Familial Chylomicronemia Syndrome (FCS) Testing Program

Program Overview

In partnership with Akcea Therapeutics, 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 provider

Clinical Features

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 be severe and life threatening and include primarily debilitating pancreatitis and abdominal pain, hepatosplenomegaly, eruptive xanthomas, and lipemia retinalis. Patients may also feel numbness or tingling and feel fatigued and display cognitive impairment. Laboratory anomalies include chylomicronemia, 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. In addition, secondary causes of hypertriglyceridemia such as pregnancy, diabetes, alcohol use, lymphoproliferative disorders, estrogen therapy, and use of certain medications including specific serotonin uptake inhibitors, and antihypertensive agents, may lead to misdiagnosis of FCS (Burnett et al. 2017. PubMed ID: 20301485; Stroes et al. 2017. PubMed ID: 27998715). 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 (<10-15 g/day), low carbohydrates, and little alcohol (Kawashiri et al. 2005. PubMed ID: 16174715).

Genetics

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. 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). 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). Pathogenic loss of function variants in FCS comprise mainly missense, nonsense, and splicing variants, though copy number variants involving APOA5, APOC2, LPL, 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 copy number variants 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.

Testing Strategy

This test is performed via Sequencing and CNV Detection via NextGen Sequencing using exome sequencing.

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.

Criteria For Test

Candidates for this test are patients in the US with severe refractory hypertriglyceridemia - patient must have 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.

Ordering

  1. Determine if the individual meets eligibility criteria and discuss the test.
  2. Order the test using the test requisition form or fill out an online order via the sponsored testing order site.
  3. Collect a blood, saliva, or buccal specimen in the collection tube. For information on ordering specimen kits, see Specimen Collection and Shipping section.
  4. The genetic test will be processed at PreventionGenetics and the results will be sent to the ordering healthcare provider about 18 days after the lab receives the specimens and all appropriately completed paperwork. The ordering healthcare provider will discuss the results with the patient and/or caregiver.

Specimen Collection and Shipping

Specimen Collection

WHOLE BLOOD

Collect 3 ml - 5 ml of whole blood in EDTA (purple top tube) or ACD (yellow top tube).

SALIVA

OrageneTM or GeneFiXTM Saliva Collection kit used according to manufacturer instructions.

OCD-100 BUCCAL SWAB

OCD-100 Buccal Swab used according to manufacturer instructions.

Shipping and Handling Instructions

Label all specimen containers with the patient’s name, date of birth, and/or ID number. At least two identifiers should be listed on specimen containers. Specimen deliveries are accepted Monday-Saturday for all specimen types. Holiday schedules will be posted on our website at least one week prior to major holidays.

WHOLE BLOOD

DO NOT FREEZE. During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube. In cold weather include an unfrozen ice pack in the shipping container as insulation. At room temperature, blood specimens are stable for up to 48 hours. If refrigerated, blood specimens are stable for up to one week.

SALIVA AND BUCCAL

Specimens may be shipped at room temperature.

Specimen collection kits: Blood, saliva, or buccal specimen collection kits, which contain the TRF and the shipping label, may be requested through the kit order form or via the online order form.