Genetic testing may have an important role in select patients with dyslipidemia, as it can assist in clinical diagnosis, guide optimal management and prevention strategies, and identify affected family members. A scientific statement from the National Lipid Association published in the Journal of Clinical Lipidology outlined the implications of genetic testing in dyslipidemia.
Several factors have contributed to the increased use of genetic testing in dyslipidemia, including better understanding of the genetic basis of many monogenic dyslipidemias, increased availability of advanced genetic technologies, and potential benefits of diagnosing a genetic cause of dyslipidemia. The results of a genetic test may have a significant effect on the compliance and motivation of patients and can help to facilitate targeted treatment for specific disorders.
As there are no clear indications for genetic testing for most dyslipidemias, experts representing the National Lipid Association reviewed the technical, biological, clinical, and ethical implications for genetic tests in dyslipidemia.
Monogenic dyslipidemias are caused by rare large-effect mutations, and of 25 monogenic dyslipidemias, familial hypercholesterolemia (FH) is the most common. Although genetic testing for mutations that cause monogenic or Mendelian dyslipidemia may have clinical utility, the importance of testing for common small-effect DNA variants to assess for susceptibility to dyslipidemia is not clear.
For patients with a phenotypic presentation of a genetic lipid disorder, molecular diagnosis can affect clinical decision making and patient care, as well as direct screening of family members. Clinicians should recommend to their patients that they communicate their diagnosis, including genetic testing results, to at-risk relatives and provide these patients with available communication assistance tools.
There are several methods for genetic testing, including the genotyping of only previously described DNA variants and/or a scan of all DNA nucleotide positions within a single gene, a panel of selected genes, or the complete exome or genome. Sequencing panels targeted to known dyslipidemia genes are more commonly used than exome or genome sequencing. Although there are no universal standards, the results of a genetic test generally include several required elements.
Before completing genetic testing, the clinician should thoroughly explain the potential implications to the patient and obtain informed consent. It is important to understand the limitations of genetic testing, including cost issues; the potential for different results from different laboratories, including false positive and false negative results; and the possibility of detecting incidental findings or variants of unknown significance.
There are many different polygenic scores for low-density lipoprotein (LDL) cholesterol, but none is the accepted gold standard for clinical use and the clinical utility of these scores is not clear.
For patients with FH, genetic testing may predict clinical outcomes. However, patients with elevated LDL cholesterol or clinically suspected FH are all at very high risk for cardiovascular disease, irrespective of the precise genetic etiology, and management should be based on elevated LDL cholesterol levels and not genotype.
For patients with severe hypertriglyceridemia, the cause is usually multifactorial or polygenic. Irrespective of the etiology, treatment includes dietary changes and medications such as fibrates, niacin, or high doses of omega-3 fatty acids.
There is no evidence that genetic testing in cases of low high-density lipoprotein cholesterol syndromes will guide interventions that improve cardiovascular outcomes.
Genetic counseling, including risk assessment, anticipatory guidance, family-based care, and psychological assessment, should be provided to all patients with heritable lipid disorders prior to genetic testing.
Taken together, the expert panel suggested that genetic testing may provide important information in select patients, but it is also vital to understand the limitations of genetic testing.
Brown EE, Sturm AC, Cuchel M, et al. Genetic testing in dyslipidemia: a scientific statement from the National Lipid Association [published online May 7, 2020]. J Clin Lipidol. doi:10.1016/j.jacl.2020.04.011