Data Sheet 1_Modeling thoracic aortic genetic variants in the zebrafish: useful for predicting clinical pathogenicity?.docx

Thoracic aortic aneurysm and dissection (TAAD) significantly impact cardiovascular morbidity and mortality. A large subset of TAAD cases, particularly those with an earlier onset, is linked to heritable genetic defects. Despite progress in characterizing genes associated with both syndromic and non-syndromic heritable TAAD, the causative gene remains unknown in most cases. Another important bottleneck in the correct and timely diagnosis of TAAD is the large proportion of variants of unknown significance (VUS) that are routinely encountered upon medical genetic testing. Reliable functional modeling data is required to accurately identify new causal genes and to determine the pathogenicity of VUS. To address this gap, our collaborative effort—comprising teams from Yale University, University of Kentucky, and Ghent University—explores a novel approach: modeling TAAD in zebrafish. Leveraging the unique advantages of this animal model promises to allow for accelerated variant pathogenicity assessment, ultimately enhancing patient care. In this review, we critically explore the currently available zebrafish-based approaches that can be used for testing pathogenicity of genes and variants related to TAAD, and we offer an outlook on the implementation of these strategies for clinical applications.

胸主动脉瘤与主动脉夹层（Thoracic aortic aneurysm and dissection, TAAD）对心血管疾病的发病率与死亡率具有显著负面影响。大量胸主动脉瘤与主动脉夹层病例，尤其是发病年龄较早的患者，均与遗传性基因缺陷相关。尽管目前在表征综合征性与非综合征性遗传性TAAD相关基因方面已取得一定进展，但多数病例的致病基因仍未明确。而胸主动脉瘤与主动脉夹层的精准及时诊断面临的另一重要瓶颈，是临床基因检测中频繁检出的大量意义未明变异（variants of unknown significance, VUS）。要精准鉴定新的致病基因并明确意义未明变异的致病性，亟需可靠的功能模型实验数据作为支撑。为填补这一研究空白，由耶鲁大学、肯塔基大学与根特大学研究团队组成的合作课题组，探索了一种全新策略：利用斑马鱼构建胸主动脉瘤与主动脉夹层疾病模型。依托该动物模型的独特优势，有望加速变异致病性评估进程，最终改善患者的诊疗预后。本综述将系统梳理并批判性探讨当前可用于检测TAAD相关基因与变异致病性的斑马鱼模型研究方法，并对这些策略向临床应用转化的前景进行展望。