Genetic Testing in Dyslipidemia

Brown EE, Sturm AC, Cuchel M, et al.
Genetic testing in dyslipidemia: A scientific statement from the National Lipid Association. J Clin Lipidol 2020;May 7:[Epub ahead of print].

The following are key points to remember about this scientific statement from the National Lipid Association on genetic testing in dyslipidemia:

  1. Genetic causes of dyslipidemia can be monogenic or polygenic. Monogenic dyslipidemias are caused by rare DNA variants and have a strong impact on phenotype. Genetic testing for monogenic dyslipidemias may be clinically useful. Polygenic dyslipidemias are due to multiple common genetic variants. Clinical usefulness of polygenic scoring is unclear at this time.
  2. Currently, 25 monogenic dyslipidemias have a well-established molecular genetic basis. These tend to be characterized by extreme levels of low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol, and/or other lipids.
  3. Monogenic dyslipidemias may be associated with clinical manifestations such as failure to thrive, accelerated atherosclerosis, corneal opacities, xanthomas, pancreatitis, or neuropathy.
  4. Familial hypercholesterolemia, the best-known monogenic dyslipidemia, is associated with accelerated atherosclerosis. The heterozygous form occurs in about 1 of 250 persons.
  5. Severe hypertriglyceridemia is 50-100 times more likely to have a polygenic than monogenic origin, yet genetic testing may be useful in certain forms such as familial chylomicronemia.
  6. Genetic testing can be beneficial in several clinical scenarios, particularly if results might alter treatment, including the following:
  7. Monogenic DyslipidemiaTreatment
    abetalipoproteinemiadietary fat reduction, high-dose fat soluble vitamins
    cerebrotendinous xanthomatosischenodeoxycholic acid
    cholesteryl ester storage diseasesebelipase
    familial hypercholesterolemiainsurance eligibility for PCSK9 or lomitapide
    sitosterolemiareduced dietary sterol intake, ezetimibe

  8. Genetic testing may be performed via targeted screening for known DNA variants or screening of all DNA nucleotide positions of ≥1 gene or the exome.
  9. Authors recommend using a Clinical Laboratory Improvement Amendments certified laboratory that offers the appropriate gene panel for the probable diagnosis. Some of these are listed in the supplement and on the National Institutes of Health website.
  10. Risks of genetic testing include expense, identification of nonpaternity, and genetic discrimination by life insurance or long-term disability insurance companies.
  11. Cost is typically $300-$600 for targeted genetic testing, $800-$1,200 for exome sequencing, and $1,500-$5,000 for genome sequencing. Insurance coverage varies widely.
  12. Incidental findings may be discovered by genetic testing. The American College of Medical Genetics recommends disclosing incidental findings from about 60 genes, listed on the National Center for Biotechnology Information website.
  13. Family members of patients with monogenic dyslipidemia should undergo biochemical (lipid) testing and/or DNA testing. Cascade testing involves screening of family members in a progressive fashion, starting with first-degree relatives.
  14. Genetic counseling by a skilled clinician or certified genetic counselor is recommended before and after genetic testing. A starting point for locating a genetic counselor is available on the National Society of Genetic Counselors website.

Keywords: Hyperlipoproteinemia Type I, Hyperlipoproteinemia Type II, Cholesterol, LDL, Cholesterol, HDL, Genetic Testing, Genetic Counseling, PCSK9 protein, human, Proprotein Convertase 9, Exome, Abetalipoproteinemia

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