Genetic Testing in Dyslipidaemia: An Approach Based on Clinical Experience

Elsevier

Available online 15 November 2022, 101720

Best Practice & Research Clinical Endocrinology & MetabolismSummary

We have used DNA sequencing in our lipid clinic for > 20 years. Dyslipidaemia is typically ascertained biochemically. For moderate deviations in the lipid profile, the etiology is often a combination of a polygenic susceptibility component plus secondary non-genetic factors. For severe dyslipidaemia, a monogenic etiology is more likely, although a discrete single-gene cause is frequently not found. A severe phenotype can also result from strong polygenic predisposition that is aggravated by secondary factors. A young age of onset plus a family history of dyslipidaemia or atherosclerotic cardiovascular disease can suggest a monogenic etiology. With severe dyslipidaemia, clinical examination focuses on detecting manifestations of monogenic syndromic conditions. For all patients with dyslipidaemia, secondary causes must be ruled out. Here we describe an experience-based practical approach to genetic testing of patients with severe deviations of low-density lipoprotein, triglycerides, high-density lipoprotein and also combined hyperlipidaemia and dysbetalipoproteinemia.

Introduction

Dyslipidaemia often results from a combination of genetic and non-genetic factors (1). In patients with dyslipidaemia, differentiating between contributions of primary genetic and secondary non-genetic factors can guide clinical care (1). Identifying potentially modifiable secondary factors is essential. Furthermore, identifying a rare genetic disorder has implications for prognosis, treatment and family counselling. Thus, when a patient is referred with dyslipidaemia, genetic causes must be considered and secondary causes must be ruled out (1). As availability and accessibility to genetic testing becomes more routine, a strategy is needed to effectively deploy this powerful methodology within the context of clinical care (2), 3), 4∗)). Here, based on our experience over > 20 years with DNA testing in the lipid clinic, we consider how it might help certain patients with dyslipidaemia and sketch out a practical approach for clinicians (5), 6), 7), 8)). The main dyslipidaemia types to be discussed here are: 1) severe deviations of low-density lipoprotein (LDL) cholesterol; 2) severely elevated levels of triglyceride; and 3) severe deviations of high-density lipoprotein (HDL) cholesterol; and 4) combined hyperlipidaemia and dysbetalipoproteinemia. In an accompanying manuscript, we discuss in greater depth the potential benefits and drawbacks of genetic testing in dyslipidaemia (9).

Section snippetsGenetic and secondary causes of dyslipidaemia: general considerations

Dyslipidaemia is usually first ascertained and defined by the main biochemical disturbance (1). For mild-to-moderate deviations from the normal range, the etiology can be a combination of a polygenic susceptibility component aggravated by secondary factors (10), 11), 12)). For severe deviations, the likelihood of a monogenic etiology is increased (13). If a monogenic dyslipidaemia is suspected, presence of characteristic clinical features should be assessed (1,13). However, in severe

Types of genetic testing for dyslipidaemia

Genetic testing refers to methods that: 1) focus only on known DNA variants (e.g. microarrays or TaqMan genotyping); 2) survey all DNA bases within coding regions of a single gene or several selected genes, comprising a targeted gene panel; 3) survey all DNA bases within coding regions of all human genes (exome sequencing); or 4) survey every DNA base of the genome (genome sequencing) (2). Today, targeted sequencing panels, exome and genome sequencing all fall under the general heading of “next

Rare monogenic dyslipidaemias

There are 25 syndromic lipid disorders that result from rare pathogenic large-effect DNA variants or “mutations” in single genes (13). These disorders are characterized by extreme deviations of plasma lipid values (13). Monogenic disorders show classical Mendelian segregation patterns in families, either autosomal dominant (monoallelic) or autosomal recessive (biallelic). The molecular basis of most of these disorders has been solved. Patients can display characteristic pathognomonic symptoms

The genetic basis of dyslipidaemia is often polygenic in nature

Many adults with dyslipidaemia have polygenic susceptibility, even when an obvious secondary factor is present. Our research and clinical experience indicate that susceptibility to dyslipidaemia starts with an inherited accumulation of many common lipid-altering genetic variants, usually single nucleotide polymorphisms or SNPs (6), 7), 8)). An individual SNP allele has a very small effect on plasma levels, but cumulatively these effects can add up and force the expression of clinical

Role of genetic testing in clinical evaluation of dyslipidaemia

In patients with mild-to-moderate "garden variety" dyslipidaemia, genetic testing for either monogenic rare or common polygenic dyslipidaemia is not presently indicated, since no evidence exists that such information affects diagnosis, prognosis or treatment. However, once a patient is identified with dyslipidaemia, biochemical screening of other family members is still valuable. This is because small-effect polygenic SNPs tend to cluster within families, although as mentioned not adhering to a

When should genetic testing be considered in patients with dyslipidaemia?

