-
摘要: 家族性高胆固醇血症(FH)是一种常见的常染色体显性或隐性遗传代谢病，常用的临床诊断标准主要根据患者的低密度脂蛋白胆固醇(LDL-C)水平和健康调查信息进行诊断，其确诊率十分有限。基因检测到LDLR、APOB、PCSK 9 和LDLRAP1等基因致病性突变是诊断FH的金标准。近年来，随着FH基因诊断技术的应用，新的致病基因不断被发现，有效提升了FH患者的检出率。本文就FH致病相关基因、基因诊断策略、国内外基因诊断进展及基因诊断面临的挑战等方面进行综述，以期在了解基因诊断的基础上，为中国探索建立切实可行的FH基因诊断方案提供参考，进一步促进FH的诊断与规范化管理。Abstract: Familial hypercholesterolemia(FH) is a common autosomal dominant or recessive inherited metabolic disease. Now the commonly used clinical diagnostic criteria for FH rely on LDL-C level and patient's health survey information, and the diagnosis rate is very limited. So genetic detection of pathogenic variants of LDLR, APOB, PCSK 9 and LDLRAP 1 genes was the gold standard for the diagnosis of FH. In recent years, with the application of FH genetic diagnosis technology, newly pathogenicity genes have been discovered continuously, effectively improving the detection rate of FH. This paper reviewed FH pathogen-related genes, genetic diagnosis strategies, the progress of genetic diagnosis at home and abroad and the challenges facing genetic diagnosis. Based on the understanding of genetic diagnosis, we aim to explore and establish feasible genetic diagnosis scheme, and further promote the diagnosis and standardization managements of FH in China.
-
-
表 1 FH主要突变基因信息
Table 1. FH mainly mutation genetic information
基因 编码蛋白及其作用 染色体位置 遗传方式 突变引起的疾病 LDLR 低密度脂蛋白受体：清除血浆LDL-C的关键细胞表面受体，在维持体内胆固醇代谢平衡方面具有重要地位 19p13.1-13.3 AD FH APOB 载脂蛋白B：LDL颗粒的主要蛋白、LDLR配体 2p24.1 AD FH PCSK9 前蛋白转化酶枯草溶菌素9：在LDLR降解中起作用 1p32.3 AD FH LDLRAP1 LDLR衔接蛋白1：与LDLR胞浆相互作用，促进LDL内化 1p36.11 AR ARH SREBP2 胆固醇调节元件结合蛋白-2：主要调控胆固醇生物合成和内稳态相关基因 22q13 AD FH EPHX2 环氧化物水解酶2：具有脂质磷酸酶活性，在血浆脂蛋白颗粒中环氧化物的处理中起作用 8p21-p12 AD FH CETP 胆固醇酯转移蛋白：促进胆固醇酯与TG在HDL颗粒和载脂蛋白之间交换 16q21 AD FH STAP1 信号转导适配蛋白家族1：功能未知/不完全与高胆固醇血症相关 4q13.2 AD FH APOA5 载脂蛋白A5：在脂质代谢中发挥重要作用 11q23.3 AD FH GHR 生长激素受体：突变导致生长激素对肝脏LDLR mRNA表达、LDL-C分解代谢与清除作用减弱 5p13.1-p12 AD FH APOE 载脂蛋白E：参与脂蛋白代谢的主要载脂蛋白，致病突变增加对其受体的亲和力，导致LDLR的下调 19q13.32 AD 异常脂肪蛋白血
症，表型似FHABCG5、ABCG8 三磷酸腺苷结合盒转运蛋白G5、G8：在控制植物固醇吸收过程中发挥关键作用 2p21 AR 植物固醇血症 LIPA 胆固醇酯脂肪酶：水解胆固醇酯或甘油三酯 10q23.31 AR 胆固醇酯脂肪酶
缺乏症，FH表型PNPLA5 patatin样磷脂酶结构域5：影响脂肪细胞分化、甘油三酯水解 22q13.31 AR FH表型 CYP27A1 线粒体甾醇27-羟化酶：致病性突变可引起脑腱黄色瘤病，这是一种以胆固醇水平轻度升高和黄色瘤为特征的疾病 2q33-qter AR FH表型 CYP7A1 胆固醇7α-羟化酶：致病突变使得体内胆固醇清除障碍 8q12.1 AR FH表型 注：LDLR：低密度脂蛋白受体；AR：常染色体隐性遗传；AD：常染色体显性遗传；ARH：常染色体隐性高胆固醇血症；FH：家族性高胆固醇血症；TG：甘油三酯；HDL：高密度脂蛋白；LDL：低密度脂蛋白。 
