Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype–phenotype relationship for variants reported to date

Lipids in Health and Disease · 11 authors, 5 centres

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TL;DR

This study identified two novel LPL gene variants in patients with hypertriglyceridemia-related acute pancreatitis and performed a comprehensive analysis of 55 known LPL frameshift variants.

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The study employed Sanger sequencing of the LPL gene in patients with hypertriglyceridemia-related acute pancreatitis and systematically reviewed 53 previously reported LPL frameshift variants. Central results indicate that 6–7% residual LPL function correlates with delayed onset and milder expression of familial chylomicronemia syndrome. Furthermore, some frameshift variants may generate protein products with residual function, either by acting as in-frame variants or by affecting splicing, as predicted by SpliceAI for two candidate variants. The study's strengths include reporting novel variants and conducting the first comprehensive analysis of this variant type. The implications are that not all frameshift variants result in complete loss-of-function, which has broader relevance for interpreting such variants in other disease genes.

STUDY TYPE

other

SPECIALTY

endocrinology

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AI pipeline

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ORIGINAL PAPER

PMC10422730

Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype–phenotype relationship for variants reported to date

Lipids in Health and Disease

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ABSTRACT

Abstract Background Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Homozygous or compound heterozygous LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), whereas simple heterozygous LPL variants are associated with hypertriglyceridemia (HTG) and HTG-related disorders. LPL frameshift coding sequence variants usually cause complete functional loss of the affected allele, thereby allowing exploration of the impact of different levels of LPL function in human disease. 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 through PubMed keyword searching. Original reports were manually evaluated for the following information: zygosity status of the variant, plasma LPL activity of the variant carrier, disease referred for genetic analysis, patient’s age at genetic analysis, and patient’s disease history. SpliceAI was employed to predict the potential impact of collated variants on splicing. Results Two novel rare variants were identified, and 53 known LPL frameshift coding sequence variants were collated. Of the 51 variants informative for zygosity, 30 were simple heterozygotes, 12 were homozygotes, and 9 were compound heterozygotes. Careful evaluation of the 55 variants with respect to their clinical and genetic data generated several interesting findings. First, we conclude that 6–7% residual LPL function could significantly delay the age of onset of FCS and reduce the prevalence of FCS-associated syndromes. Second, whereas a large majority of LPL frameshift coding sequence variants completely disrupt gene function through their "frameshift" nature, a small fraction of these variants may act wholly or partly as "in-frame" variants, leading to the generation of protein products with some residual LPL function. Third, we identified two candidate LPL frameshift coding sequence variants that may retain residual function based on genotype–phenotype correlation or SpliceAI-predicted data. Conclusions This study reported two novel LPL variants and yielded new insights into the genotype–phenotype relationship as it pertains to LPL frameshift coding sequence variants. Supplementary Information The online version contains supplementary material available at 10.1186/s12944-023-01898-w. Keywords: Aberrant splicing, Cryptic splice site, Familial chylomicronemia syndrome, Genotype–phenotype relationship, Hypertriglyceridemia-related acute pancreatitis, In-frame variant, Lipoprotein lipase, LPL frameshift variant, Triglyceride, Zygosity

CITATION EXPORT

Guofu Zhang, Yuepeng Hu, Qi Yang et al.. Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype–phenotype relationship for variants reported to date. Lipids in Health and Disease. (2023). https://doi.org/10.1186/s12944-023-01898-w

AUTHORS

11 · 5 CENTRES

Guofu Zhang, Yuepeng Hu, Qi Yang, Na Pu, Gang Li, Jingzhu Zhang, Zhihui Tong, Emmanuelle Masson, David N Cooper, Jian-Min Chen, Weiqin Li

1Department of Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
2Univ Brest, Inserm, EFS, UMR 1078, GGB, 29200 Brest, France
3Service de Génétique Médicale Et de Biologie de La Reproduction, CHRU Brest, 29200 Brest, France
4Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK
5Institute of Critical Care Medicine, Nanjing University, Nanjing, China