The following are key points to remember from this article about clinical genetic testing for familial hypercholesterolemia (FH):

1. FH is a relatively common genetic condition (estimated prevalence in the United States is about 1:220) that results in premature atherosclerotic cardiovascular disease (ASCVD) due to lifelong exposure to elevated low-density lipoprotein cholesterol (LDL-C). Ninety percent of the >1 million with FH in the United States are undiagnosed. This statement provides the rationale for genetic testing for FH and recommendations for its utilization in the clinical setting. It is expected that genetic testing will facilitate the diagnosis of FH, the initiation and intensity of recommended lipid-lowering therapy (LLT), and the identification of affected relatives, thus reducing the burden of CVD in families with FH.
2. Data from the CASCADE FH Registry (Cascade Screening for Awareness and Detection of FH) indicate that FH genetic testing is underutilized for patients in the United States, with genetic testing reported in 3.9% of individuals in the registry with a clinical diagnosis. In contrast, extensive or population screening has been performed in many European countries, and the United Kingdom. If not identified and appropriately treated from an early age, untreated male subjects are at a 50% risk for a fatal or nonfatal coronary event by age 50 years, and untreated female subjects are at a 30% risk by age 60 years. About 2% of early myocardial infarction cases (males ≤50 years of age, females ≤60 years of age) have a pathogenic variant in the main gene known to cause FH, the LDL receptor (LDLR). Early diagnosis and medical management beginning in childhood with statins and other LLTs have the potential to reduce the incidence of atherosclerosis in patients with FH to that of individuals without FH.
3. FH encompasses a spectrum of clinical phenotypes with a broad range of pathogenic variants. The rarest is homozygous FH (HoFH), with a frequency of about 1 in 200,000-300,000 and LDL-C range of about 350-1000 mg/dl; heterozygous FH (HeFH) with LDL-C 160-400 mg/dl; and the more common polygenic FH with LDL-C 130-190 mg/dl. The molecular etiology of HoFH includes two alleles of the same gene encoding LDLR (null or defective), or compound heterozygous, which has two different alleles each of which is associated with HeFH including LDLR null, LDLR defective, proprotein convertase subtilisin/kexin 9 (PCSK9), and apolipoprotein B (APOB). The atherogenic risk in FH is determined by additional pathogenic or protective genetic variation. Polygenic FH is assumed to have multiple LDL-C raising single-nucleotide polymorphisms. A markedly elevated Lp(a) is included in the spectrum of FH. The specific type of pathogenic variant and its severity (i.e., LDLR-defective vs. receptor-null) is associated with the degree of hypercholesterolemia and the risk for coronary artery disease (CAD) development, including premature CAD risk; LDLR null variants are the most severe and non-null LDLR variants, APOB and PCSK9 pathogenic variants, generally having a milder phenotype. Pathogenic variant type is an independent predictor of attainment of LDL-C treatment goals.
4. The clinical FH phenotype includes ranges of LDL-C levels that are very high, clinical history of premature CVD, family history of hypercholesterolemia and/or CVD, and the presence of tendon xanthomas and corneal arcus, which are incorporated in both the Dutch Lipid Clinic and Simon Broome Register group tools for identifying persons with FH. Based on more recent studies, each has a low sensitivity for detecting FH. Deoxyribonucleic acid (DNA) testing evidence of a pathogenic variant causative of FH is required for a definite diagnosis of FH. Physical examination findings and family history of premature ASCVD are present in only a minority of molecularly defined FH patients. In a Spanish registry, tendon xanthomas were present in <15% of FH, and similarly in a US study program, only 8% of affected relatives had xanthomas at the time of genetic testing. Family history of premature CVD and hypercholesterolemia as criteria for FH in adults is less reliable because of the use of statins, and potentially masks FH in children.
5. Most importantly, using high specific LDL-C cut-points for identifying FH misses a significant percentage with genetic mutations and particularly with pathogenic FH variants. In a report that included >26,000 with genetic sequencing from seven case-control studies in FH with and without CAD and five prospective cohort studies, although the average LDL-C level was 190 mg/dl in those with an FH pathogenic variant, 55% of those with a pathogenic variant had LDL-C levels <190 mg/dl and 27% had an LDL-C level <130 mg/dl. In a cohort of >50,000 individuals who underwent whole exome sequencing using the Dutch Lipid Clinic criteria, a probable or definite FH clinical diagnosis was present in just 24% of those with an FH variant, and a maximum LDL-C level ≥190 mg/dl was absent in 45% of those with an FH variant.
