Diagnostics

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Familial Hypercholesterolemia Panel

The Familial Hypercholesterolemia (FH) Panel is a comprehensive NGS panel that can be used to confirm a clinical diagnosis of FH or identify or at-risk individuals. Familial hypercholesterolemia is characterized by severely elevated levels of LDL cholesterol, which lead to plaque formations in major blood vessels starting at a young age, contributing to an increased risk for early cardiovascular disease. Patients experience coronary artery disease and increased risk for severe cardiovascular events, like heart attacks. Some patients may also experience the formation of xanthomas (fatty deposits) around their eyelids and the tendons of the extremities.

Prevalence

Familial hypercholesterolemia affects approximately 1 in 200 individuals (Nordestgaard et al, 2013).

Included Disorders

This panel includes genes associated with familial hypercholesterolemia.

Inheritance and Penetrance

The majority of familial hypercholesterolemia (FH) is inherited in an autosomal dominant fashion, with the exception of mutations in the LDLRAP1 gene, which are inherited in an autosomal recessive manner. However, individuals with multiple mutations in an autosomal dominant FH gene, such as LDLR and APOB have a more severe presentation than individuals with a single mutation.
Penetrance in autosomal dominant familial hypercholesterolemia is incomplete, with an estimated 73-90% of individuals with a mutation in LDLR or PCSK9 developing disease (Khera et al, 2016; Naoumova et al, 2005), with reduced penetrance also being reported in APOB (Fahed and Nemer, 2011).

Clinical Sensitivity

Individuals with a definite diagnosis of familial hypercholesterolemia will be identified to have a mutation in one of the genes on this panel in 60-80% of cases (Marduel et al, 2010). The yield of genetic testing in patients with a “possible” diagnosis of familial hypercholesterolemia is reduced (Graham et al, 2005).

Methodology and Analytical Sensitivity

Next-generation sequencing technology is used to test clinically relevant portions of each gene, including coding exons, adjacent intron/exon boundaries, and selected introns/noncoding variants. Pathogenic and likely pathogenic variants are confirmed by orthogonal methods. Copy number variants, including intragenic deletions and duplications are detected to a resolution of a single exon. Analytical sensitivity of the assay is 99.5%.

Indications for Testing

  • Personal or family history of elevated LDL cholesterol; >190 mg/dL in individuals older than 20 years and >160 mg/dL in individuals younger than 20 years
  • Physical findings of familial hypercholesterolemia including xanthomas and corneal arci
  • Family history of familial hypercholesterolemia

Included Genes (4)

APOB LDLR LDLRAP1 PCSK9

References

  1. Fahed AC, Nemer GM. Familial hypercholesterolemia: the lipids or the genes?. Nutr Metab (Lond). 2011;8(1):23.
  2. Graham CA, Mcilhatton BP, Kirk CW, et al. Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate. Atherosclerosis. 2005;182(2):331-40.
  3. Khera AV, Won HH, Peloso GM, et al. Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. J Am Coll Cardiol. 2016;67(22):2578-89.
  4. Marduel M, Carrié A, Sassolas A, et al. Molecular spectrum of autosomal dominant hypercholesterolemia in France. Hum Mutat. 2010;31(11):E1811-24.
  5. Naoumova RP, Tosi I, Patel D, et al. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol. 2005;25(12):2654-60.
  6. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478-90a.