Robarts Research Institute, and Department of Biochemistry, Schulich School of Medicine and Dentistry.
Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
Curr Opin Lipidol. 2019 Apr;30(2):63-70. doi: 10.1097/MOL.0000000000000581.
DNA copy number variations (CNVs) are large-scale mutations that include deletions and duplications larger than 50 bp in size. In the era when single-nucleotide variations were the major focus of genetic technology and research, CNVs were largely overlooked. However, CNVs clearly underlie a substantial proportion of clinical disorders. Here, we update recent progress in identifying CNVs in dyslipidemias.
Until last year, only the LDLR and LPA genes were appreciated as loci within which clinically relevant CNVs contributed to familial hypercholesterolemia and variation in Lp(a) levels, respectively. Since 2017, next-generation sequencing panels have identified pathogenic CNVs in at least five more genes underlying dyslipidemias, including a PCSK9 whole-gene duplication in familial hypercholesterolemia; LPL, GPIHBP1, and APOC2 deletions in hypertriglyceridemia; and ABCA1 deletions in hypoalphalipoproteinemia.
CNVs are an important class of mutation that contribute to the molecular genetic heterogeneity underlying dyslipidemias. Clinical applications of next-generation sequencing technologies need to consider CNVs concurrently with familiar small-scale genetic variation, given the likely implications for improved diagnosis and treatment.
DNA 拷贝数变异（CNVs）是一种大规模的突变，包括 50bp 以上的缺失和重复。在单核苷酸变异成为遗传技术和研究主要关注点的时代，CNVs 在很大程度上被忽视了。然而，CNVs 显然是许多临床疾病的基础。在这里，我们更新了在血脂异常中识别 CNVs 的最新进展。
直到去年，人们才认识到 LDLR 和 LPA 基因是导致家族性高胆固醇血症和 Lp(a)水平变化的具有临床意义的 CNVs 所在的基因座。自 2017 年以来，下一代测序技术已在至少五个导致血脂异常的基因中发现了致病性 CNVs，包括家族性高胆固醇血症中 PCSK9 全基因重复；高甘油三酯血症中的 LPL、GPIHBP1 和 APOC2 缺失；以及低α脂蛋白血症中的 ABCA1 缺失。
CNVs 是导致血脂异常分子遗传异质性的重要突变类型。鉴于其对改善诊断和治疗的可能影响，下一代测序技术的临床应用需要同时考虑 CNVs 和熟悉的小规模遗传变异。