下载: 导出CSV
表 2 国内外FH基因诊断情况
Table 2. FH genetic diagnosis at home and abroad
地区 病例数 临床诊断标准 基因诊断方法 主要研究结果 参考文献 中国 208 DLCN MLPA ①诊断出48种不同突变，其中LDLR突变45种(包括6个新突变)，APOB、APOE、ABCG5突变各1种；②患者携带LDLR错义突变的LDL-C水平，较携带拷贝数变异、剪接突变和无义突变的要高。 [24] 中国 108 DLCN、
Simon
BroomeSanger测序、
MLPA①复合杂合子是中国最常见的HoFH类型；②LDLR基因中检出84个突变，并发现了7个致病性(或可能致病性)的新突变，其中W483X(c.1448 G>A)，A627T(c.1879 G>A)，H583Y(c.1747 C>T)是最常见的突变；③第4外显子突变数量最多(20.5%)。 [25] 中国台湾 285 DLCN NGS ①41例受试者检出FH突变，其中40例为杂合突变，1例为双杂合突变(LDLR c.1867A>G和APOB c.10579C>T)；②检出16个突变，其中13个为错义单核苷酸突变、2个为剪接突变、1个为移码突变；③LDLR c.986G>A、c.268G>A与LDL-C高水平和早发CAD相关。 [26] 德国 336 DLCN NGS ①诊断出73种共计126个不同的序列突变，包括11个新(可能)致病性的突变，其中LDLR基因突变最多(84.9%)；②APOB基因发现19个致病突变；③PCSK9基因和LDLRAP1基因未发现致病突变。 [28] 挪威 29 449 DLCN Sanger测序和
MLPA①LDLR基因检出259个突变，包含29个新的突变；②Sanger测序鉴定出错义突变123个、缺失突变38个、无义突变28个；③APOB基因检出2个致病性突变(p.R3527Q和p.R3527W)；④PCSK9基因检出3个致病性突变(p.S127R、p.R215H和p.D374Y)。 [30] 美国 50 726 DLCN 外显子测序
技术诊断出了35个致病性突变，其中29个LDLR、4个APOB和2个PCSK9。 [31] 日本 801 日本
标准NGS ①LDLR基因检出137个突变，包括18个大的缺失/重复突变、92个(可能)致病性突变、44个意义不明确性突变、1个良性突变；②PCSK9基因检出21个突变，4个致病性或可能致病性突变、10个意义不明确性突变、7个良性突变。 [32] 印度 54 DLCN 靶向外显子
组测序①发现19个不同的突变，其中主要是错义突变；②LDLR基因检出5个突变，其中包括1个新的致病突变；③首次在CETP、APOA5、EPHX2和SREBP2基因中发现致病突变；④APOB基因检出3个致病突变(c.3829C>T，c.12649T>C，c.10520G>A)；⑤PCSK9基因c.2038C>T，系首次在印度FH患者中发现。 [16]
下载: 导出CSV
-
[1] Tokgozoglu L, Kayikcioglu M. Familial hypercholesterolemia: Global burden and approaches[J]. Curr Cardiol Rep, 2021, 23(10): 151. doi: 10.1007/s11886-021-01565-5
[2] Chen YJ, Chen IC, Chen YM, et al. Prevalence of genetically defined familial hypercholesterolemia and the impact on acute myocardial infarction in Taiwanese population: A hospital-based study[J]. Front Cardiovasc Med, 2022, 9: 994662. doi: 10.3389/fcvm.2022.994662
[3] 李云云, 折剑青, 罗玲, 等. 家族性高胆固醇血症合并极高危ASCVD 1例[J]. 临床心血管病杂志, 2022, 38(6): 513-516. https://lcxxg.whuhzzs.com/article/doi/10.13201/j.issn.1001-1439.2022.06.017
[4] Beheshti SO, Madsen CM, Varbo A, et al. Worldwide prevalence of familial hypercholesterolemia: Meta-analyses of 11 million subjects[J]. J Am Coll Cardiol, 2020, 75(20): 2553-2566. doi: 10.1016/j.jacc.2020.03.057
[5] EAS Familial Hypercholesterolaemia Studies Collaboration(FHSC). Global perspective of familial hypercholesterolaemia: A cross-sectional study from the EAS familial hypercholesterolaemia studies collaboration(FHSC)[J]. Lancet, 2021, 398(10312): 1713-1725. doi: 10.1016/S0140-6736(21)01122-3
