Clinical Implications of the Molecular Basis of Familial Hypercholesterolemia and Other Inherited Dyslipidemias

Abstract

In this issue of Circulation , van der Graaf and colleagues1 studied 1430 children, aged 4 to 18 years, who were referred to an academic pediatric lipid clinic in the Netherlands because of dyslipidemia from July 1989 to January 2008. The objective was to determine what proportion of those with the phenotype of autosomal dominant hypercholesterolemia (ADH) had mutations in the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9. Article see p 1167 Inclusion criteria for ADH included a low-density lipoprotein cholesterol (LDL-C) level >95th percentile for age and sex and an autosomal dominant inheritance pattern of hypercholesterolemia, defined as at least 1 biological parent on treatment for hypercholesterolemia and a family history of hypercholesterolemia and cardiovascular disease (CVD).1 Exclusion criteria included children with secondary causes of hypercholesterolemia, a body mass index cut-off at the 75th percentile for age and sex, those referred through the national cascade screening program, and those from families with a known molecular diagnosis. Of the 269 children who remained after applying the exclusion criteria, 255 (95%) carried a functional mutation (LDLR 95%; APOB 5%). No mutations in proprotein convertase subtilisin/kexin 9 were detected. The authors concluded that in the vast majority of children with the ADH phenotype, a causative mutation can be identified, and that most of the large-effect genes underlying ADH are known. This result differed from several other reports that found widely different mutation detection rates that varied from 20% to 90%2,–,6 and were likely due to different use of inclusion and exclusion criteria and the more extensive molecular dissection employed in this study. What is the implication of the results of this study for clinicians? For pediatricians and family practitioners, it must be appreciated that the …