Murdock David R, Guo Dong-Chuan, DePaolo John S, Schwarze Ulrike, Duan Xue-Yan, Cecchi Alana C, Marin Isabella C, Tang YingYing, Chong Jessica X, Bamshad Michael J, Leppig Kathleen A, Byers Peter H, Damrauer Scott M, Milewicz Dianna M
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA.
Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
NPJ Genom Med. 2025 Mar 21;10(1):25. doi: 10.1038/s41525-025-00472-w.
Individuals with heritable thoracic aortic disease (HTAD) face a high risk of deadly aortic dissections, but genetic testing identifies causative variants in only a minority of cases. We explored the contribution of non-canonical splice variants (NCVAS) to thoracic aortic disease (TAD) using SpliceAI and sequencing data from diverse cohorts, including 551 early-onset sporadic dissection cases and 437 HTAD probands with exome sequencing, 57 HTAD pedigrees with whole genome sequencing, and select sporadic cases with clinical panel testing. NCVAS were identified in syndromic HTAD genes such as FBN1, SMAD3, and COL3A1, including intronic variants in FBN1 in two Marfan syndrome (MFS) families. Validation in the Penn Medicine BioBank and UK Biobank showed enrichment of NCVAS in HTAD-associated genes among dissections. These findings suggest NCVAS are an underrecognized contributor to TAD, particularly in sporadic dissection and unsolved MFS cases, highlighting the potential of advanced splice prediction tools in genetic diagnostics.
患有遗传性胸主动脉疾病（HTAD）的个体面临致命性主动脉夹层的高风险，但基因检测仅在少数病例中识别出致病变异。我们使用SpliceAI和来自不同队列的测序数据，探讨了非典型剪接变异（NCVAS）对胸主动脉疾病（TAD）的影响，这些队列包括551例早发性散发性夹层病例和437例进行外显子组测序的HTAD先证者、57个进行全基因组测序的HTAD家系以及通过临床检测板检测的部分散发性病例。在诸如FBN1、SMAD3和COL3A1等综合征性HTAD基因中鉴定出了NCVAS，包括两个马凡综合征（MFS）家族中FBN1的内含子变异。在宾夕法尼亚大学医学生物银行和英国生物银行中的验证表明，在夹层中HTAD相关基因中NCVAS富集。这些发现表明，NCVAS是TAD中一个未被充分认识的因素，特别是在散发性夹层和未解决的MFS病例中，凸显了先进的剪接预测工具在基因诊断中的潜力。
