Diagnostic Yield of Gene Testing in Severe Hypercholesterolemia

Study Questions:

What is the prevalence of a familial hypercholesterolemia (FH) mutation among those with severe hypercholesterolemia and implications for coronary artery disease (CAD) risk according to mutation status beyond the observed low-density lipoprotein (LDL) cholesterol?


Whole exome sequencing was performed in seven previously described CAD case-control cohorts of the Myocardial Infarction Genetics Consortium. Three genes causative for FH (LDLR, APOB, PCSK9) were sequenced in 26,025 participants from seven case-control studies (5,540 CAD cases, 8,577 CAD-free controls) and five prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database. Odds ratios for CAD were calculated using logistic regression with adjustment for gender, cohort, and the first five principal components of ancestry.


Among 8,577 CAD-free control participants, 430 had LDL cholesterol ≥190 mg/dl; of these, only eight (1.9%) carried a FH mutation. Similarly, among 11,908 participants from five prospective cohorts, 956 had LDL cholesterol ≥190 mg/dl, and of these, only 16 (1.7%) carried a FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers when compared with noncarriers. When compared to a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had six-fold higher risk for CAD (odds ratio [OR], 6.0; 95% confidence interval [CI], 5.2-6.9), whereas those with LDL cholesterol ≥190 mg/dl as well as a FH mutation demonstrated 22-fold increased risk (OR, 22.3; 95% CI, 10.7-53.2).


The authors concluded that among individuals with LDL cholesterol ≥190 mg/dl, gene sequencing identified a FH mutation in <2%, but for any given observed LDL cholesterol, FH mutation carriers are at substantially increased risk for CAD.


This study reports that among those with severe hypercholesterolemia, only a small fraction (<2%) carries a FH mutation. However, within any level of LDL cholesterol, those who carried FH mutation were at substantially higher risk for CAD compared to those who did not. This increased CAD risk among mutation carriers appears at least partially due to a greater cumulative exposure to LDL cholesterol over a lifetime. Additional research is indicated to determine the relative contributions of other genetic variants and lifestyle factors and evaluate the clinical utility/benefit of genetic testing in patients with severe hypercholesterolemia.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Primary Hyperlipidemia

Keywords: Coronary Artery Disease, Cholesterol, LDL, Dyslipidemias, Genetic Testing, Hypercholesterolemia, Hyperlipoproteinemia Type II, Metabolic Syndrome X, Primary Prevention, Risk Factors

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