Molecular characterization of a rare heterozygous APOA5 variant in a Chinese family with moderate hypertriglyceridemia.

BACKGROUND

The development of hypertriglyceridemia (HTG) can be attributed to either a monogenic or a polygenic etiologic basis, and the understanding of this molecular basis is incomplete. APOA5 plays a critical role in triglyceride (TG) metabolism, and APOA5 deficiency is a recognized cause of HTG. However, the effects of rare APOA5 variants observed only in isolated cases are often difficult to establish conclusively. This study aims to find the genetic cause of moderate HTG in a Chinese family, and conduct preliminary in silico verification.

METHODS

Eight family members received biochemical testing, and genetic testing based on whole-exome sequencing (WES). Basic information including body mass index (BMI), medical history, prescription for TG management, and smoking and drinking habits was recorded. Comprehensive residue conservation analysis and computational simulation of protein structure stability were performed to measure the impact of the assumptive causal variant.

RESULTS

A rare heterozygous APOA5 variant (p.R223C) was identified. Specifically, six family members who carried the variant had substantially higher fasting plasma TG level than the admitted threshold (1.7 mmol/L) with the highest of 4.96 mmol/L, while a non-carrier in this family was normal in TG. The p. R223C variant was absent from ClinVar and gnomAD databases. Besides, in silico predictions results supported the variant's potential deleteriousness.

CONCLUSION

This study presents a familial case of moderate HTG associated with a rare APOA5 variant, which is classified as Likely Pathogenic (LP) according to the ACMG/AMP guideline. The real effect of this variant requires further investigation via biochemical or cell-based studies.