PDF(Pubmed)
Abstract：
While biallelic rare APOA5 pathogenic loss-of-function (LOF) variants cause familial chylomicronemia syndrome, heterozygosity for such variants is associated with highly variable triglyceride phenotypes ranging from normal to severe hypertriglyceridemia, often in the same individual at different time points. Here we provide an updated overview of rare APOA5 variants in hypertriglyceridemia.
Currently, most variants in APOA5 that are considered to be pathogenic according to guidelines of the American College of Medical Genetics and Genomics are those resulting in premature termination codons. There are minimal high quality functional data on the impact of most rare APOA5 missense variants; many are considered as variants of unknown or uncertain significance. Furthermore, particular common polymorphisms of APOA5 , such as p.Ser19Trp and p.Gly185Cys in Caucasian and Asian populations, respectively, are statistically overrepresented in hypertriglyceridemia cohorts and are sometimes misattributed as being causal for chylomicronemia, when they are merely risk alleles for hypertriglyceridemia.
Both biallelic and monoallelic LOF variants in APOA5 are associated with severe hypertriglyceridemia, although the biochemical phenotype in the monoallelic state is highly variable and is often exacerbated by secondary factors. Currently, with few exceptions, the principal definitive mechanism for APOA5 pathogenicity is through premature truncation. The pathogenic mechanisms of most missense variants in APOA5 remain unclear and require additional functional experiments or family studies.
Currently, most variants in APOA5 that are considered to be pathogenic according to guidelines of the American College of Medical Genetics and Genomics are those resulting in premature termination codons. There are minimal high quality functional data on the impact of most rare APOA5 missense variants; many are considered as variants of unknown or uncertain significance. Furthermore, particular common polymorphisms of APOA5 , such as p.Ser19Trp and p.Gly185Cys in Caucasian and Asian populations, respectively, are statistically overrepresented in hypertriglyceridemia cohorts and are sometimes misattributed as being causal for chylomicronemia, when they are merely risk alleles for hypertriglyceridemia.
Both biallelic and monoallelic LOF variants in APOA5 are associated with severe hypertriglyceridemia, although the biochemical phenotype in the monoallelic state is highly variable and is often exacerbated by secondary factors. Currently, with few exceptions, the principal definitive mechanism for APOA5 pathogenicity is through premature truncation. The pathogenic mechanisms of most missense variants in APOA5 remain unclear and require additional functional experiments or family studies.
摘要：
目的：双等位基因罕见APOA5致病性功能丧失（LOF）变异体可引起家族性乳糜微粒血症，这些变异的杂合性与从正常到严重的高甘油三酯血症的高度可变的甘油三酯表型相关。通常在同一个人的不同时间点。在这里，我们提供了高甘油三酯血症中罕见的APOA5变体的最新概述。
结果：目前，根据美国医学遗传学和基因组学学院的指南，APOA5中被认为具有致病性的大多数变体是导致过早终止密码子的变体。关于最罕见的APOA5错义变体的影响，只有很少的高质量功能数据；许多被认为是未知或不确定意义的变体。此外，特别常见的APOA5多态性，如p.Ser19Trp和p.Gly185Cys在高加索和亚洲人群中，分别,在高甘油三酯血症队列中统计上的比例过高，有时被误认为是乳糜微粒血症的原因，当它们仅仅是高甘油三酯血症的风险等位基因时。
结论：APOA5的双等位基因和单等位基因LOF变异体均与严重的高甘油三酯血症相关，尽管单等位基因状态的生化表型是高度可变的，并且经常被次要因素加剧。目前,除了少数例外,APOA5致病性的主要确定机制是通过过早截短。APOA5中大多数错义变体的致病机制仍不清楚，需要进行其他功能实验或家族研究。
结果：目前，根据美国医学遗传学和基因组学学院的指南，APOA5中被认为具有致病性的大多数变体是导致过早终止密码子的变体。关于最罕见的APOA5错义变体的影响，只有很少的高质量功能数据；许多被认为是未知或不确定意义的变体。此外，特别常见的APOA5多态性，如p.Ser19Trp和p.Gly185Cys在高加索和亚洲人群中，分别,在高甘油三酯血症队列中统计上的比例过高，有时被误认为是乳糜微粒血症的原因，当它们仅仅是高甘油三酯血症的风险等位基因时。
结论：APOA5的双等位基因和单等位基因LOF变异体均与严重的高甘油三酯血症相关，尽管单等位基因状态的生化表型是高度可变的，并且经常被次要因素加剧。目前,除了少数例外,APOA5致病性的主要确定机制是通过过早截短。APOA5中大多数错义变体的致病机制仍不清楚，需要进行其他功能实验或家族研究。
