A comparative analysis of phenotypic predictors of mutations in familial hypercholesterolemia

Context: The gold standard for diagnosing familial hypercholesterolemia (FH) is identification of a causative pathogenic mutation. However, genetic testing is expensive and not widely available.

Objective: To compare the validity of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), Make Early Diagnosis to Prevent Early Deaths (MEDPED) and American Heart Association (AHA) criteria in predicting an FH-causing mutation.

Design, Setting, and Patients: An adult cohort of unrelated patients referred to a lipid clinic for genetic testing.

Main Outcome Measures: Odds ratio (OR), area-under-the-curve (AUC), sensitivity and specificity.

Results: A pathogenic FH-causing mutation was detected in 30% of 885 patients tested. Elevated LDL-cholesterol and personal or family history of tendon xanthomata were independent predictors of a mutation (ORs range 5.32-15.2, P<0.001). Prediction of a mutation for the DLCN and SB definite and MEDPED criteria (ORs 9.4, 11.7. 10.5, respectively) was higher than with the AHA criteria (OR 4.67). The balance of sensitivity and specificity was in decreasing order DLCN definite (Youden Index 0.487), MEDPED (0.457), SB definite (0.274) and AHA criteria (0.253), AUC being significantly higher with DLCN definite and MEDPED than other criteria (P<0.05). Pre-treatment LDL-cholesterol and tendon xanthomata had the highest AUC in predicting a mutation.

Conclusions: The DLCN, SB and MEDPED criteria are valid predictors of an FH-causing mutation in patients referred to a lipid clinic, but concordance between these phenotypic criteria is only moderate. Use of pre-treatment LDL-cholesterol and tendon xanthomata alone may be particularly useful for deciding who should be genetically tested for FH.