[6] Ingles J, Macciocca I, Morales A, et al. Genetic testing in inherited heart diseases[J]. Heart Lung Circ, 2020, 29(4): 505-511. doi: 10.1016/j.hlc.2019.10.014
[7] Sturm AC, Knowles JW, Gidding SS, et al. Clinical genetic testing for familial hypercholesterolemia: JACC scientific expert panel[J]. J Am Coll Cardiol, 2018, 72(6): 662-680. doi: 10.1016/j.jacc.2018.05.044
[8] Hendricks-Sturrup RM, Clark-LoCascio J, Lu CY. A global review on the utility of genetic testing for familial hypercholesterolemia[J]. J Pers Med, 2020, 10(2): 23. doi: 10.3390/jpm10020023
[9] Harada-Shiba M, Arai H, Ishigaki Y, et al. Guidelines for diagnosis and treatment of familial hypercholesterolemia 2017[J]. J Atheroscler Thromb, 2018, 25(8): 751-770. doi: 10.5551/jat.CR003
[10] Brandts J, Ray KK. Familial hypercholesterolemia: JACC focus seminar 4/4[J]. J Am Coll Cardiol, 2021, 78(18): 1831-1843. doi: 10.1016/j.jacc.2021.09.004
[11] Chora JR, Iacocca MA, Tichy L, et al. The clinical genome resource(ClinGen)familial hypercholesterolemia variant curation expert panel consensus guidelines for LDLR variant classification[J]. Genet Med, 2022, 24(2): 293-306. doi: 10.1016/j.gim.2021.09.012
[12] Gidding SS, Champagne MA, de Ferranti SD, et al. The agenda for familial hypercholesterolemia: A scientific statement from the American heart association[J]. Circulation, 2015, 132(22): 2167-92. doi: 10.1161/CIR.0000000000000297
[13] Vrablik M, Tichy L, Freiberger T, et al. Genetics of familial hypercholesterolemia: New insights[J]. Front Genet, 2020, 11: 574474. doi: 10.3389/fgene.2020.574474
[14] Iacocca MA, Hegele RA. Role of DNA copy number variation in dyslipidemias[J]. Curr Opin Lipidol, 2018, 29(2): 125-132. doi: 10.1097/MOL.0000000000000483
[15] Berberich AJ, Hegele RA. The complex molecular genetics of familial hypercholesterolaemia[J]. Nat Rev Cardiol, 2019, 16(1): 9-20. doi: 10.1038/s41569-018-0052-6
[16] Pillai KKB, Shah SAV, Reddy LL, et al. Targeted exome sequencing in South Indian patients with familial hypercholesterolemia[J]. Clin Chim Acta, 2022, 527: 47-55. doi: 10.1016/j.cca.2021.12.022
[17] Moldovan V, Banescu C, Dobreanu M. Molecular diagnosis methods in familial hypercholesterolemia[J]. Anatol J Cardiol, 2020, 23(3): 120-127.
