Editorial: designing targeted sequencing panels for dyslipidemia.
Editorial: designing targeted sequencing panels for dyslipidemia.
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社论：设计血脂异常的靶向测序面板。
DOI：
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发表时间：
2019
影响因子：
4.4
通讯作者：
R. Hegele
中科院分区：
文献类型：
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作者：
R. Hegele
DOI：10.1097/MOL.0000000000000579在脂类方面的最新进展之一是将下一代测序技术嵌入临床，以辅助血脂异常的诊断。为检测已知基因的致病突变而设计的靶向测序板是目前首选的方法[1]。这项技术正被广泛应用于家族性高胆固醇血症的临床治疗。在本期《血脂学观点》中，Ernst Schaefer博士及其同事(第56-62页)讨论了一种单基因血脂异常的诊断方法，包括家族性高胆固醇血症，其中靶向DNA测序发挥了核心作用。尽管靶向测序小组设计各不相同，但在相对常见的家族性高胆固醇血症(HeFH)杂合型中，总是筛选出三个核心致病基因。它们分别是LDLR、APOB和PCSK9，分别编码低密度脂蛋白受体、载脂蛋白B和前蛋白转换酶枯草杆菌可信9型[2]。在转诊的低密度脂蛋白胆固醇高于5 mmoL/L和临床疑似高血压的患者中，约有一半的病例发现这三个基因的致病变异[3]。在未经治疗的低密度脂蛋白胆固醇水平较高的患者中--即超过8 mmoL/L--找到致病变异的可能性上升到90%以上[3]。其他几种可能性可以解释对三个主要基因进行定向测序没有发现致病突变的患者的临床特征。例如，家族性高胆固醇血症的第四个典型基因，即LDLRAP1(或ARH)编码低密度脂蛋白受体适配器蛋白1[4]。LDLRAP1功能缺失变异杂合子没有临床表型，而两个等位基因罕见突变的个体具有严重的表型，类似于典型的纯合子家族性高胆固醇血症(HoFH)，原因是双等位基因LDLR突变。LDLRAP1应被纳入针对家族性高胆固醇血症的NGS靶向研究小组[1]。偶尔，患者表现出家族性高胆固醇血症表型，这些表型是由通常导致其他血脂异常的基因突变引起的，包括APOE、LIPA和ABCG5以及
DOI:10.1097/MOL.0000000000000579 Among recent advances in lipidology has been the embedding of next-generation sequencing (NGS) in the clinic to assist with dyslipidemia diagnosis. Targeted sequencing panels designed to detect pathogenic mutations in known genes are the currently preferred method [1]. This technology is finding widespread clinical application for familial hypercholesterolemia. In this issue of Current Opinion in Lipidology, Dr Ernst Schaefer and colleagues (pp. 56– 62) discuss a diagnostic approach to monogenic dyslipidemias, including familial hypercholesterolemia, in which targeted DNA sequencing plays a central role. Although targeted sequencing panel design varies, three core causative genes are always screened for in the relatively common heterozygous form of familial hypercholesterolemia (HeFH). These are LDLR, APOB and PCSK9 encoding the LDL receptor, apolipoprotein (apo) B and proprotein convertase subtilisin kexin type 9, respectively [2]. In referred patients with LDL cholesterol more than 5 mmol/l and clinically suspected HeFH, pathogenic variants in these three genes are found in about half of cases [3]. Among patients with higher untreated LDL cholesterol levels – that is more than 8 mmol/l – the likelihood of finding a causative variant rises to more than 90% [3]. Several other possibilities could explain clinical features in patients in whom targeted sequencing of the three major genes finds no pathogenic mutation. For instance, a fourth canonical gene for familial hypercholesterolemia, namely LDLRAP1 (or ARH) encodes the LDL receptor adapter protein 1 [4]. Heterozygotes for loss-of-function variants in LDLRAP1 have no clinical phenotype, whereas individuals with rare mutations on both alleles have a severe phenotype that resembles typical homozygous familial hypercholesterolemia (HoFH) due to bi-allelic LDLR mutations. LDLRAP1 should be included in targeted NGS panels for familial hypercholesterolemia [1]. Occasionally, patients express familial hypercholesterolemia phenocopies that result from mutations in genes that usually cause other dyslipidemias, including APOE, LIPA and ABCG5 and