BACKGROUND In 2013, our laboratory designed a targeted sequencing panel, "LipidSeq", to study the genetic determinants of dyslipidemia and metabolic disorders. Over the last 6 years, we have analyzed 3262 patient samples obtained from our own Lipid Genetics Clinic and international colleagues. Here, we highlight our findings and discuss research benefits and clinical implications of our panel. METHODS LipidSeq targets 69 genes and 185 single-nucleotide polymorphisms (SNPs) either causally related or associated with dyslipidemia and metabolic disorders. This design allows us to simultaneously evaluate monogenic-caused by rare single-nucleotide variants (SNVs) or copy-number variants (CNVs)-and polygenic forms of dyslipidemia. Polygenic determinants were assessed using three polygenic scores, one each for low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol. RESULTS Among 3262 patient samples evaluated, the majority had hypertriglyceridemia (40.1%) and familial hypercholesterolemia (28.3%). Across all samples, we identified 24,931 unique SNVs, including 2205 rare variants predicted disruptive to protein function, and 77 unique CNVs. Considering our own 1466 clinic patients, LipidSeq results have helped in diagnosis and improving treatment options. CONCLUSIONS Our LipidSeq design based on ontology of lipid disorders has enabled robust detection of variants underlying monogenic and polygenic dyslipidemias. In more than 50 publications related to LipidSeq, we have described novel variants, the polygenic nature of many dyslipidemias-some previously thought to be primarily monogenic-and have uncovered novel mechanisms of disease. We further demonstrate several tangible clinical benefits of its use.

中文翻译：

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六年的 LipidSeq 经验：从针对血脂异常的混合靶向测序组中获得的临床和研究经验。


背景2013年，我们实验室设计了靶向测序panel“LipidSeq”，用于研究血脂异常和代谢紊乱的遗传决定因素。在过去 6 年里，我们分析了从我们自己的脂质遗传学诊所和国际同事获得的 3262 份患者样本。在这里，我们重点介绍我们的发现，并讨论我们小组的研究益处和临床意义。方法 LipidSeq 针对与血脂异常和代谢紊乱有因果关系或相关的 69 个基因和 185 个单核苷酸多态性 (SNP)。这种设计使我们能够同时评估由罕见单核苷酸变异（SNV）或拷贝数变异（CNV）引起的单基因和多基因形式的血脂异常。使用三个多基因评分评估多基因决定因素，低密度脂蛋白胆固醇、甘油三酯和高密度脂蛋白胆固醇各一个。结果 在评估的 3262 名患者样本中，大多数患有高甘油三酯血症 (40.1%) 和家族性高胆固醇血症 (28.3%)。在所有样本中，我们鉴定了 24,931 个独特的 SNV，其中包括 2205 个预测会破坏蛋白质功能的罕见变异，以及 77 个独特的 CNV。考虑到我们自己的 1466 名临床患者，LipidSeq 结果有助于诊断和改善治疗方案。结论 我们基于脂质紊乱本体论的 LipidSeq 设计能够可靠地检测单基因和多基因血脂异常的变异。在 50 多篇与 LipidSeq 相关的出版物中，我们描述了新的变异、许多血脂异常的多基因性质（其中一些以前被认为主要是单基因的），并揭示了疾病的新机制。我们进一步证明了其使用的几个切实的临床益处。