The goal of genetic testing is to provide personalized advice that helps the patient and provider make appropriate decisions for their healthcare. There are currently no recommendations for genetic testing in dyslipidaemia based on the highest grade of clinical evidence, i.e. no randomized clinical trials yielding specific indications with definitive beneficial outcomes. Lower grade evidence based on expert opinion suggests that specific accredited, validated genetic tests can be useful in

General algorithm incorporating genetic testing into lipid management

Figure 1 shows how genetic analysis can be integrated into clinical care of patients referred with dyslipidaemia. Today, the most common instigating factor is a suggestive or informative lipid profile, with an analyte (or combination) deviating from a cut point suggesting a genetic component (Figure 2). Clinical assessment can identify characteristic features that suggest a monogenic lipid disorder, thus increasing the potential positive yield from genetic testing (Figure 3). Clinical features

Genetic testing in states of severely elevated LDL cholesterol: familial hypercholesterolaemia

Genetic testing is most commonly ordered for FH, an autosomal semi-dominant disorder, which means that heterozygotes with one copy of a pathogenic variant express a phenotype that is intermediate in severity between normal individuals and homozygotes for biallelic pathogenic variants (22,23). The heterozygous form of FH has a population prevalence of ∼ 1 in 300 (22). Most cases of FH are caused by one of >3000 reported pathogenic variants in the LDLR gene encoding the LDL receptor (22). Other

Genetic testing when LDL cholesterol is severely depressed: hypobetalipoproteinemia

Primary hypobetalipoproteinemia refers to a group of extremely rare inherited dyslipidaemias that are characterized by very low or absent plasma LDL cholesterol (<0.5 mmol of < 19 mg/dL) (24). During the work-up of patients with hypobetalipoproteinaemia, secondary causes such as chronic liver disease, chronic pancreatitis, cystic fibrosis, end-stage renal disease, hyperthyroidism, cachexia and malabsorption, should be excluded.

Hypobetalipoproteinaemia can result from decreased production or

Genetic testing in patients with hypertriglyceridaemia

Unlike HeFH, hypertriglyceridaemia is predominantly polygenic in origin (14,15,31). Only a tiny minority of cases of severe hypertriglyceridaemia defined as triglyceride > 10 mmol/L or > 885 mg/dL have an underlying monogenic cause (32). The monogenic form of severe hypertriglyceridaemia is known as familial chylomicronaemia syndrome (FCS) and has a prevalence of ∼1 in 300,000, while multifactorial chylomicronaemia syndrome (MCS) is a polygenic condition with a prevalence of ∼1 in 400 (32).

Genetic testing when HDL cholesterol is markedly elevated: hyperalphalipoproteinemia

Hyperalphalipoproteinemia - here defined as HDL cholesterol > 2 mmol/L (>78 mg/dL) – is essentially a biochemical finding seen in 1 in 40 to 80 adults with no consistent clinical or syndromic features (13). Some patients with markedly elevated HDL cholesterol have corneal arcus. Rare monogenic conditions associated with extreme elevations of HDL cholesterol > 2.6 mmol/L (>100 mg/dL) include biallelic LOF mutations in: 1) CETP, encoding cholesteryl ester transfer protein, which mediates the

Genetic testing when HDL cholesterol is markedly depressed: hypoalphalipoproteinemia

Isolated hypoalphalipoproteinemia - here defined as HDL cholesterol as < 0.5 mmol/L (<19 mg/dL) with no other lipid disturbance - is seen in ∼ 1 in 30 to 80 adults. Most often low HDL cholesterol presents together with hypertriglyceridaemia and in this context would have similar underlying secondary and genetic contributors as MCS, as discussed above (4). But for isolated low HDL cholesterol, secondary factors include obesity, inactivity, a high fat or high glycemic index diet, metabolic

Genetic testing in patients with combined hyperlipidaemia

Combined hyperlipidaemia – defined here as total cholesterol > 6 mmol/L (>232 mg/dL) and triglyceride > 3 mmol/L (>265 mg/dL) often with other lipid abnormalities, is a common clinical phenotype that is seen in ∼ 1 in 30 to 60 adults. Next generation sequencing now shows that combined hyperlipidaemia is not a monogenic condition but instead it is polygenic in most cases, with no increase in pathogenic variants in such canonical genes as LDLR or LPL (44), 45), 46)). The polygenic profile in

Genetic testing in patients with dysbetalipoproteinemia

Dysbetalipoproteinemia is clinically ascertained as a subset of patients with combined hyperlipidaemia, since the abnormally accumulated intermediate density lipoprotein (IDL), remnants or beta-migrating VLDL particles contain equimolar concentrations of cholesterol and triglyceride. Prevalence estimates range from ∼1 in 10,000 to 20,000 people (1). The condition generally presents in adulthood (1), and in women becoming severe post-menopausally. While the biochemical definition can overlap

Conclusion

Cost and accessibility of DNA sequencing are becoming less of an obstacle to implementation of this technology routinely in the clinic. For patients with rare, monogenic dyslipidaemias, of which FH and FCS are the most prominent examples, a positive genetic diagnosis can have repercussions with respect to management and access to treatments, as well as implications for the family. Table 2 provides some guidance for genetic testing for monogenic lipid disorders. However, for most individuals

Practice points•

Dyslipidaemia is usually ascertained biochemically based on deviation from the normal range

Rare monogenic lipid disorders are only a tiny subset of patients with deviations in the lipid profile

The presence of syndromic features plus absence of secondary factors with early and severe clinical expression are all clues that a monogenic dyslipidaemia may be present

Heterozygous familial hypercholesterolemia is more common than all other monogenic dyslipidaemias put together

Clinical algorithms that

Research agenda•

To develop evidence based clinical algorithms that incorporate screening for rare lipid disorders

To precisely quantify at the population level the relative contributions of monogenic versus polygenic factors in patients with extreme deviations of the lipid profile

To determine the value of a positive genetic test result for a monogenic dyslipidaemia in guiding specific therapies including biological treatments, gene therapy and gene editing

Funding

R.A.H. is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair, and the Martha G. Blackburn Chair in Cardiovascular Research. R.A.H. holds operating grants from the Canadian Institutes of Health Research (Foundation award), the Heart and Stroke Foundation of Ontario (G-21-0031455) and the Academic Medical Association of Southwestern Ontario (INN21-011).

Disclosure of competing interest

R.A.H. reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, HLS Therapeutics, Novartis, Pfizer, Regeneron and Sanofi.

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