复合杂合变异所致家族性高胆固醇血症2例患者的临床表现及遗传学分析  

Clinical manifestations and genetic analysis of two patients with familial hypercholesterolemia caused by complex heterozygous variants

作　　者：连想 李小燕 王可心 田春营 刘子兮 王喜福[1] Lian Xiang;Li Xiaoyan;Wang Kexin;Tian Chunying;Liu Zixi;Wang Xifu(Emergency Critical Care Center,Beijing Anzhen Hospital Affiliated to Capital Medical University,Beijing 100029,China;Beijing Institute of Heart,Lung and Blood Vessel Disease,Key Laboratory of Remodeling-related Cardiovascular Disease of the Ministry of Education,Beijing Anzhen Hospital Affiliated to Capital Medical University,Beijing 100029,China;Adult Cardiac Critical Care Center,Beijing Anzhen Hospital Affiliated to Capital Medical University,Beijing 100029,China)

机构地区：[1]首都医科大学附属北京安贞医院急诊危重症中心,北京100029 [2]首都医科大学附属北京安贞医院,北京市心肺血管疾病研究所,北京100029 [3]首都医科大学附属北京安贞医院成人心脏危重症中心,北京100029

出　　处：《中华医学遗传学杂志》2025年第2期212-218,共7页Chinese Journal of Medical Genetics

基　　金：北京市自然科学基金项目(7232042)。

摘　　要：目的探讨2例复合杂合变异所致家族性高胆固醇血症(FH)患者的基因检测结果,明确其临床表现与基因变异的关系。方法选择2018年于首都医科大学附属北京安贞医院就诊的2例FH患者(患者1、2)作为研究对象。采用回顾性研究方法,收集2例患者的临床及家族史资料。采集2例患者的外周静脉血各2 mL,对血液样本进行基因组DNA提取。应用Sanger测序法对经全外显子组测序(WES)检测的2例患者相关变异位点进行验证。根据美国医学遗传学与基因组学学会(ACMG)制定的《遗传变异分类标准与指南》(以下简称为"ACMG指南"),对检出的变异位点进行致病性评级,并应用多重生物信息学软件(SIFT、PolyPhen-2和SWISS-MODEL),对变异位点有害性进行分析。本研究通过了首都医科大学附属北京安贞医院医学伦理委员会的审查(批准号:2024215X)。结果患者1以早发冠心病起病,入院时血脂检测结果显示,血清总胆固醇(TC)浓度为9.86 mmol/L(正常参考值为3.10~5.20 mmol/L),血清低密度脂蛋白胆固醇(LDL-C)浓度为8.37 mmol/L(正常参考值为1.27~3.12 mmol/L)。患者1采取瑞舒伐他汀联合依折麦布治疗1个月后,降血脂效果不明显,将降血脂治疗方案调整为阿托伐他汀联合依折麦布与普罗布考治疗1年后,患者1出现阵发性胸痛症状,复查血脂水平显示,血清TC浓度为4.50 mmol/L,LDL-C浓度为3.55 mmol/L,继续采用原降血脂方案治疗,血清LDL-C浓度维持为2.65~3.66 mmol/L。患者2体检时发现血脂水平异常升高及颈动脉硬化,其体检时血清TC浓度为11.82 mmol/L,血清LDL-C浓度为9.63 mmol/L,接受瑞舒伐他汀治疗后,血脂下降效果显著。WES结果提示,患者1携带LDLR基因(NM_(0)00527.4)c.1871_(1)873del(p.Ile624del)和c.1747C>T(p.His583Tyr)杂合变异;患者2携带LDLR基因c.1747C>T(p.His583Tyr)和APOB基因(NM_(0)00384)c.6936_(6)937inv(p.Ile2313Val)杂合变异。根据ACMG指南,LDLR基因c.1747C>T(p.His583Tyr)被判ObjectiveTo investigate the gene detection results of 2 patients with familial hypercholesterolemia(FH)caused by complex heterozygous variation,and to clarify the relationship between clinical manifestations and gene variation.MethodsTwo patients(patient 1 and 2)with FH who visited Beijing Anzhen Hospital Affiliated to Capital Medical University in 2018 were selected as research subjects.A retrospective study method was used to collect clinical and family history data of the two patients.And 2 mL of peripheral venous blood from each of the two patients was collected,and genomic DNA extraction was performed on the blood samples.Sanger sequencing was used to validate the variant sites of the two patients detected by whole-exome sequencing(WES).Pathogenicity of variants was classified based on the American College of Medical Genetics and Genomics(ACMG)Standards and Guidelines for the Classification of Genetic Variants(hereinafter referred to as the"ACMG Guidelines"),and the impact of variant was analyzed using multiple bioinformatics tools including SIFT,PolyPhen-2,and SWISS-MODEL.This study has been approved by Beijing Anzhen Hospital Affiliated to Capital Medical University(Ethics No.2024215X).ResultsPatient 1 initially presented with early-onset coronary heart disease,with initial lipid levels of serum total cholesterol(TC)9.86 mmol/L(normal reference value:3.10~5.20 mmol/L)and serum low-density lipoprotein cholesterol(LDL-C)8.37 mmol/L(normal reference value:1.27~3.12 mmol/L)on admission.Patient 1 initially underwent treatment with rosuvastatin combined with ezetimibe for one month,but the lipid-lowering effect was not significant.The lipid-lowering therapy was then adjusted to atorvastatin combined with ezetimibe and probucol.After one year of treatment,the patient developed paroxysmal chest pain symptoms.A follow-up lipid profile showed a serum TC level of 4.50 mmol/L and a LDL-C level of 3.55 mmol/L.The lipid-lowering regimen was continued,and the serum LDL-C levels were maintained between 2.65 and 3.66 mmol/

关 键 词：高胆固醇血症Ⅱ型 LDLR基因 APOB基因 基因检测 脂蛋白类 LDL 血脂异常 降血脂药物 

分 类 号：R589.2[医药卫生—内分泌]