Diagnostics

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Pan Dyslipidemia Panel

The Pan Dyslipidemia Panel is a comprehensive next-generation (NGS) panel that can be used to confirm a clinical diagnosis of a hereditary dyslipidemia or identify at-risk individuals.

Inherited dyslipidemias are a clinically and genetically heterogeneous group of disorders that result in elevated or abnormal concentrations of cholesterol and other lipids in the bloodstream, which can lead to heart attacks and other cardiovascular complications at an early age. Dyslipidemia can occur in isolation are as a feature of a syndromic disorder, and lipid build up can cause problems for other organ systems in addition to cardiovascular disease. Familial hypercholesterolemia, the most common of the inherited dyslipidemias, is characterized by severely elevated levels of LDL cholesterol, which lead to plaque formations in major blood vessels starting at a young age, and contribute 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

Inherited dyslipidemias affect more than 1 in 200 individuals, with the most common disorder being familial hypercholesterolemia (Nordestgaard et al, 2013).
Included Disorders:

This panel includes genes associated with

  • Cerebrotendinous xanthomatosis
  • Familial hypercholesterolemia
  • Familial hypertriglyceridemia
  • Lipoprotein lipase deficiency
  • Sitosterolemia
  • Tangier disease
  • Wolman disease

Inheritance and Penetrance

Hereditary dyslipidemias can be inherited in an autosomal dominant and autosomal recessive fashion.

The most common inherited dyslipidemia, familial hypercholesterolemia, is typically inherited in an autosomal dominant fashion, with the exception of variants in the LDLRAP1 gene, which are inherited in an autosomal recessive manner. However, individuals with biallelic pathogenic variants in an autosomal dominant FH gene, such as LDLR and APOB, have a more severe presentation than individuals with a single variant.

Penetrance in autosomal dominant familial hypercholesterolemia is incomplete, with an estimated 73-90% of individuals with a disease-causing variant in LDLR or PCSK9 developing disease (Khera et al, 2016; Naoumova et al, 2005), with reduced penetrance has been also being reported in APOB (Fahed and Nemer, 2011). The penetrance of other autosomal recessive dyslipidemias is high, although some forms of inherited dyslipidemia may show reduced and age-related penetrance.

Clinical Sensitivity

Inherited dyslipidemias are a clinically and genetically heterogeneous group of disorders; therefore, the sensitivity of this panel is dependent on the patient’s specific phenotype. This panel is expected to have high sensitivity for the autosomal recessive disorders included in this panel that are only known to be caused by mutations in a single gene, including cerebrotendinous xanthomatosis and lipoprotein lipase deficiency (Verrips et al, 2000; Brunzell, 2011). This panel is also expected to detect >95% cases of sitosterolemia (Lu et al, 2001).

Individuals with a definite diagnosis of familial hypercholesterolemia have been identified to have a pathogenic variant 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 flanking bases, 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. To request analysis of a specific single exon copy number variant, please contact our Client Services team prior to ordering. Analytical sensitivity and specificity of the assay is >99%.

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 suggestive of an inherited dyslipidemia
  • Clinical features suggestive of an inherited dyslipidemia

Included Genes (21)

ABCA1 ANGPTL3 APOB CYP27A1 LCAT LIPA LPL
ABCG5 APOA1 APOC2 GPD1 LDLR LIPC PCSK9
ABCG8 APOA5 APOC3 GPIHBP1 LDLRAP1 LMF1 SAR1B


References

  1. Burnett JR, Hooper AJ, Hegele RA. Familial Lipoprotein Lipase Deficiency. 1999 Oct 12 [Updated 2017 Jun 22]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
  2. Fahed AC, Nemer GM. Familial hypercholesterolemia: the lipids or the genes?. Nutr Metab (Lond). 2011;8(1):23.
  3. 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.
  4. 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.
  5. Lu K, Lee MH, Hazard S, et al. Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. Am J Hum Genet. 2001;69(2):278-90.
  6. Marduel M, Carrié A, Sassolas A, et al. Molecular spectrum of autosomal dominant hypercholesterolemia in France. Hum Mutat. 2010;31(11):E1811-24.
  7. 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.
  8. 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.
  9. Verrips A, Hoefsloot LH, Steenbergen GC, et al. Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain. 2000;123 ( Pt 5):908-19.