6. Genetic negative or genotype negative phenotype positive should be considered for other molecular etiologies including polygenic, high Lp(a), and undiscovered FH genes. Cascade testing by obtaining LDL-C levels in first-degree relatives of persons with genetic mutations is not reliable because of the overlap between LDL-C levels in those with HeFH and without, probably with the exception of children with a parent with HeFH. When the proband is a child, testing allows for reverse cascade testing, particularly necessary when neither parent appears to have an FH clinical phenotype. Genetic testing leads to a threefold increase in persons taking LLT. FH genetic testing should be accompanied by pre- and post-test genetic counseling. Family members of an FH gene+ will be relieved if they test negative. The prevalence of FH pathogenic variants in adults with LDL-C levels ≥190 mg/dl and no additional clinical or family history data is only about 2%. However, the prevalence of genetically confirmed FH in patients with acute coronary syndrome who are ≤65 years of age and with LDL-C levels ≥160 mg/dl is about 9%; the prevalence in unselected adults with level of LDL-C ≥250 mg/dl is about 13% in a US-based cohort.
7. FH genetic testing provides prognostic information and the ability to perform refined risk stratification. Compared with a reference group with LDL-C levels <130 mg/dl and no pathogenic variant, individuals with LDL-C levels ≥190 mg/dl and no FH pathogenic variant had a sixfold higher risk for CAD, whereas those with LDL-C levels ≥190 mg/dl and an FH pathogenic variant exhibited a 22-fold increased risk for CAD. The presence of an FH pathogenic variant increases CAD risk >3-fold at the same LDL-C level, presumably related to greater lifelong exposure to elevated LDL-C levels. Even for those with LDL-C <130 mg/dl, CAD risk is higher in those with an FH pathogenic variant compared with those without. Similarly, those with a family history of premature CAD and genetically confirmed FH have a higher prevalence of coronary artery calcification and abnormal stress test results.
8. Summary recommendations in proband (index case): Genetic testing for FH should be offered to individuals of any age in whom a strong clinical index of suspicion for FH exists based on examination of the patient’s clinical and/or family histories. This index of suspicion includes the following:
• Children with persistent (≥2) LDL-C levels ≥160 mg/dl or adults with persistent LDL-C levels ≥190 mg/dl without an apparent secondary cause of hypercholesterolemia and with ≥1 first-degree relative similarly affected or with premature CAD (male ≤55 years, female ≤65 years) or where family history is not available (e.g., adoption).
• Children with persistent LDL-C levels ≥190 mg/dl or adults with persistent LDL-C levels ≥250 mg/dl without an apparent secondary cause of hypercholesterolemia, even in the absence of a positive family history. (Evidence Grade: Class of Recommendation IIa, Strength of Evidence B-NR.)
9. Genetic testing for FH may be considered in the following clinical scenarios:
• Children with persistent LDL-C levels ≥160 mg/dl (without an apparent secondary cause of hypercholesterolemia) with an LDL-C level ≥190 mg/dl in ≥1 parent or a family history of hypercholesterolemia and premature CAD.
• Adults with no pretreatment LDL-C levels available, but with a personal history of premature CAD and family history of both hypercholesterolemia and premature CAD.
• Adults with persistent LDL-C levels ≥160 mg/dl (without an apparent secondary cause of hypercholesterolemia) in the setting of a family history of hypercholesterolemia and either a personal history or a family history of premature CAD. (Evidence Grade: Class of Recommendation IIb, Strength of Evidence C-EO.)
10. Summary recommendations in at-risk relatives: Cascade genetic testing for the specific variant(s) identified in the FH proband (known familial variant testing) should be offered to all first-degree relatives. If first-degree relatives are unavailable, or do not wish to undergo testing, known familial variant testing should be offered to second-degree relatives. Cascade genetic testing should commence throughout the entire extended family until all at-risk individuals have been tested and all known relatives with FH have been identified. (Evidence Grade: Class of Recommendation I, Strength of Evidence B-R.)

Keywords: Acute Coronary Syndrome, Apolipoproteins B, Atherosclerosis, Coronary Artery Disease, Cholesterol, LDL, Dyslipidemias, Exercise Test, Genetic Counseling, Genetic Testing, Genotype, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Lipoproteins, LDL, Mutation, Myocardial Infarction, Phenotype, Primary Prevention, Proprotein Convertases, Receptors, LDL, Subtilisins, Xanthomatosis

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