Monogenic Variants Common in Familial Chylomicronemia Syndrome

Monogenic variants were found to be more common than oligogenic variants in lipoprotein lipase (LPL) pathway genes for patients with suspected familial chylomicronemia syndrome, an inherited form of severe hypertriglyceridemia (sHTG). These findings were presented at the National Lipid Association (NLA) Scientific Sessions 2023, held in Atlanta, Georgia, between June 1st and June 4th, 2023.

Investigators aimed to characterize pathogenic and probable pathogenic variants, reduced penetrance risk alleles, and variants of unknown significance across 7 LPL pathway genes among patients with suspected familial chylomicronemia.

Investigators performed DNA next generation sequencing and copy number variant analysis among 127 patients residing in Canada and the United States. They analyzed deidentified genetic variant data of LPL, APOA5, APOC2, CREB3L3, LMF1, GPD1, and GPIHBP1 genes for associated FCS symptoms, zygosity, and allele frequency.

Among patients included in the analysis, the median age at onset of severe hypertriglyceridemia was 33 (range, 4-60) years, 77.9% were European, and 81.1% had at least 1 comorbid condition. Comorbidities among the patients included pancreatitis, lipemia retinalis, xanthomata, hepatosplenomegaly, and plasma lactescence. Of note, 11.8% of patients had atherosclerotic cardiovascular disease.  

Investigators found at least 1 variant in LPL, APOA5, APOC2, CREB3L3, LMF1 genes of 86 (68.7%) patients, of whom 32.3% had no genetic cause determined for the variation. Oligogenic variants in multiple genes (including 5 homozygotes) were noted among 14 (11%) patients, and 57% had monogenic variants (including 5 homozygotes).

There were 66 patients with 93 APOA5 variants identified, of whom 65 had at least 1 risk allele, 2 pathogenic variants, and 2 likely pathogentic heterozygotes. There were 29 LPL variants, 6 LMF1, 2 APOC2, and 2 CREB3L3 identified, which accounted for 22% of variants overall. In both APOC2 and LMF1 genes, there was 1 likely pathogenic variant identified. The investigators identified 16 variants of unknown significance in LPL, APOA5, APOC2, CREB3L3, and LMF1 genes overall, whereas no variants were identified in GPD1 and GPIHBP1 genes.

The investigators noted 11 patients with pathogenic LPL variants (3 homozygous for classic FCS variants). There were 9 additional patients in whom the LPL risk allele was found (triglyceride level, ≤13,000 mg/dL). They also identified 1 LPL variant that was likely pathogenic. Among all patients, 18.1% had classic familial chylomicronemia syndrome with LPL heterozygotes and 2.4% had LPL homozygotes.

Study limitations include potential ascertainment bias and a population that may not reflect all patients with severe hypertriglyceridemia. In addition, some genetic variants may not have been identified, and data were unavailable for genotype and phenotype correlations.

 According to the investigators, “Given these allele frequencies in an enriched population, genetic testing for patients suspected of FCS [familial chylomicronemia syndrome] is warranted to further characterize FCS associated variants.”

Disclosure: This research was supported by Ionis Pharmaceuticals. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.