[18] 中华医学会心血管病学分会动脉粥样硬化及冠心病学组, 中华心血管病杂志编辑委员会. 家族性高胆固醇血症筛查与诊治中国专家共识[J]. 中华心血管病杂志, 2018, 46(2): 99-103. doi: 10.3760/cma.j.issn.0253-3758.2018.02.006
[19] Amerizadeh A, Javanmard SH, Sarrafzadegan N, et al. Familial hypercholesterolemia(FH)registry worldwide: A systematic review[J]. Curr Probl Cardiol, 2022, 47(10): 100999. doi: 10.1016/j.cpcardiol.2021.100999
[20] Chen P, Chen X, Zhang S. Current status of familial hypercholesterolemia in China: A need for patient FH registry systems[J]. Front Physiol, 2019, 10: 280. doi: 10.3389/fphys.2019.00280
[21] Chora JR, Medeiros AM, Alves AC, et al. Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: Application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis[J]. Genet Med, 2018, 20: 591-598. doi: 10.1038/gim.2017.151
[22] 中华医学会检验医学分会. 中国临床血脂检测指南[J]. 中华检验医学杂志, 2022, 45(10): 1017-1033. doi: 10.3760/cma.j.cn114452-20220829-00497
[23] 中国血脂管理指南修订联合专家委员会. 中国血脂管理指南(2023年)[J]. 中华心血管病杂志, 2023, 51(3): 221-255. doi: 10.3760/cma.j.cn112148-20230119-00038
[24] Wang H, Yang H, Liu Z, et al. Targeted genetic analysis in a Chinese cohort of 208 patients related to familial hypercholesterolemia[J]. J Atheroscler Thromb, 2020, 27(12): 1288-1298. doi: 10.5551/jat.54593
[25] Jiang L, Stoekenbroek RM, Zhang F, et al. Homozygous familial hypercholesterolemia in China: Genetic and clinical characteristics from a real-world, multi-center, cohort study[J]. J Clin Lipidol, 2022, 16(3): 306-314. doi: 10.1016/j.jacl.2022.03.003
[26] Lee WJ, Chuang HN, Chen YM, et al. Familial hypercholesterolemia genetic variations and long-term cardiovascular outcomes in patients with hypercholesterolemia who underwent coronary angiography[J]. Genes(Basel), 2021, 12(9): 1413.
[27] 吴硕, 赵志豪, 史宛鑫, 等. 脂蛋白a在心血管疾病中的研究进展[J]. 临床心血管病杂志, 2021, 37(12): 1151-1156. doi: 10.13201/j.issn.1001-1439.2021.12.017
[28] Rieck L, Bardey F, Grenkowitz T, et al. Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia[J]. Clin Genet, 2020, 98(5): 457-467. doi: 10.1111/cge.13826
[29] Sharifi M, Futema M, Nair D, et al. Genetic architecture of familial hypercholesterolaemia[J]. Curr Cardiol Rep, 2017, 19(5): 44. doi: 10.1007/s11886-017-0848-8
[30] Leren TP, Bogsrud MP. Molecular genetic testing for autosomal dominant hypercholesterolemia in 29, 449 Norwegian index patients and 14, 230 relatives during the years 1993-2020[J]. Atherosclerosis, 2021, 322: 61-66. doi: 10.1016/j.atherosclerosis.2021.02.022
[31] Abul-Husn NS, Manickam K, Jones LK, et al. Genetic identification of familial hypercholesterolemia within a single U.S. health care system[J]. Science, 2016, 354(6319): aaf7000. doi: 10.1126/science.aaf7000
[32] Hori M, Ohta N, Takahashi A, et al. Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients[J]. Atherosclerosis, 2019, 289: 101-108. doi: 10.1016/j.atherosclerosis.2019.08.004
[33] Chacón-Camacho OF, Pozo-Molina G, Méndez-Catalá CF, et al. Familial hypercholesterolemia: update and review[J]. Endocr Metab Immune Disord Drug Targets, 2022, 22(2): 198-211. doi: 10.2174/1871530321666210208212148
[34] Hendricks-Sturrup RM, Lu CY. Understanding implementation challenges to genetic testing for familial hypercholesterolemia in the United States[J]. J Pers Med, 2019, 9(1): 9. doi: 10.3390/jpm9010009
-
图(1)
表(2)
计量
- 文章访问数: 1652
- PDF下载数: 291
- 施引文献: 0