Genetic Testing for Familial Hypercholesterolemia

Study Questions:

Which suspected familial hypercholesterolemia (FH) patients should undergo genetic screening?


The development cohort consisted of 26,167 FH patients and 37,939 unaffected relatives in the Dutch FH screening program. The validation cohort consisted of 1,436 patients attending a lipid clinic with suspected FH, and 1,767 unaffected persons. Cross-sectional data included medical history, lipid profile, and DNA analysis. Primary outcome was the presence of a FH mutation.


The final model included age; sex, low-density lipoprotein cholesterol (LDL-C), high-density protein cholesterol (HDL-C), triglycerides, history/age of cardiovascular disease (CVD), statin use, smoking, ethyl alcohol; and hypertension. Compared to unaffected subjects, FH patients were younger with lower body mass index, smoked and drank less, had more CVD, less hypertension and diabetes mellitus, higher LDL, lower HDL/triglycerides, and higher use of statins. The area under the curve (AUC) was 85.4% (95% confidence interval [CI], 85.0-85.9) with a calibration slope of 1.02 (1.00 is optimal). In the validation cohort, the AUC was 95.4% (95% CI, 94.7-96.1%) and the calibration slope was 1.06.


The authors concluded that this model may be useful to estimate the probability of a FH mutation in individual patients and therefore aid in decisions for genetic testing referrals.


Although homozygous FH is rare, heterozygous FH is relatively common, occurring in approximately 1 in 300 individuals. Early diagnosis and treatment can make a major impact towards reducing future CVD risk. Thus, identification of FH mutations and cascade genetic screening may be highly advantageous. However, which patients to refer for genetic testing remains controversial. The goal of this study was develop a model that might lead to a greater positive yield from genetic testing, and the authors show superiority in this regard over other commonly used algorithms. The precise equation will be available online as a calculator to aid in selection of suspected FH patients for genetic screening.

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