Non-canonical splice variants in thoracic aortic dissection cases and Marfan syndrome with negative genetic testing
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) usin...
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Nature Portfolio
2025-03-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-025-00472-w |
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| author | 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 |
| author_facet | 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 |
| author_sort | David R. Murdock |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4afefe527bb44a42bf708c4df94b991b |
| institution | Kabale University |
| issn | 2056-7944 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Genomic Medicine |
| spelling | doaj-art-4afefe527bb44a42bf708c4df94b991b2025-08-20T03:41:50ZengNature Portfolionpj Genomic Medicine2056-79442025-03-011011910.1038/s41525-025-00472-wNon-canonical splice variants in thoracic aortic dissection cases and Marfan syndrome with negative genetic testingDavid R. Murdock0Dong-chuan Guo1John S. DePaolo2Ulrike Schwarze3Xue-yan Duan4Alana C. Cecchi5Isabella C. Marin6YingYing Tang7Jessica X. Chong8Michael J. Bamshad9Kathleen A. Leppig10Peter H. Byers11Scott M. Damrauer12Dianna M. Milewicz13Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth)Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth)Department of Surgery, University of Pennsylvania Perelman School of MedicineDepartment of Laboratory Medicine and Pathology, University of WashingtonDepartment of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth)Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth)Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth)Molecular Genetics Laboratory, New York City Office of Chief Medical ExaminerDivision of Genetic Medicine, Department of Pediatrics, University of WashingtonDivision of Genetic Medicine, Department of Pediatrics, University of WashingtonDivision of Medical Genetics, Department of Medicine, University of WashingtonDepartment of Laboratory Medicine and Pathology, University of WashingtonDepartment of Surgery, University of Pennsylvania Perelman School of MedicineDepartment of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth)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.https://doi.org/10.1038/s41525-025-00472-w |
| spellingShingle | 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 Non-canonical splice variants in thoracic aortic dissection cases and Marfan syndrome with negative genetic testing npj Genomic Medicine |
| title | Non-canonical splice variants in thoracic aortic dissection cases and Marfan syndrome with negative genetic testing |
| title_full | Non-canonical splice variants in thoracic aortic dissection cases and Marfan syndrome with negative genetic testing |
| title_fullStr | Non-canonical splice variants in thoracic aortic dissection cases and Marfan syndrome with negative genetic testing |
| title_full_unstemmed | Non-canonical splice variants in thoracic aortic dissection cases and Marfan syndrome with negative genetic testing |
| title_short | Non-canonical splice variants in thoracic aortic dissection cases and Marfan syndrome with negative genetic testing |
| title_sort | non canonical splice variants in thoracic aortic dissection cases and marfan syndrome with negative genetic testing |
| url | https://doi.org/10.1038/s41525-025-00472-w |
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