Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.

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The 10-kb deletion ("French Canadian mutation") of the low-density lipoprotein (LDL) receptor gene is the most common mutation causing familial hypercholesterolemia among subjects of French Canadian descent. In affected subjects, it results in a null allele of the LDL receptor gene and provides a unique opportunity to examine single-allele regulation of this gene in humans. We sought to ascertain the response of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in subjects with the French Canadian mutation of the LDL receptor gene and to correlate this response with biochemical variables and the haplotype of the nondeletion LDL receptor allele. The prevalence of nonresponders to high doses of HMG CoA reductase inhibitors (denned as <15% decrease in LDL cholesterol [LDL-C] from baseline values after dietary intervention) was ascertained in 105 patients heterozygous for the 10-kb deletion after excluding first-degree relatives and those on combined lipid-lowering therapy or other lipid-lowering agents. Lipoprotein cholesterol levels were examined after a diet period (30% calories as fat) and after receiving HMG CoA reductase inhibitors as monotherapy for a minimum of 3 months. The mean reduction in total cholesterol was 45±23%, in LDL-C 33±15%, and in F amilial hypercholesterolemia (FH) is a genetic disorder characterized by elevated plasma levels of total cholesterol due to elevated low-density lipoprotein (LDL) cholesterol (LDL-C) and cutaneous lipid deposits (xanthelasmas, xanthomas, and corneal arcus) as well as the presence of premature coronary artery disease in probands and family members.1 ' 2 Mutations within the gene coding for the LDL receptor have been identified as the cause of FH.3 Multiple mutations have been described, 4 and five classes of phenotypes at the cellular level have been established. Class 1 defects do not produce LDL receptor protein (null allele); class 2 defects encode proteins that are blocked between the endoplasmic reticulum and the Golgi complex; class 3 defects encode proteins that do triglycerides 32±49% (all P<.005). There was a slight increase in high-density lipoprotein cholesterol of 8.5±18% (P>.05). Overall, 68.4% of patients had more than a 30% decrease in LDL-C levels and 23% had a decrease ranging from 15% to 30%; 8.6% of patients failed to respond, and some even showed an increase in their LDL-C levels (mean change, 1.2±11.9%). This response was independent of age, gender, triglycerides, or high-density lipoprotein cholesterol levels. There was no significant overall effect of the apolipoprotein E phenotype in predicting the degree of total cholesterol or LDL-C reduction. Haplotypes of the LDL receptor gene were determined with the use of five polymorphic markers. The 10-kb deletion is known to be present on a single haplotype, thus allowing the haplotype determination of the nondeletion allele. Analysis of the nondeletion allele of the LDL receptor did not reveal a difference between responders and nonresponders, suggesting that a defec...