Incorporation of genetic testing significantly increases the number of individuals diagnosed with familial hypercholesterolemia

Published:March 02, 2020DOI:


      • Genetic testing increases detection of people with familial hypercholesterolemia.
      • Patients often do not meet clinical criteria owing to lack of physical sequela.
      • Hypertriglyceridemia should not rule out familial hypercholesterolemia.


      It is estimated that less than 10% of cases of familial hypercholesterolemia (FH) in the United States have been diagnosed. Low rates of diagnosis may in part be attributable to affected patients not meeting the clinical diagnostic criteria of the Dutch Lipid Clinic Network (DLCN), Simon Broome, or US MEDPED diagnostic criteria.


      The objective of this study was to assess the utility of incorporating genetic testing into a patient's evaluation for FH.


      We retrospectively reviewed patients seen in the Advanced Lipids Disorders Clinic at Johns Hopkins Hospital between January 2015 and May 2018. Between June 2018 and December 2018, patients were consented to a prospective registry. DLCN, Simon Broome, and MEDPED criteria were applied to each patient, before and after genetic testing. Genetic testing included sequencing and deletion duplication analysis of four genes (LDLR, PCSK9, APOB, and LDLRAP1).


      The retrospective review and prospective study identified 135 adult probands who were seen in our clinic for evaluation of heterozygous FH. Twenty-nine individuals (21%) were heterozygous for a pathogenic or likely pathogenic monogenic variant. Before genetic testing, using the DLCN criteria, 35 (26%) individuals met criteria for a definite diagnosis of FH. Thirty patients (22%) met criteria using Simon Broome, and 29 (21%) patients met criteria using US MEDPED before genetic analysis. Depending on the criteria, incorporating genetic testing identified 11–14 additional patients with FH.


      Incorporating genetic testing diagnosed almost 50% more patients with definite FH in comparison to classification solely on clinical grounds.


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        • Goldberg A.C.
        • Hopkins P.N.
        • Toth P.P.
        • et al.
        Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
        J Clin Lipidol. 2011; 5: 133-140
        • Hovingh G.K.
        • Davidson M.H.
        • Kastelein J.J.
        • O’Connor A.M.
        Diagnosis and treatment of familial hypercholesterolaemia.
        Eur Heart J. 2013; 34: 962-971
        • Nordestgaard B.G.
        • Chapman M.J.
        • Humphries S.E.
        • 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: 3478-3490a
        • Slack J.
        Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states.
        Lancet. 1969; : 1380-1382
        • Williams R.R.
        • Hunt S.C.
        • Schumacher M.C.
        • et al.
        Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics.
        Am J Cardiol. 1993; 72: 171-176
        • World Health Organization
        Familial hypercholesterolaemia. Report of a second WHO consultation.
        World Health Organization, Geneva1999
      1. Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group.
        BMJ. 1991; 303: 893-896
        • Haase A.
        • Goldberg A.C.
        Identification of people with heterozygous familial hypercholesterolemia.
        Curr Opin Lipidol. 2012; 23: 282-289
        • 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
        • Law M.R.
        • Wald N.J.
        • Rudnicka A.R.
        Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.
        BMJ. 2003; 326: 1423
        • Robinson J.G.
        Pharmacologic Treatment of Dyslipidemia and Cardiovascular Disease.
        in: Kwiterovich P.O. The Johns Hopkins Textbook of dyslipidemia. Lippincott Williams and Wilkins, Philadelphia2010: 266-276
        • Friedewald W.T.
        • Levy R.I.
        • Fredrickson D.S.
        Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
        Clin Chem. 1972; 18: 499-502
        • Tsouli S.G.
        • Xydis V.
        • Argyropoulou M.I.
        • Tselepis A.D.
        • Elisaf M.
        • Kiortsis D.N.
        Regression of Achilles tendon thickness after statin treatment in patients with familial hypercholesterolemia: an ultrasonographic study.
        Atherosclerosis. 2009; 205: 151-155
        • Damgaard D.
        • Larsen M.L.
        • Nissen P.H.
        • et al.
        The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population.
        Atherosclerosis. 2005; 180: 155-160
        • Civeira F.
        • Ros E.
        • Jarauta E.
        • et al.
        Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia.
        Am J Cardiol. 2008; 102: 1187-1193
        • Clarke R.E.
        • Padayachee S.T.
        • Preston R.
        • et al.
        Effectiveness of alternative strategies to define index case phenotypes to aid genetic diagnosis of familial hypercholesterolaemia.
        Heart. 2013; 99: 175-180
        • Natarajan P.
        • Peloso G.M.
        • Zekavat S.M.
        • et al.
        Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.
        Nat Commun. 2018; 9: 3391
        • 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
        • Sniderman A.D.
        Applying apoB to the diagnosis and therapy of the atherogenic dyslipoproteinemias: a clinical diagnostic algorithm.
        Curr Opin Lipidol. 2004; 15: 433-438