From the, Cardiometabolic Unit, Clinical Department of Endocrinology, Department of Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden.
Department of Medicine, Integrated Cardiometabolic Center (ICMC), Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden.
J Intern Med. 2021 Aug;290(2):404-415. doi: 10.1111/joim.13287. Epub 2021 May 6.
To investigate whether genotyping could be used as a cost-effective screening step, preceding next-generation sequencing (NGS), in molecular diagnosis of familial hypercholesterolaemia (FH) in Swedish patients.
Three hundred patients of Swedish origin with clinical suspicion of heterozygous FH were analysed using a specific array genotyping panel embedding 112 FH-causing mutations in the LDLR, APOB and PCSK9 genes. The mutations had been selected from previous reports on FH patients in Scandinavia and Finland. Mutation-negative cases were further analysed by NGS. In 181 patients with probable or definite FH using the Dutch lipid clinics network (DLCN) criteria (score ≥ 6), a causative mutation was identified in 116 (64%). Of these, 94 (81%) were detected by genotyping. Ten mutations accounted for more than 50% of the positive cases, with APOB c.10580G>A being the most common. Mutations in LDLR predominated, with (c.2311+1_2312-1)(2514)del (FH Helsinki) and c.259T>G having the highest frequency. Two novel LDLR mutations were identified. In patients with DLCN score < 6, mutation detection rate was significantly higher at younger age.
A limited number of mutations explain a major fraction of FH cases in Sweden. Combination of selective genotyping and NGS facilitates the clinical challenge of cost-effective genetic screening in suspected FH. The frequency of APOB c.10580G>A was higher than previously reported in Sweden. The lack of demonstrable mutations in the LDLR, APOB and PCSK9 genes in ~1/3 of patients with probable FH strongly suggests that additional genetic mechanisms are to be found in phenotypic FH.
研究基因分型是否可以作为一种具有成本效益的筛选步骤，在瑞典患者家族性高胆固醇血症（FH）的分子诊断中，在下一代测序（NGS）之前进行。
对 300 名具有杂合子 FH 临床怀疑的瑞典裔患者进行分析，使用了一种特殊的基因分型面板，其中嵌入了 LDLR、APOB 和 PCSK9 基因中的 112 种 FH 致病突变。这些突变是从斯堪的纳维亚和芬兰的 FH 患者的先前报告中选择的。突变阴性病例进一步通过 NGS 进行分析。在 181 名使用荷兰脂质诊所网络（DLCN）标准（评分≥6）的可能或明确 FH 患者中，在 116 名（64%）患者中鉴定出了致病突变。其中，94 名（81%）通过基因分型检测到。有 10 种突变占阳性病例的 50%以上，最常见的是 APOB c.10580G>A。LDLR 突变占主导地位，（c.2311+1_2312-1）（2514）del（FH Helsinki）和 c.259T>G 频率最高。发现了两种新的 LDLR 突变。在 DLCN 评分<6 的患者中，突变检测率在较年轻的年龄明显更高。
少数突变解释了瑞典 FH 病例的主要部分。选择性基因分型和 NGS 的结合有助于在疑似 FH 中进行具有成本效益的遗传筛查的临床挑战。APOB c.10580G>A 的频率高于瑞典先前报道的频率。约 1/3 的可能 FH 患者的 LDLR、APOB 和 PCSK9 基因中未发现可证明的突变，强烈表明表型 FH 中存在其他遗传机制。
