ESPE Abstracts

Background and aims: GPIHBP1 is an accessory protein of lipoprotein lipase (LPL) essential for its functioning. Mutations in the GPIHBP1 gene cause a deficit in the action of LPL, leading to severe hypertriglyceridemia and increased risk for acute pancreatitis.

Methods: We describe one patient (three years and seven months old boy) with a novel homozygous Missense mutation in GPIHBP1 gene with cDNA change c.422G>T, Amino acid change p.Trp141Leu.

Results: The patient was from the sothern region of saudia arabia and presented the same homozygous variant located in GPIHBP1(NM_178172.6):c.422G>T (p.Trp141Leu), Chr8(GRCh37):g. acceptor site of the GPIHBP1 gene. This new variant was named(NM_178172.6)T, according to HGV. To our knowledge, this variant has not been reported in the literature and is not present in general population databases (gnomAD: no frequency, dbSNP: rs1284611659). Algorithms developed to predict the effect of missense changes do not agree on the potential impact of this missense change (based on 3 pathogenic predictions from PolyPhen-2, MutationTaster, and SIFT; 9 uncertain predictions from MetaLR, MetaSVM, MetaRNN, BLOSUM, DANN, EIGEN, FATHMM, M-CAP, and MVP; 4 benign predictions from BayesDel, LRT, MutPred, and PrimateAI). However, this information is not predictive enough to determine or rule out pathogenicity, and direct evidence, such as in-vitro or in-vivo functional characterization study, is unavailable. Interestingly, missense variants affecting the neighboring amino acids have been linked to hypertriglyceridemia [p.Pro140Ala (PMID: 36325899); p.Gln142Glu (PMID:30037590)]. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. but Considering the homozygous variant in GPIHBP1 and the supportive phenotype of the patient, a genetic diagnosis of hyperlipoproteinemia type ID was made. recommendations. We verified this new GPIHBP1 variant's effect by using the Human Splicing Finder (HSF) tool. This mutation changes the GPIHBP1 pre-mRNA processing and possibly causes the skipping of the exon 3 of the GPIHBP1 gene, affecting almost 50% of the cysteine-rich Lys6 GPIHBP1 domain. Patient presented with severe hypertriglyceridemia (1176 mg/dl and low HDL (12 mg/dl [5-41). patient yet has no previous history of acute pancreatitis but significant Tendon xanthomas.

Conclusion: We describe a novel GPIHBP1 pathogenic intronic mutation of patient from the southern region of Saudia arabia, suggesting the occurrence of a founder effect.