Clinical Research Unit, Khoo Teck Puat Hospital, 768828, Singapore.
Division of Endocrinology, Khoo Teck Puat Hospital, 768828, Singapore.
Atherosclerosis. 2018 Feb;269:106-116. doi: 10.1016/j.atherosclerosis.2017.12.028. Epub 2017 Dec 27.
Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by the presence of high plasma low density lipoproteins cholesterol (LDL-c). Patients with FH, with mutation detected, are at increased risk of premature cardiovascular disease compared to those without mutations. The aim of the study was to assess the type of mutations in patients, clinically diagnosed with FH in Singapore.
Patients (probands) with untreated/highest on-treatment LDL-c>4.9 mmol/l were recruited (June 2015 to April 2017). Anthropometric, biochemical indices, blood and family history were collected. DNA was extracted and Next Generation Sequencing (NGS) was performed in 26 lipid-related genes, including LDLR, APOB and PCSK9, and validated using Sanger. Multiplex-ligation probe analyses for LDLR were performed to identify large mutation derangements. Based on HGVS nomenclature, LDLR mutations were classified as "Null"(nonsense, frameshift, large rearrangements) and "Defective"(point mutations which are pathogenic).
Ninety-six probands were recruited: mean age: (33.5 ± 13.6) years. 52.1% (n = 50) of patients had LDLR mutations, with 15 novel mutations, and 4.2% (n = 4) had APOB mutations. Total cholesterol (TC) and LDL-c were significantly higher in those with LDLR mutations compared to APOB and no mutations [(8.53 ± 1.52) vs. (6.93 ± 0.47) vs. (7.80 ± 1.32)] mmol/l, p = 0.012 and [(6.74 ± 0.35) vs. (5.29 ± 0.76) vs. (5.98 ± 1.23)] mmol/l, p=0.005, respectively. Patients with "null LDLR" mutations (n = 13) had higher TC and LDL-c than "defective LDLR" mutations (n = 35): [(9.21 ± 1.60) vs. (8.33 ± 1.41)]mmol/l, p = 0.034 and [(7.43 ± 1.47) vs. (6.53 ± 1.21)]mmol/l, p=0.017, respectively.
To our knowledge, this is the first report of mutation detection in patients with clinically suspected FH by NGS in Singapore. While percentage of mutations is similar to other countries, the spectrum locally differs.
家族性高胆固醇血症（FH）是一种常染色体显性遗传疾病，其特征是血浆中低密度脂蛋白胆固醇（LDL-c）水平升高。与无突变的患者相比，携带突变的 FH 患者发生心血管疾病的风险更高。本研究旨在评估在新加坡临床诊断为 FH 的患者的突变类型。
招募未经治疗/最高治疗 LDL-c>4.9mmol/L 的患者（2015 年 6 月至 2017 年 4 月）。收集人体测量、生化指标、血液和家族史。提取 DNA，对 26 个脂质相关基因（包括 LDLR、APOB 和 PCSK9）进行下一代测序（NGS），并使用 Sanger 进行验证。对 LDLR 进行多重连接探针分析，以鉴定大的突变重排。根据 HGVS 命名法，将 LDLR 突变分为“无效”（无义、移码、大重排）和“缺陷”（致病性点突变）。
共招募了 96 名患者：平均年龄（33.5±13.6）岁。52.1%（n=50）的患者存在 LDLR 突变，其中 15 个为新突变，4.2%（n=4）存在 APOB 突变。与 APOB 和无突变相比，LDLR 突变患者的总胆固醇（TC）和 LDL-c 显著升高[(8.53±1.52) vs. (6.93±0.47) vs. (7.80±1.32)]mmol/L，p=0.012 和 [(6.74±0.35) vs. (5.29±0.76) vs. (5.98±1.23)]mmol/L，p=0.005。与“缺陷 LDLR”突变（n=35）相比，“无效 LDLR”突变（n=13）患者的 TC 和 LDL-c 更高：[(9.21±1.60) vs. (8.33±1.41)]mmol/L，p=0.034 和 [(7.43±1.47) vs. (6.53±1.21)]mmol/L，p=0.017。
据我们所知，这是新加坡首次通过 NGS 对临床疑似 FH 患者进行突变检测的报告。虽然突变的百分比与其他国家相似，但当地的突变谱有所不同。
