Objective: Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS) are the prototypes of monogenic and polygenic conditions underlying genetically based severe hypertriglyceridemia. These conditions have been only partially investigated so that a systematic comparison of their characteristics remains incomplete. We aim to compare genetic profiles and clinical outcomes in FCS and MCS. Approach and Results: Thirty-two patients with severe hypertriglyceridemia (triglyceride >1000 mg/dL despite lipid-lowering treatments with or without history of acute pancreatitis) were enrolled. Rare and common variants were screened using a panel of 18 triglyceride-raising genes, including the canonical LPL , APOC2 , APOA5 , GP1HBP1 , and LMF1 . Clinical information was collected retrospectively for a median period of 44 months. Across the study population, 37.5% were classified as FCS due to the presence of biallelic, rare mutations and 59.4% as MCS due to homozygosity for nonpathogenic or heterozygosity for pathogenic variants in canonical genes, as well as for rare and low frequency variants in noncanonical genes. As compared with MCS, FCS patients showed a lower age of hypertriglyceridemia onset, higher levels of on-treatment triglycerides, and 3-fold higher incidence rate of acute pancreatitis. Conclusions: Our data indicate that the genetic architecture and natural history of FCS and MCS are different. FCS expressed the most severe clinical phenotype as determined by resistance to triglyceride-lowering medications and higher incidence of acute pancreatitis episodes. The most common genetic abnormality underlying FCS was represented by biallelic mutations in LPL while APOA5 variants, in combination with high rare polygenic burden, were the most frequent genotype of MCS.

中文翻译：

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遗传性乳糜微粒血症综合征的突变谱和长期临床结果

客观的：家族性乳糜微粒血症综合征 (FCS) 和多因素乳糜微粒血症综合征 (MCS) 是基于遗传的严重高甘油三酯血症的单基因和多基因病症的原型。这些条件仅得到部分研究，因此对其特征的系统比较仍然不完整。我们的目标是比较 FCS 和 MCS 的基因谱和临床结果。 方法和结果：32 名患有严重高甘油三酯血症的患者（尽管进行了降脂治疗，甘油三酯>1000 mg/dL，有或没有急性胰腺炎病史）纳入研究。使用一组 18 个甘油三酯升高基因（包括典型的职业联赛,APOC2,APOA5,GP1HBP1， 和LMF1。回顾性收集中位时间为 44 个月的临床信息。在整个研究人群中，37.5% 的人由于存在双等位基因、罕见突变而被归类为 FCS，59.4% 的人由于典型基因中非致病性变异的纯合性或致病性变异的杂合性以及非典型基因中的罕见和低频变异而被归类为 MCS。基因。与MCS相比，FCS患者高甘油三酯血症发病年龄较低，治疗期间甘油三酯水平较高，急性胰腺炎发病率高出3倍。 结论：我们的数据表明 FCS 和 MCS 的遗传结构和自然史是不同的。FCS 表达了最严重的临床表型，这取决于对降甘油三酯药物的耐药性和急性胰腺炎发作的较高发生率。FCS 中最常见的遗传异常表现为双等位基因突变职业联赛尽管APOA5变异与高度罕见的多基因负担相结合，是 MCS 最常见的基因型。