Non-canonical splice variants in thoracic aortic dissection cases and Marfan syndrome with negative genetic testing.

IF 4.7 2区医学 Q1 GENETICS & HEREDITY

NPJ Genomic Medicine Pub Date : 2025-03-21 DOI:10.1038/s41525-025-00472-w

David R Murdock, Dong-Chuan Guo, John S DePaolo, Ulrike Schwarze, Xue-Yan Duan, Alana C Cecchi, Isabella C Marin, YingYing Tang, Jessica X Chong, Michael J Bamshad, Kathleen A Leppig, Peter H Byers, Scott M Damrauer, Dianna M Milewicz

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引用次数: 0

Abstract

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.

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胸主动脉夹层病例和马凡综合征中的非典型剪接变体，基因检测结果呈阴性。

患有遗传性胸主动脉疾病（HTAD）的人面临着致命的主动脉夹层的高风险，但基因检测只能在少数病例中确定致病变体。我们利用 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 例早发散发性主动脉夹层病例和 437 例通过外显子组测序的 HTAD 疑似病例、57 例通过全基因组测序的 HTAD pedigrees，以及通过临床面板测试的部分散发性病例。在FBN1、SMAD3和COL3A1等HTAD综合征基因中发现了NCVAS，包括两个马凡综合征（MFS）家族中FBN1的内含子变异。宾夕法尼亚医学生物库和英国生物库的验证结果表明，NCVAS富集在HTAD相关基因中。这些研究结果表明，NCVAS是导致TAD的一个未被充分认识的因素，尤其是在散发性解剖和未解决的MFS病例中，这凸显了先进的剪接预测工具在基因诊断中的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.40

自引率

1.90%

发文量

审稿时长

17 weeks

期刊介绍： npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.