A Comparative Analysis of Phenotypic Predictors of Mutations in Familial Hypercholesterolemia

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

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.

An adult cohort of unrelated patients referred to a lipid clinic for genetic testing.

Odds ratio (OR), area under the curve (AUC), sensitivity, and specificity.

A pathogenic FH-causing mutation was detected in 30% of 885 patients tested. Elevated low-density lipoprotein (LDL) cholesterol and personal or family history of tendon xanthomata were independent predictors of a mutation (OR range 5.3 to 16.1, P < 0.001). Prediction of a mutation for the DLCN and SB definite and MEDPED criteria (ORs 9.4, 11.7, and 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). Pretreatment LDL cholesterol and tendon xanthomata had the highest AUC in predicting a mutation.

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 pretreatment LDL cholesterol and tendon xanthomata alone may be particularly useful for deciding who should be genetically tested for FH.