FCS is a rare, genetic form of severe hypertriglyceridemia (sHTG) and is characterized by extremely elevated triglyceride levels and corresponding build-up of large triglyceride-containing particles in the blood called chylomicrons, which can result in severe health complications. It is caused by impaired function of the enzyme lipoprotein lipase (LPL). Because of limited LPL production or function, people with FCS cannot effectively break down chylomicrons, lipoprotein particles that are 90% triglycerides. FCS is estimated to impact one to 13 people per million in the U.S. People living with FCS are at high risk of acute pancreatitis (AP) in addition to other chronic health issues such as severe, recurrent abdominal pain. People living with FCS experience debilitating psychosocial symptoms, and are sometimes unable to work, adding to the burden of disease.
This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.
What is the Program?
In partnership with Ionis Pharmaceuticals, this program provides no-cost genetic testing for familial chylomicronemia syndrome (FCS), a genetic condition which is characterized by high plasma triglyceride levels resulting from improper breakdown of chylomicron lipoproteins by the LPL enzyme. No-cost FCS testing is available for patients with a clinical diagnosis of FCS and is being offered to residents of the US and Canada who meet testing eligibility criteria. The test must be ordered by a qualified healthcare professional.
To qualify for the testing program, candidates must reside in the United States or Canada and have evidence of severe refractory hypertriglyceridemia, defined by a minimum of 2 consecutive fasting triglyceride levels ≥750 mg/dL or 8.4 mmol/L in the absence of secondary causes or medical conditions known to cause HTG.
Order the test using the test requisition form.
Collect a blood, saliva, or buccal specimen in the collection tube. For information on ordering specimen kits, see Specimen Collection and Shipping section.
Program Information
Familial chylomicronemia syndrome (FCS) is characterized by high plasma triglyceride levels resulting from improper breakdown of chylomicron lipoproteins by the LPL enzyme (Brahm and Hegele. 2015. PubMed ID: 25732519; Chait and Eckel. 2019. PubMed ID: 31035285). Triglyceride levels below 1.7 mmol/L (150 mg/dL) are considered normal, while patients with chylomicronemia typically have triglyceride levels over 10 mmol/L (Stroes et al. 2017. PubMed ID: 27998715; Rare Disease Report). The FCS phenotype includes high triglyceride levels and at least one physical manifestation of chylomicronemia. Manifestations of FCS can include hepatosplenomegaly, eruptive xanthomas, and lipemia retinalis. Severe cases of FCS can result in abdominal pain and debilitating pancreatitis. Patients may also feel numbness or tingling (Davidson et al. 2018. PubMed ID: 29784572) and can feel fatigued and display cognitive impairment. Laboratory anomalies include chylo micronemia, hyperlipoproteinemia, hypertriglyceridemia, decreased plasma apolipoprotein C-II, and cloudy or pinkish-colored blood (Burnett et al. 2017. PubMed ID: 20301485; Brahm and Hegele. 2015. PubMed ID: 25732519).
The prevalence of FCS is around 1 per million individuals worldwide (Brahm et al. 2015. PubMed ID: 25732519), but in one study of French Canadians, the prevalence was observed to be as high as 200 per million individuals (Gagne et al. 1989. PubMed ID: 2914262). Diagnosis is complicated by several factors. For example, while many patients develop symptoms in childhood, many other patients are not diagnosed until their teens or later as symptoms like recurring pancreatitis and abdominal pain begin to occur more frequently. Reduced LPL enzyme activity is a key feature of FCS, and functional assays of LPL activity are used for making a diagnosis. However, such assays are not always readily available and the output of these assays often shows considerable variability (Chait and Eckel. 2019. PubMed ID: 31035285).
