Department of Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam, The Netherlands (R.H., M.L.H., A.G.d.J., G.K.H.).
Spaarne Gasthuis, Haarlem, The Netherlands (R.H.).
Arterioscler Thromb Vasc Biol. 2021 Feb;41(2):934-943. doi: 10.1161/ATVBAHA.120.314482. Epub 2020 Nov 5.
Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor () mutations account for >90% of cases, apolipoprotein B () mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 () gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays. Approach and Results: Patients with clinically diagnosed FH underwent genetic analysis of , and if negative, sequential testing of and . We analyzed cosegregation of hypercholesterolemia with novel variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; <0.001). In vitro studies demonstrated the pathogenicity of the G516V variant.
In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in . Pathogenicity is established beyond doubt for the G516V variant.
家族性高胆固醇血症（FH）的特征是低密度脂蛋白胆固醇升高，心血管风险显著增加。在有遗传诊断的患者中，低密度脂蛋白受体（LDLR）突变占>90%，载脂蛋白 B（APOB）突变占≈5%，而前蛋白转化酶枯草溶菌素 kexin 9（PCSK9）获得性功能突变则较为罕见（<1%的病例）。我们旨在通过遗传级联筛查和体外功能测定评估 FH 患者队列中几种新型 LDLR 变异的功能影响。
临床诊断为 FH 的患者接受 LDLR 基因分析，如果为阴性，则进行 和 的序贯检测。我们分析了与新型 LDLR 变异相关的高胆固醇血症共分离情况。通过计算机分析确定获得性功能状态，并通过体外功能测定进行验证。在 1055 名临床 FH 患者中，我们在 27 名（2.6%）患者中发现了非同义变异，其中 7 名患者携带了 4 种先前报道的获得性功能变异之一。在其余 20 名 FH 患者中，我们发现了 7 种新型 LDLR 变异。G516V 变异（c.1547G>T）在 5 名索引患者中发现，并通过级联筛查发现了 15 名额外的携带者。与 27 名非携带者相比，这些携带者的低密度脂蛋白胆固醇水平更高（236±73 与 124±35 mg/dL；<0.001）。体外研究表明 G516V 变异具有致病性。
在我们的研究中，1.14%的临床 FH 病例显然归因于 LDLR 中的致病性变异。G516V 变异的致病性无疑已得到确立。
