Soukarieh Omar, Meguerditchian Caroline, Proust Carole, Aïssi Dylan, Eyries Mélanie, Goyenvalle Aurélie, Trégouët David-Alexandre
INSERM, Bordeaux Population Health, U1219, Molecular Epidemiology of Vascular and Brain Disorders, University of Bordeaux, Bordeaux, France.
Department of Genetics, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France.
Front Cardiovasc Med. 2022 Mar 21;9:841032. doi: 10.3389/fcvm.2022.841032. eCollection 2022.
High-throughput sequencing (HTS) technologies are revolutionizing the research and molecular diagnosis landscape by allowing the exploration of millions of nucleotide sequences at an unprecedented scale. These technologies are of particular interest in the identification of genetic variations contributing to the risk of rare (Mendelian) and common (multifactorial) human diseases. So far, they have led to numerous successes in identifying rare disease-causing mutations in coding regions, but few in non-coding regions that include introns, untranslated (UTR), and intergenic regions. One class of neglected non-coding variations is that of 5'UTR variants that alter upstream open reading frames (upORFs) of the coding sequence (CDS) of a natural protein coding transcript. Following a brief summary of the molecular bases of the origin and functions of upORFs, we will first review known 5'UTR variations altering upORFs and causing rare cardiovascular disorders (CVDs). We will then investigate whether upORF-affecting single nucleotide polymorphisms could be good candidates for explaining association signals detected in the context of genome-wide association studies for common complex CVDs.
高通量测序（HTS）技术正在彻底改变研究和分子诊断领域，它能以前所未有的规模对数百万个核苷酸序列进行探索。这些技术在识别导致罕见（孟德尔式）和常见（多因素）人类疾病风险的遗传变异方面尤为重要。到目前为止，它们在识别编码区导致罕见疾病的突变方面取得了众多成功，但在包括内含子、非翻译区（UTR）和基因间区域在内的非编码区却鲜有成效。一类被忽视的非编码变异是5'UTR变体，它会改变天然蛋白质编码转录本编码序列（CDS）的上游开放阅读框（upORF）。在简要总结upORF的起源和功能的分子基础之后，我们将首先回顾已知的改变upORF并导致罕见心血管疾病（CVD）的5'UTR变异。然后，我们将研究影响upORF的单核苷酸多态性是否可能是解释在常见复杂CVD的全基因组关联研究中检测到的关联信号的良好候选因素。