Genetic testing has emerged as the preferred method of FCS diagnosis because it allows for identification of the mutated FCS gene and distinguishes FCS from other much more common causes of chylomicronemia such as multifactorial chylomicronemia syndrome (MFCS) and familial partial lipodystrophy (FPLD) (Chait and Eckel. 2019. PubMed ID: 31035285). Therapeutic approaches to lowering triglyceride levels vary depending upon the cause of chylomicronemia. Lipid lowering drugs used to treat other metabolic lipid disorders are ineffective in the treatment of FCS. The current standard of care for FCS involves a strict diet with extremely low levels of fat (<15-20 g/day), low carbohydrates, and little alcohol (Williams et al. 2018. PubMed ID: 29804909).
FCS is caused by biallelic pathogenic variants in APOC2 (Fojo et al. 1989. PubMed ID: 2592354), APOA5 (Marcais et al. 2005. PubMed ID: 16200213), GPIHBP1 (Beigneux et al. 2009. PubMed ID:19304573), LMF1 (Peterfy et al. 2007. PubMed ID: 17994020), GPD1 (Joshi et al. 2014. PubMed ID: 24549054), and LPL (Jap et al. 2003. PubMed ID: 12883259). Heterozygous carriers of pathogenic variants in APOA5, GPIHBP1, and LPL may also be at risk for elevated triglyceride levels. Heterozygous variants in the CREB3L3 gene have also been identified in patients with elevated triglycerides and have been associated primarily with a phenotypically similar disorder known as multifactorial chylomicronemia syndrome (MFCS; D’Erasmo et al. 2019. PubMed ID: 31619059, Dron et al. 2020. PubMed ID: 32580631, Lee et al. 2011. PubMed ID: 21666694, Johansen. 2014. PubMed ID: 24503134; Johansen et al. 2012. PubMed ID: 22135386).
The gene products of APOC2, APOA5, GPIHBP1, LMF1, and LPL are all involved in the breakdown of chylomicrons in plasma (Brahm and Hegele. 2015. PubMed ID: 25732519). GPD1 encodes glycerol-3-phosphate dehydrogenase-1, which catalyzes the interconversion of dihydroxyacetone phosphate and glycerol-3-phosphate (G3P); G3P is needed for synthesis of triglycerides (Basel-Vanagaite et al. 2012. PubMed ID: 22226083). CREB3L3 is a transcription factor that regulates expression of genes involved in triglyceride hydrolysis (Lee et al. 2011. PubMed ID: 21666694).
The vast majority of FCS cases are attributed to pathogenic variants in LPL (~95%), followed by APOC2 (~2%), GPIHBP1 (~2%), APOA5, GPD1, and LMF1 (<1%; Burnett et al. 2017. PubMed ID: 20301485; Brahm and Hegele. 2015. PubMed ID: 25732519; Chokshi et al. 2014. PubMed ID: 24793350; Joshi et al. 2014. PubMed ID: 24549054). Variants in CREB3L3 are found frequently in patients with non-monogenic hypertriglyceridemia (Dron et al. 2020. PubMed ID: 32580631) but have also been reported with variable penetrance in patients with autosomal dominant hypertriglyceridemia (Cefalu et al. 2015. PubMed ID: 26427795). Pathogenic loss of function variants in FCS comprise mainly missense, nonsense, and splicing variants, though copy number variants (CNVs) involving APOA5, APOC2, LDL, and GPIHBP1 have been reported in FCS patients (Hegele et al. 2018. PubMed ID: 29748148). In one study of 67 individuals with a clinical diagnosis of FCS, 52 individuals had a confirmed genetic diagnosis of FCS; 5 of the patients were either homozygous or compound heterozygous for CNVs including what may be a recurring deletion in GPIHBP1 that includes exons 3-4 (Hegele et al. 2018. PubMed ID: 29748148). De novo variants have been observed for the FCS genes, but in most cases pathogenic variants are inherited from parental carriers.
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Olezarsen, formerly known as IONIS-APOCIII-LRx and AKCEA-APOCIII-LRx, is an RNA-targeted investigational LIgand-Conjugated Antisense (LICA) medicine being evaluated for people at risk of disease due to elevated triglyceride levels, including those with familial chylomicronemia syndrome (FCS). Olezarsen is designed to inhibit the body’s production of apoC-III, a protein produced in the liver that regulates triglyceride metabolism in the blood.
