Department of Internal Medicine, University of Genova, Genova, Italy.
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Atherosclerosis. 2020 Nov;312:72-78. doi: 10.1016/j.atherosclerosis.2020.08.027. Epub 2020 Sep 9.
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma levels of low density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease (ASCVD). HoFH is caused by pathogenic variants in several genes, such as LDLR, APOB and PCSK9, responsible for autosomal dominant hypercholesterolemia (ADH), and LDLRAP1 responsible for autosomal recessive hypercholesterolemia (ARH). Aim of this study was the review of the clinical and molecular features of patients with HoFH identified in Italy from 1989 to 2019.
Data were collected from lipid clinics and laboratories, which had performed molecular diagnosis in suspected HoFH. Clinical data included baseline lipid levels and ASCVD events.
A total of 125 subjects with ADH were identified, of whom 60 were true homozygotes, 58 compound heterozygotes and 7 double heterozygotes for LDLR (likely) pathogenic variants. Compared with compound heterozygotes, true homozygotes showed a more severe lipid phenotype and more ASCVD events. ADH carriers of LDLR negative variants (R-NEG) presented with a more aggressive phenotype, as compared to carriers of LDLR defective variants (R-DEF). Kaplan-Meier analysis showed that the median age of ASCVD event-free survival was 25 years of age in R-NEG as opposed to 50 years of age in R-DEF patients. A total of 66 patients with ARH were also identified, of whom 46 were homozygotes and 20 compound heterozygotes. The phenotypic features of ARH patients were similar to those of R-DEF/ADH patients. Overall, 45% ADH patients and 33% ARH patients did not meet the classic diagnostic criteria for HoFH.
In our cohort, the phenotypic variability of HoFH was dependent on the candidate gene involved and the functional impact of its variants on the LDL receptor pathway.
纯合家族性高胆固醇血症（HoFH）是一种罕见的遗传性疾病，其特征为低密度脂蛋白胆固醇（LDL-C）水平极高，且存在发生早发性动脉粥样硬化性心血管疾病（ASCVD）的高危风险。HoFH 是由 LDLR、APOB 和 PCSK9 等几个基因的致病变异引起的，这些基因导致常染色体显性高胆固醇血症（ADH），而 LDLRAP1 则导致常染色体隐性高胆固醇血症（ARH）。本研究旨在回顾 1989 年至 2019 年期间在意大利发现的 HoFH 患者的临床和分子特征。
从进行 HoFH 疑似分子诊断的脂质诊所和实验室收集数据。临床数据包括基线血脂水平和 ASCVD 事件。
共发现 125 例 ADH 患者，其中 60 例为真性纯合子，58 例为复合杂合子，7 例为 LDLR（可能）致病性变异的双杂合子。与复合杂合子相比，真性纯合子的血脂表型更严重，ASCVD 事件更多。与 LDLR 缺陷变异（R-DEF）携带者相比，LDLR 阴性变异（R-NEG）携带者的表型更具侵袭性。Kaplan-Meier 分析显示，R-NEG 患者无 ASCVD 事件的中位年龄为 25 岁，而 R-DEF 患者为 50 岁。还发现了 66 例 ARH 患者，其中 46 例为纯合子，20 例为复合杂合子。ARH 患者的表型特征与 R-DEF/ADH 患者相似。总体而言，45%的 ADH 患者和 33%的 ARH 患者不符合 HoFH 的经典诊断标准。
在本队列中，HoFH 的表型变异性取决于所涉及的候选基因及其变异对 LDL 受体途径的功能影响。
