What is the clinical evidence from this study?

Study design: Observational. Population: Moderate hypertriglyceridemia (n=8). Intervention: Heterozygous APOA5 variant (p.R223C) vs. Non-carrier family member. Primary outcome: Fasting plasma triglyceride (TG) level.

What does this research mean for the field?

The rare heterozygous APOA5 variant p.R223C co-segregates with moderate hypertriglyceridemia and is classified as a likely pathogenic genetic cause of the condition. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To identify the molecular genetic etiology underlying familial moderate hypertriglyceridemia and evaluate the functional impact of the candidate variant.

June 1, 2026Frontiers in GeneticsOpen Access

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

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Key result

Rare APOA5 variant p.R223C linked to moderate hypertriglyceridemia in a familial case series.

Why the study?

The molecular basis of hypertriglyceridemia remains incompletely understood, and the effects of rare APOA5 variants observed in isolated cases are difficult to establish conclusively.

Key Points

To identify the molecular genetic etiology underlying familial moderate hypertriglyceridemia and evaluate the functional impact of the candidate variant.
Assessed eight family members (N=8) using biochemical lipid, liver, and renal profiling alongside whole-exome sequencing and Sanger sequencing.
Conducted in silico residue conservation analyses, protein structural stability modeling, and pathogenicity classification according to ACMG/AMP criteria.
Identified a rare heterozygous APOA5 missense variant (g.chr11:116661278G>A, c.667C>T, p.R223C) absent from ClinVar, dbSNP, and gnomAD databases.
Observed elevated fasting plasma triglycerides above 1.7 mmol/L (reaching up to 4.96 mmol/L) across all six untreated variant carriers, whereas the single non-carrier had normal triglyceride levels.
Classified the p.R223C variant as Likely Pathogenic based on multi-tool computational scores (REVEL score: 0.702) and familial co-segregation.

Study Design

Type

Observational (n=8)

Multicenter

Structured PICO

Population

8 members of a Chinese family evaluated for familial moderate hypertriglyceridemia using biochemical and genetic testing.

Exposure

Whole-exome sequencing (WES) and in silico verification

Outcome

Genetic cause of moderate hypertriglyceridemiasurrogate

Identification of a rare APOA5 variant (p.R223C) associated with moderate hypertriglyceridemia in a Chinese family expands the genetic spectrum of monogenic hypertriglyceridemia.

Limitations

Lack of in vitro or in vivo functional studies to confirm the exact mechanism
Two family members did not undergo whole-exome sequencing due to economic constraints
Potential confounding by co-occurring HTG-risk variants and lifestyle factors
The real effect of this variant requires further investigation via biochemical or cell-based studies.

Implication

Hypothesis-generating for APOA5 p.R223C in familial hypertriglyceridemia; leaves open causality and broader relevance.

Abstract

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.

Discussion

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Published by Frontiers in Genetics · CC BY

Cite This Study

Liu et al. (2026) conducted an observational in Moderate hypertriglyceridemia (n=8). Heterozygous APOA5 variant (p.R223C) vs. Non-carrier family member was evaluated on Fasting plasma triglyceride (TG) level. The rare heterozygous APOA5 variant p.R223C was identified in seven family members and co-segregated with moderate hypertriglyceridemia in six untreated individuals.

synapsesocial.com/papers/6a218419f6aa648d3a5818e8 https://doi.org/10.3389/fgene.2026.1796970

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Implication

Hypothesis-generating for APOA5 p.R223C in familial hypertriglyceridemia; leaves open causality and broader relevance.

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

Key Points

Study Design

Structured PICO

Limitations

Implication

Abstract

Discussion

Figures from the paper

Cite This Study

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

Key Points

Study Design

Structured PICO

Limitations

Implication

Abstract

Discussion

Figures from the paper

Cite This Study

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