Genetic testing in dyslipidemia: A scientific statement from the National Lipid Association


      • In selected patients, genetic testing can help in diagnosis and management.
      • Pursuit of genetic testing must weigh potential benefits, risks, and patient preference.
      • Genetic counseling is recommended before and after genetic testing.
      • Understanding limitations of genetic testing is central to deriving the greatest benefit.


      The genetic basis for more than 2 dozen monogenic dyslipidemias has largely been defined. Genetic technologies, such as DNA sequencing, can detect both rare and common DNA variants underlying dyslipidemias, and these methods are increasingly available. Although patients with extreme abnormalities in low-density lipoprotein cholesterol, triglycerides, or high-density lipoprotein cholesterol may be considered for genetic testing, it is only in a minority of patients that the results will alter treatment or outcomes. Currently, there is potential clinical utility of genetic testing for familial hypercholesterolemia, familial chylomicronemia syndrome, sitosterolemia, lysosomal acid lipase deficiency, and a few other rare disorders, and this will increase the demand for reliable genetic diagnostic methods at lower cost. Clinical indications for genetic testing for most dyslipidemias are not clearly established and currently no guidelines exist. A shared decision-making model between the patient and the provider is essential as patient values and preferences play a very strong role. Potential benefits of genetic testing include providing a firm diagnosis in many cases, guiding optimal management and prevention strategies, advancing care strategies beyond currently available treatments, and contributing to overall scientific progress. Understanding the limitations and risks of genetic testing techniques is also important, as is careful interpretation of genetic test results to achieve the greatest benefit. Here we review laboratory methods, as well as technical, biological, clinical, and ethical implications and applications of genetic testing in dyslipidemias.


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        • Jacobson T.A.
        • Ito M.K.
        • Maki K.C.
        • et al.
        National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary.
        J Clin Lipidol. 2014; 8: 473-488
        • Jacobson T.A.
        • Maki K.C.
        • Orringer C.E.
        • et al.
        • NLA Expert Panel
        National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 2.
        J Clin Lipidol. 2015; 9: S1-S122.e1
        • Hopkins P.N.
        • Toth P.P.
        • Ballantyne C.M.
        • Rader D.J.
        National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
        J Clin Lipidol. 2011; 5: S9-S17
        • Halperin J.L.
        • Levine G.N.
        • Al-Khatib S.M.
        • et al.
        Further Evolution of the ACC/AHA Clinical Practice Guideline Recommendation Classification System: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        J Am Coll Cardiol. 2016; 67: 1572-1574
        • Hegele R.A.
        Plasma lipoproteins: genetic influences and clinical implications.
        Nat Rev Genet. 2009; 10: 109-121
        • Dron J.S.
        • Hegele R.A.
        Polygenic influences on dyslipidemias.
        Curr Opin Lipidol. 2018; 29: 133-143
        • Hegele R.A.
        • Borén J.
        • Ginsberg H.N.
        • 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
        • Defesche J.C.
        • Gidding S.S.
        • Harada-Shiba M.
        • Hegele R.A.
        • Santos R.D.
        • Wierzbicki A.S.
        Familial hypercholesterolaemia.
        Nat Rev Dis Primers. 2017; 3: 17093
        • Sturm A.C.
        • Knowles J.W.
        • Gidding S.S.
        • et al.
        Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel.
        J Am Coll Cardiol. 2018; 72: 662-680
        • Stahel P.
        • Xiao C.
        • Hegele R.A.
        • Lewis G.F.
        Polygenic risk for hypertriglyceridemia can mimic a major monogenic mutation.
        Ann Intern Med. 2017; 167: 360-361
        • Khera A.V.
        • Chaffin M.
        • Aragam K.G.
        • et al.
        Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations.
        Nat Genet. 2018; 50: 1219-1224
        • Dron J.S.
        • Hegele R.A.
        The evolution of genetic-based risk scores for lipids and cardiovascular disease.
        Curr Opin Lipidol. 2019; 30: 71-81
        • Talmud P.J.
        • Shah S.
        • Whittall R.
        • et al.
        Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.
        Lancet. 2013; 381: 1293-1301
        • Futema M.
        • Shah S.
        • Cooper J.A.
        • et al.
        Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries.
        Clin Chem. 2015; 61: 231-238
        • Wang J.
        • Dron J.S.
        • Ban M.R.
        • et al.
        Polygenic versus monogenic causes of hypercholesterolemia ascertained clinically.
        Arterioscler Thromb Vasc Biol. 2016; 36: 2439-2445
        • Dron J.S.
        • Wang J.
        • Low-Kam C.
        • et al.
        Polygenic determinants in extremes of high-density lipoprotein cholesterol.
        J Lipid Res. 2017; 58: 2162-2170
        • Dron J.S.
        • Wang J.
        • Cao H.
        • et al.
        Severe hypertriglyceridemia is primarily polygenic.
