Lipids in Health and Disease · 11 authors, 5 centres
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This study identified two novel LPL frameshift variants in patients with hypertriglyceridemia-related acute pancreatitis and analyzed 53 previously reported variants. The analysis revealed that 6–7% residual LPL function can significantly delay familial chylomicronemia syndrome onset and reduce associated syndromes. Some frameshift variants may act as in-frame variants, retaining partial function, which has implications for genotype–phenotype correlations in LPL deficiency.
**Background:** Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Biallelic LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), while monoallelic variants are associated with hypertriglyceridemia (HTG) and related disorders. Frameshift coding sequence variants typically cause complete loss of function, providing a model to study the impact of different LPL activity levels.
**Methods:** All exons and flanking intronic regions of LPL were Sanger sequenced in patients with HTG-related acute pancreatitis (HTG-AP) or HTG-AP in pregnancy. Previously reported LPL frameshift coding sequence variants were collated from the Human Gene Mutation Database and PubMed. Original reports were evaluated for zygosity, plasma LPL activity, disease, age at analysis, and disease history. SpliceAI was used to predict splicing impact.
**Key Results:** Two novel rare variants were identified: c.32dup (p.(Ala12Glyfs*29)) in two unrelated pregnant women with HTG-AP, and c.77_88+1del (p.(Ala26Lysfs*13)) in a 43-year-old woman with HTG-AP. Additionally, 53 previously reported LPL frameshift variants were collated. Of 51 variants with known zygosity, 30 were simple heterozygotes, 12 homozygotes, and 9 compound heterozygotes. Analysis showed that 6–7% residual LPL function could significantly delay FCS onset and reduce syndrome prevalence. One homozygous variant (c.767_768insTAAATATT) was experimentally shown to generate an in-frame transcript with residual function. SpliceAI predicted that c.94_98del may also generate in-frame transcripts, while c.953del (associated with mild phenotype) was not predicted to affect splicing.
**Clinical Implications:** The findings highlight the importance of residual LPL function in modifying FCS severity and age of onset. Identifying variants that retain partial function may inform prognosis and genetic counseling. The study also demonstrates that some frameshift variants can act as in-frame variants, which has broader implications for genotype–phenotype correlations in other disease genes.