Phenotype in Individuals with Heterozygous Rare Variants in LIPC Encoding Hepatic Lipase

Hepatic lipase deficiency is a rare genetic condition caused by biallelic loss-of-function variants in the <i>LIPC</i> gene encoding hepatic lipase. These variants reduce or abolish the protein's lipolytic activity, resulting in elevated plasma lipids. The condition is classified as autosomal recessive, since dyslipidemia is inconsistently observed in heterozygous patients with only one <i>LIPC</i> variant. However, this has been concluded from historical studies encompassing a few families and having very small sample sizes. Here, we conduct a retrospective chart review of 46 heterozygous subjects, each harboring one rare pathogenic <i>LIPC</i> variant. We compare plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and apolipoprotein B to those of matched controls without <i>LIPC</i> variants. Variant pathogenicity is classified according to the guidelines of the American College of Medical Genetics and Genomics. We observe that levels of total cholesterol, LDL-C, and triglycerides are significantly elevated in the <i>LIPC</i> variant heterozygotes, but HDL-C and apolipoprotein B are not. When filtering solely with respect to pathogenic or likely pathogenic variants, all lipid variables emerge as significantly elevated compared to controls. Thus, hepatic lipase deficiency may not necessarily be a recessive condition, but perhaps semi-dominant since individuals with one variant are phenotypically distinct from the controls. These hypothesis-generating findings regarding <i>LIPC</i> genetic variations observed in a clinical cohort should be evaluated in larger populations and databases.