        J Clin Lipidol. 2019; 13: 80-88
        • Berberich A.J.
        • Hegele R.A.
        The complex molecular genetics of familial hypercholesterolaemia.
        Nat Rev Cardiol. 2019; 16: 9-20
        • Nordestgaard B.G.
        • Chapman M.J.
        • Humphries S.E.
        • et al.
        European Atherosclerosis Society Consensus Panel. 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: 3478-3490
        • Luirink I.K.
        • Wiegman A.
        • Kusters D.M.
        • et al.
        20-year follow-up of statins in children with familial hypercholesterolemia.
        N Engl J Med. 2019; 381: 1547-1556
        • Chait A.
        • Eckel R.H.
        The Chylomicronemia syndrome is most often multifactorial: a narrative review of causes and treatment.
        Ann Intern Med. 2019; 170: 626-634
        • Brahm A.J.
        • Hegele R.A.
        Chylomicronaemia--current diagnosis and future therapies.
        Nat Rev Endocrinol. 2015; 11: 352-362
        • Berberich A.J.
        • Hegele R.A.
        The role of genetic testing in dyslipidaemia.
        Pathology. 2019; 51: 184-192
        • Marais D.
        Dysbetalipoproteinemia: an extreme disorder of remnant metabolism.
        Curr Opin Lipidol. 2015; 26: 292-297
        • Schaefer E.J.
        • Geller A.S.
        • Endress G.
        The biochemical and genetic diagnosis of lipid disorders.
        Curr Opin Lipidol. 2019; 30: 56-62
        • Burnett J.R.
        • Hooper A.J.
        • Hegele R.A.
        in: Adam M.P. Ardinger H.H. Pagon R.A. GeneReviews(R). University of Washington, Seattle1993 (Seattle, WA)
        • Tzavella E.
        • Hatzimichael E.
        • Kostara C.
        • Bairaktari E.
        • Elisaf M.
        • Tsimihodimos V.
        Sitosterolemia: A multifaceted metabolic disorder with important clinical consequences.
        J Clin Lipidol. 2017; 11: 1095-1100
        • Salen G.
        • Steiner R.D.
        Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX).
        J Inherit Metab Dis. 2017; 40: 771-781
        • Schaefer E.J.
        • Anthanont P.
        • Diffenderfer M.R.
        • Polisecki E.
        • Asztalos B.F.
        Diagnosis and treatment of high density lipoprotein deficiency.
        Prog Cardiovasc Dis. 2016; 59: 97-106
        • Dron J.S.
        • Wang J.
        • McIntyre A.D.
        • et al.
        Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias.
        BMC Med Genomics. 2020; 13: 23
        • Dilliott A.A.
        • Farhan S.M.K.
        • Ghani M.
        • et al.
        Targeted next-generation sequencing and bioinformatics pipeline to evaluate genetic determinants of constitutional disease.
        J Vis Exp. 2018; : 57266
        • Hegele R.A.
        Editorial: designing targeted sequencing panels for dyslipidemia.
        Curr Opin Lipidol. 2019; 30: 53-55
        • Cirino A.L.
        • Harris S.
        • Lakdawala N.K.
        • et al.
        Role of genetic testing in inherited cardiovascular disease: a review.
        JAMA Cardiol. 2017; 2: 1153-1160
        • Dedoussis G.V.
        • Schmidt H.
        • Genschel J.
        LDL-receptor mutations in Europe.
        Hum Mutat. 2004; 24: 443-459
        • Rios J.J.
        • Shastry S.
        • Jasso J.
        • et al.
        Deletion of GPIHBP1 causing severe chylomicronemia.
        J Inherit Metab Dis. 2012; 35: 531-540
        • Iacocca M.A.
        • Hegele R.A.
        Role of DNA copy number variation in dyslipidemias.
        Curr Opin Lipidol. 2018; 29: 125-132
        • Richards S.
        • Aziz N.
        • Bale S.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
        Genet Med. 2015; 17: 405-424
        • Hudson K.
        • Javitt G.
        • Burke W.
        • Byers P.
        • American Society of Human Genetics Social Issues C.
        ASHG Statement on direct-to-consumer genetic testing in the United States.
        Obstet Gynecol. 2007; 110: 1392-1395
        • Tandy-Connor S.
        • Guiltinan J.
        • Krempely K.
        • et al.
        False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care.
        Genet Med. 2018; 20: 1515-1521
        • Khera A.V.
        • Won H.H.
        • Peloso G.M.
        • et al.
        Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.
        J Am Coll Cardiol. 2016; 67: 2578-2589
        • Trinder M.
        • Li X.
        • DeCastro M.L.
        • et al.
        Risk of premature atherosclerotic disease in patients with monogenic versus polygenic familial hypercholesterolemia.
        J Am Coll Cardiol. 2019; 74: 512-522
        • Ference B.A.
        • Ginsberg H.N.
        • Graham I.
        • et al.
        Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
        Eur Heart J. 2017; 38: 2459-2472
        • Garg A.
        • Garg V.
        • Hegele R.A.
        • Lewis G.F.
        Practical definitions of severe versus familial hypercholesterolaemia and hypertriglyceridaemia for adult clinical practice.
        Lancet Diabetes Endocrinol. 2019; 7: 880-886
        • Raal F.J.
        • Honarpour N.
        • Blom D.J.
        • et al.
        Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial.
        Lancet. 2015; 385: 341-350
        • Paquette M.
        • Bernard S.
        • Hegele R.A.
        • Baass A.
        Chylomicronemia: Differences between familial chylomicronemia syndrome and multifactorial chylomicronemia.
        Atherosclerosis. 2019; 283: 137-142
        • Hegele R.A.
        • Tsimikas S.
        Lipid-lowering agents.
        Circ Res. 2019; 124: 386-404
        • Shamburek R.D.
        • Bakker-Arkema R.
        • Auerbach B.J.
        • et al.
        Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement.
        J Clin Lipidol. 2016; 10: 356-367
        • Michael Gibson C.
        • Korjian S.
        • Tricoci P.
        • et al.
        Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I).
        Circulation. 2016; 134: 1918-1930
        • Geller A.S.
        • Polisecki E.Y.
        • Diffenderfer M.R.
        • et al.
        Genetic and secondary causes of severe HDL deficiency and cardiovascular disease.
        J Lipid Res. 2018; 59: 2421-2435
        • Cameron L.D.
        • Muller C.
        Psychosocial aspects of genetic testing.
        Curr Opin Psychiatry. 2009; 22: 218-223
        • Green R.C.
        • Lautenbach D.
        • McGuire A.L.
        GINA, genetic discrimination, and genomic medicine.
        N Engl J Med. 2015; 372: 397-399
        • Hayden E.C.
        Technology: The $1,000 genome.
        Nature. 2014; 507: 294-295
        • Sboner A.
        • Mu X.J.
        • Greenbaum D.
        • Auerbach R.K.
        • Gerstein M.B.
        The real cost of sequencing: higher than you think!.
        Genome Biol. 2011; 12: 125
        • Iacocca M.A.
        • Chora J.R.
        • Carrie A.
        • et al.
        ClinVar database of global familial hypercholesterolemia-associated DNA variants.
        Hum Mutat. 2018; 39: 1631-1640
        • Famiglietti M.L.
        • Estreicher A.
        • Breuza L.
        • et al.
        An enhanced workflow for variant interpretation in UniProtKB/Swiss-Prot improves consistency and reuse in ClinVar.
        Database (Oxford). 2019; 2019: baz040
        • Niehaus A.
        • Azzariti D.R.
        • Harrison S.M.
        • et al.
        A survey assessing adoption of the ACMG-AMP guidelines for interpreting sequence variants and identification of areas for continued improvement.
        Genet Med. 2019; 21: 1699-1701
        • Houdayer F.
        • Putois O.
        • Babonneau M.L.
        • et al.
        Secondary findings from next generation sequencing: Psychological and ethical issues. Family and patient perspectives.
        Eur J Med Genet. 2019; 62: 103711
        • Hofmann B.
        Incidental findings of uncertain significance: To know or not to know--that is not the question.
        BMC Med Ethics. 2016; 17: 13
        • Ormond K.E.
        • O'Daniel J.M.
        • Kalia S.S.
        Secondary findings: How did we get here, and where are we going?.
        J Genet Couns. 2019; 28: 326-333
        • Kalia S.S.
        • Adelman K.
        • Bale S.J.
        • et al.
        Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
        Genet Med. 2017; 19: 249-255
        • Sturm A.C.
        The role of genetic counselors for patients with familial hypercholesterolemia.
        Curr Genet Med Rep. 2014; 2: 68-74
        • Uhlmann W.R.
        • Schuette J.L.
        • Yasgar B.
        A Guide to Genetic Counseling.
        2nd ed. Wiley-Blackwell, Hoboken, New Jersey2009
        • Weil J.
        Psychosocial genetic counseling.
        Oxford University Press, Oxford, United Kingdom2000
        • Sturm A.C.
        • Hershberger R.E.
        Genetic testing in cardiovascular medicine: current landscape and future horizons.
        Curr Opin Cardiol. 2013; 28: 317-325
        • Ingles J.
        • Yeates L.
        • Semsarian C.
        The emerging role of the cardiac genetic counselor.
        Heart Rhythm. 2011; 8: 1958-1962
        • Watts G.F.
        • Gidding S.
        • Wierzbicki A.S.
        • et al.
        Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation.
        Int J Cardiol. 2014; 171: 309-325
        • van der Roest W.P.
        • Pennings J.M.
        • Bakker M.
        • van den Berg M.P.
        • van Tintelen J.P.
        Family letters are an effective way to inform relatives about inherited cardiac disease.
        Am J Med Genet A. 2009; 149A: 357-363