Familial Chylomicronemia Panel

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 and Hegele. 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).

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.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Causal or likely causal variants have been identified in up to 77% of patients with a clinical diagnosis of FCS in studies that included nucleotide substitution, short deletion and insertion, and CNV analysis of APOA5, APOC2, GPIHBP1, LMF1, and LPL (Hegele et al. 2018. PubMed ID: 29748148).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).