Guerin Amanda, Iatan Iulia, Ruel Isabelle, Ngufor Linda Fri, Genest Jacques
Research Institute of the McGill University Health Centre (Guerin, Ruel, Fri Ngufor, Genest), Montréal, Que.; Centre for Heart Lung Innovation (Iatan), Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Department of Medicine, University of British Columbia, Vancouver, BC
Research Institute of the McGill University Health Centre (Guerin, Ruel, Fri Ngufor, Genest), Montréal, Que.; Centre for Heart Lung Innovation (Iatan), Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Department of Medicine, University of British Columbia, Vancouver, BC.
CMAJ Open. 2023 Aug 22;11(4):E754-E764. doi: 10.9778/cmajo.20220108. Print 2023 Jul-Aug.
BACKGROUND: Familial hypercholesterolemia (FH) is associated with premature atherosclerotic cardiovascular disease caused by elevated low-density lipoprotein cholesterol (LDL-C) levels. We determined the impact of a full next-generation sequencing (NGS) genetic panel on reclassification of patients with a clinical diagnosis of FH in Quebec compared to the partial genetic panel currently offered by the Quebec Ministère de la Santé et des Services sociaux (Ministry of Health and Social Services) (MSSS), which includes 11 variants that are common in French Canadians. METHODS: We conducted a retrospective cohort study in a subgroup of patients in the Canadian FH Registry seen at the McGill University Health Centre Preventive Cardiology/Lipid Clinic, Montréal, between September 2017 and September 2021 who were clinically diagnosed with severe hypercholesterolemia, probable FH or definite FH according to the Canadian definition of FH. Next-generation sequencing of the , and genes, and multiplex ligation-dependent probe amplification of the gene to detect genetic variants, were performed. RESULTS: Among 335 consecutive patients with heterozygous FH (184 men [54.9%] and 151 women [45.1%]), the baseline LDL-C level was 6.96 (standard deviation 1.79) mmol/L. Patients identified through cascade screening were 11 years younger on average than index patients, and smaller proportions presented to the clinic with cardiovascular risk factors. A pathogenic FH variant was identified in 169 (73.8%) of the 229 patients who underwent genetic testing; the majority had variants in the (146 [86.4%]) or (24 [14.2%]) gene. The genetic panel offered by the MSSS accounted for only 48% of the variants identified with the full NGS panel. Of the 229 patients, 90 (39.3%, 95% confidence interval 32.9%-46.0%) were reclassified from a clinical diagnosis of probable FH to definite FH after genetic screening with a full FH panel. INTERPRETATION: Genetic testing in patients suspected of having FH provided diagnostic certainty and permitted many patients with a clinical diagnosis of probable FH to be reclassified as having definite FH. Genetic screening allows for increased identification of patients with FH and may therefore help reduce the burden of cardiovascular disease and mortality rates among Canadians with FH. ClinicalTrials.gov, no. NCT02009345.
背景：家族性高胆固醇血症（FH）与因低密度脂蛋白胆固醇（LDL-C）水平升高导致的早发性动脉粥样硬化性心血管疾病相关。我们确定了与魁北克省卫生和社会服务部（MSSS）目前提供的部分基因检测板相比，全基因组下一代测序（NGS）基因检测板对魁北克临床诊断为FH的患者重新分类的影响，该部分基因检测板包括在法裔加拿大人中常见的11种变异。 方法：我们对2017年9月至2021年9月期间在蒙特利尔麦吉尔大学健康中心预防心脏病学/脂质诊所就诊的加拿大FH登记处的一组患者进行了回顾性队列研究，这些患者根据加拿大FH定义临床诊断为严重高胆固醇血症、可能的FH或确定的FH。对 、 和 基因进行下一代测序，并对 基因进行多重连接依赖探针扩增以检测基因变异。 结果：在335例连续的杂合子FH患者中（184例男性[54.9%]和151例女性[45.1%]），基线LDL-C水平为6.96（标准差1.79）mmol/L。通过级联筛查确定的患者平均比索引患者年轻11岁，且就诊时伴有心血管危险因素的比例较小。在接受基因检测的229例患者中，169例（73.8%）鉴定出致病性FH变异；大多数患者的 （146例[86.4%]）或 （24例[14.2%]）基因存在变异。MSSS提供的基因检测板仅占全基因组NGS检测板鉴定出的变异的48%。在229例患者中，90例（39.3%，95%置信区间32.9%-46.0%）在使用全FH检测板进行基因筛查后从可能的FH临床诊断重新分类为确定的FH。 解读：对疑似FH患者进行基因检测可提供诊断确定性，并使许多临床诊断为可能FH的患者重新分类为确定的FH。基因筛查有助于增加FH患者的识别，因此可能有助于减轻加拿大FH患者的心血管疾病负担和死亡率。ClinicalTrials.gov，编号NCT02009345。
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