The role of genetic testing in dyslipidaemia

Abstract

Dyslipidaemias encompass about two dozen relatively rare monogenic disorders and syndromes for which the genetic basis has largely been defined. In addition, the complex polygenic basis of disturbed lipids and lipoproteins has been characterised in many patients, and has been shown to result from accumulation of many common polymorphisms with small effects on lipids. Genetic technologies, including dedicated genotyping and sequencing methods can detect both rare and common DNA variants underlying dyslipidaemias. Some dyslipidaemias may be clinically silent for years, but early diagnosis, including genetic diagnosis, may permit early intervention to prevent or delay deleterious downstream clinical consequences, such as premature vascular disease or acute pancreatitis. The potential clinical utility of genetic testing for familial hypercholesterolaemia, familial chylomicronaemia syndrome, lysosomal acid lipase deficiency and some others will increase demand for reliable genetic diagnostic methods. We review some current technologies, such as targeted next-generation sequencing that seem to be helpful with DNA diagnosis of dyslipidaemias. We also address technical, biological and clinical limitations of genetic testing in dyslipidaemias. Finally, genetic counselling issues, the potential impact of results on patients and health care providers, current gaps and future directions will be discussed.

What Results Should Be Returned from Opportunistic Screening in Translational Research?

“…Additionally, many participants explicitly stated that they did not understand their results, suggesting again that the "helpfulness" of the results was not intrinsically connected to the reason a clinician might order a genetic test. Patients' and research participants' lack of understanding-or explicit misunderstanding-is common enough, at times raising questions about inappropriate reassurance, particularly in opportunistic screening [32]. Our participants' enthusiasm was rooted in excitement about things other than the results' clinical utility.…”

Genetic testing in dyslipidemia: A scientific statement from the National Lipid Association

“…Genetic analysis may be helpful in certain cases of severe hypertriglyceridemia, such as monogenic chylomicronemia, which is also called FCS. 22,23 Among patients with severe hypertriglyceridemia, polygenic causes are 50-to 100-fold more common than monogenic causes. 17 Other dyslipidemias include the following: 1) familial dysbetalipoproteinemia, formerly type 3 hyperlipoproteinemia, which is characterized by roughly equimolar elevations of total cholesterol and triglycerides and by tuberoeruptive and palmar xanthomas 24 ; 2) low HDL-C states, such as Tangier disease and familial lecithin cholesterol acyl transferase (LCAT) deficiency, which can present with corneal findings, neuropathy, and renal involvement 25 ; and 3) low LDL-C states, such as abetalipoproteinemia and homozygous familial hypobetalipoproteinemia, which have multisystem involvement that can be averted by early diagnosis and treatment with high dose fat soluble vitamins, particularly vitamins A and E. 26 c) If a patient has phenotypic presentation of a genetic lipid disorder, when should genetic testing be considered?…”

“…Finally, genetic results may not affect management but still have academic value, with potential to increase our understanding and also to identify possible novel therapeutic approaches. 23 II. Genetic testing a) What are the types of genetic testing now available for dyslipidemia?…”

“…Genetic testing 23 includes the following methods: 1) genotype only previously described DNA variants (eg, DNA microarrays or TaqMan genotyping) and/or 2) scan all DNA nucleotide positions within a single gene, a panel of selected genes, or exome of genome (see glossary), enabling detection of both previously known and newly discovered DNA variants (eg, Sanger or capillary electrophoresis sequencing, targeted next-generation gene sequencing panels, exome sequencing [ES], or genome sequencing [GS]). 23 Some targeted sequencing panels for dyslipidemia have been clinically validated 30,31 and are the current gold standard for diagnosis in dyslipidemias, 32 for example, targeted panels for FH genes, or ''pandyslipidemia'' panels for all monogenic dyslipidemias. 7,30 The same result from a targeted panel can be achieved by performing ES or GS analysis and then masking most results, reporting only findings from genes of interest.…”

“…53 Approximate costs per sample are $300 to 600, $800 to 1200, and $1500 to 5000 for a targeted sequencing panel, ES, and GS, respectively. 23 Insurance coverage varies widely depending on the condition and type of testing ordered. The cost billed to insurance providers can differ from the direct cost to patients; many laboratories reduce costs for out-of-pocket payments.…”