2015;33:169-79.
7. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-90.
8. Trinder M, Paquette M, Cermakova L, et al. Polygenic contribution to low-density lipoprotein cholesterol levels and cardiovascular risk in monogenic familial hypercholesterolemia. Circ Genom Precis Med 2020;Aug 13:[Epub ahead of print].
9. Raal FJ, Hovingh GK, Catapano AL. Familial hypercholesterolemia treatments: guidelines and new therapies. Atherosclerosis 2018;277:483-92.
10. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 2004;160:407-20.
11. Brown EE, Byrne KH, Davis DM, et al. Incorporation of genetic testing significantly increases the number of individuals diagnosed with familial hypercholesterolemia. J Clin Lipidol 2020;14:331-38.
12. Defesche JC, Stefanutti C, Langslet G, et al. Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia. J Clin Lipidol 2017;11:1338-46.e7.
13. Rosenson RS, Hegele RA, Koenig W. Cholesterol-lowering agents: PCSK9 inhibitors today and tomorrow. Circ Res 2019;124:364-85.
14. van den Heuvel LM, van Teijlingen MO, van der Roest W, et al. A long-term follow-up study on the uptake of genetic counseling and predictive DNA testing in inherited cardiac conditions. Circ Genom Precis Med 2020;13:524-30.
15. Dron JS, Wang J, Cao H, et al. Severe hypertriglyceridemia is primarily polygenic. J Clin Lipidol 2019;13:80-88.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Genetic Arrhythmic Conditions, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia

Keywords: Dyslipidemias, Hyperlipoproteinemia Type II, Apolipoprotein B-100, Genetic Counseling, Cholesterol, LDL, Ursidae, PCSK9 protein, human, Proprotein Convertase 9, Coronary Artery Disease, Apolipoproteins B, Hyperlipidemias, Homozygote, Heterozygote

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