Available online 22 November 2022
Author links open overlay panelHighlights•Heterozygotes for pathogenic LPL variants have highly variable TG levels
•Heterozygous LPL deficiency and familial hypercholesterolemia are not analogous
•There is little to no evidence for autosomal dominant hypertriglyceridemia
•Hypertriglyceridemia is genetically complex and almost never mendelian
AbstractBackgroundBiallelic pathogenic variants in lipoprotein lipase (LPL) cause familial chylomicronemia syndrome with severe hypertriglyceridemia (HTG), defined as plasma triglycerides (TG) > 10 mmol/L (> 875 mg/dL). TG levels in individuals with one copy of a pathogenic LPL gene variant is less familiar; some assume that the phenotype is intermediate between homozygotes and controls.
ObjectiveWe undertook an evaluation of the longitudinal TG phenotype of individuals heterozygous for pathogenic LPL variants.
MethodsMedically stable outpatients were evaluated based on having: 1) a single copy of a rare pathogenic LPL variant; and 2) serial fasting TG measurements obtained over > 1.5 years of follow-up.
ResultsFifteen patients with a single pathogenic LPL variant were followed for a mean of 10.3 years (range 1.5 to 30.3 years). TG levels varied widely both within and between patients. One patient had normal TG levels < 2.0 mmol/L (< 175 mg/dL) continuously, while four patients had at least one normal TG level. Most patients fluctuated between mild-to-moderate and severe HTG: five patients had only mild-to-moderate HTG, with TG levels ranging from 2.0 to 9.9 mmol/L (175 to 875 mg/dL), while 6 patients had at least one instance of severe HTG. Of the 203 total TG measurements from these patients, 14.8%, 67.0% and 18.2% were in the normal, mild-to-moderate and severe HTG ranges, respectively.
ConclusionThe heterozygous LPL deficient phenotype is highly variable both within and between patients. Heterozygosity confers susceptibility to a wide range of TG phenotypes, with severity likely depending on secondary factors.
Keywordscomplex trait
familial chylomicronemia syndrome
hyperlipoproteinemia type 1
hyperlipoproteinemia type 5
multifactorial chylomicronemia syndrome
hypertriglyceridemia
lipoprotein lipase deficiency
next-generation DNA sequencing
pathogenic variant
© 2022 Published by Elsevier Inc. on behalf of National Lipid Association.
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