Aliosaitiene Urte, Cerkauskiene Rimante, Laucevicius Aleksandras, Vilniskyte Migle, Sutkus Viktoras, Mainelis Antanas, Burnyte Birute, Barysiene Jurate, Petrulioniene Zaneta
Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania.
State Research Institute, Centre for Innovative Medicine, 01513 Vilnius, Lithuania.
J Cardiovasc Dev Dis. 2025 May 21;12(5):197. doi: 10.3390/jcdd12050197.
Although familial hypercholesterolemia (FH) is a common congenital cause of elevated low-density lipoprotein cholesterol (LDL-C), it remains underdiagnosed and undertreated worldwide due to its inherent genetic heterogeneity. This study aimed to determine the prevalence of genetic variants in a Lithuanian patient cohort with clinically diagnosed FH and evaluate their possible clinical implications.
A total of 172 patients were included in the retrospective analysis. The study population comprised males and females ranging from 0 to 85 years of age, with LDL-C levels exceeding 4.9 mmol/L in adults and 3.9 mmol/L in children. The subjects were divided into four groups according to the Dutch Lipid Clinic Network (DLCN) criteria (definite, probable, possible, and unlikely). Children were analyzed separately. Next-generation sequencing (NGS) has been chosen as the most appropriate technique for genetic testing. All identified variants were categorized into three groups: (1) pathogenic, (2) likely pathogenic, and (3) variants of uncertain significance. Subjects without detected variants were classified into group (4) No mutation.
Women were diagnosed with FH significantly later than men ( = 0.033). Genetic testing identified FH-causing variants in 41.86% of subjects, with 20.93% carrying pathogenic variants, 9.88% likely pathogenic, and 11.05% variants of uncertain significance (VUS). Frequently identified pathogenic variants were in and in , which are both linked to the founder effect. Genetic testing led to a reassessment of Dutch Lipid Clinic Network scores, increasing the number of individuals classified as "Definite FH" by 86.2%.
The increasing use of NGS in FH has enhanced diagnostic capabilities and suggests population-specific genetic patterns. However, it also increases VUS detection, for which reclassification rates are still low and require strenuous efforts. Moreover, despite the benefits of genetic testing, significant gender disparities remain and require further attention.
尽管家族性高胆固醇血症（FH）是低密度脂蛋白胆固醇（LDL-C）升高的常见先天性病因，但由于其内在的遗传异质性，在全球范围内仍未得到充分诊断和治疗。本研究旨在确定立陶宛临床诊断为FH的患者队列中基因变异的患病率，并评估其可能的临床意义。
回顾性分析共纳入172例患者。研究人群包括年龄在0至85岁之间的男性和女性，成人LDL-C水平超过4.9 mmol/L，儿童超过3.9 mmol/L。根据荷兰脂质诊所网络（DLCN）标准（确诊、可能、可能和不太可能）将受试者分为四组。儿童单独进行分析。下一代测序（NGS）被选为最适合基因检测的技术。所有鉴定出的变异分为三组：（1）致病性变异，（2）可能致病性变异，（3）意义未明的变异。未检测到变异的受试者分为第（4）组：无突变。
女性被诊断为FH的时间明显晚于男性（P = 0.033）。基因检测在41.86%的受试者中发现了导致FH的变异，其中20.93%携带致病性变异，9.88%为可能致病性变异，11.05%为意义未明的变异（VUS）。常见的致病性变异是 中的 和 中的 ，这两者都与奠基者效应有关。基因检测导致对荷兰脂质诊所网络评分进行重新评估，将分类为“确诊FH”的个体数量增加了86.2%。
在FH中越来越多地使用NGS提高了诊断能力，并提示了特定人群的遗传模式。然而，它也增加了VUS的检测，其重新分类率仍然很低，需要付出巨大努力。此外，尽管基因检测有诸多益处，但显著的性别差异仍然存在，需要进一步关注。
