Blokhina Anastasia V, Ershova Alexandra I, Kiseleva Anna V, Sotnikova Evgeniia A, Zharikova Anastasia A, Zaicenoka Marija, Vyatkin Yuri V, Ramensky Vasily E, Kutsenko Vladimir A, Garbuzova Elizaveta V, Divashuk Mikhail G, Litinskaya Olga A, Pokrovskaya Maria S, Shalnova Svetlana A, Meshkov Alexey N, Drapkina Oxana M
National Medical Research Center for Therapy and Preventive Medicine, Ministry of Healthcare of the Russian Federation, Petroverigsky per. 10, Bld. 3, 101000 Moscow, Russia.
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 1-73, Leninskie Gory, 119991 Moscow, Russia.
Int J Mol Sci. 2024 Nov 25;25(23):12651. doi: 10.3390/ijms252312651.
Familial dysbetalipoproteinemia (FD) is a highly atherogenic, prevalent genetically based lipid disorder. About 10% of FD patients have rare variants associated with autosomal dominant FD. However, there are insufficient data on the relationship between rare variants and FD. Genetic data from 4720 subjects were used to identify rare variants and investigate their pathogenicity for autosomal dominant FD. We observed 24 variants in 86 unrelated probands. Most variants were unique (66.7%). Five identified variants (p.Glu63ArgfsTer15, p.Gly145AlafsTer97, p.Lys164SerfsTer87, p.Arg154Cys, and p.Glu230Lys) are causal for autosomal dominant FD. One of them (p.Lys164SerfsTer87) was described for the first time. When we compared clinical data, it was found that carriers of pathogenic or likely pathogenic variants had significantly higher triglyceride levels (median 5.01 mmol/L) than carriers of benign or likely benign variants (median 1.70 mmol/L, = 0.034) and variants of uncertain significance (median 1.38 mmol/L, = 0.036). For the first time, we estimated the expected prevalence of causal variants for autosomal dominant FD in the population sample: 0.27% (one in 619). Investigating the spectrum of variants may advance our understanding of the genetic basis of FD and underscore the importance of gene sequencing in patients with lipid metabolism disorders.
家族性异常β脂蛋白血症（FD）是一种具有高度致动脉粥样硬化性的、常见的基于遗传的脂质紊乱疾病。约10%的FD患者具有与常染色体显性FD相关的罕见变异。然而，关于罕见变异与FD之间关系的数据并不充分。利用来自4720名受试者的遗传数据来识别罕见变异，并研究它们对常染色体显性FD的致病性。我们在86名无亲缘关系的先证者中观察到24种变异。大多数变异是独特的（66.7%）。鉴定出的5种变异（p.Glu63ArgfsTer15、p.Gly145AlafsTer97、p.Lys164SerfsTer87、p.Arg154Cys和p.Glu230Lys）是常染色体显性FD的病因。其中一种变异（p.Lys164SerfsTer87）是首次被描述。当我们比较临床数据时，发现致病性或可能致病性变异的携带者的甘油三酯水平（中位数5.01 mmol/L）显著高于良性或可能良性变异的携带者（中位数1.70 mmol/L，P = 0.034）以及意义未明变异的携带者（中位数1.38 mmol/L，P = 0.036）。我们首次在人群样本中估计了常染色体显性FD病因性变异的预期患病率：0.27%（619人中1人）。研究变异谱可能会增进我们对FD遗传基础的理解，并突出基因测序在脂质代谢紊乱患者中的重要性。
