A targeted sequencing approach to find novel pathogenic genes associated with sporadic aortic dissection
Aortic dissection (AD) is a heterogeneous genetic disease of the aorta with high mortality and poor prognosis. However, only few genetic causes of AD have been explored till date. After conducting a broad literature review focused on identifying potential pathogenic pathways, we designed a panel containing 152 AD-associated genes to conduct massively parallel targeted next-generation sequencing of 702 sporadic aortic dissection patients and 163 matched healthy controls. After validation by Sanger sequencing, we identified 21 definitely pathogenic and 635 likely pathogenic variants in 61.25% (430/702) of patients. In these patients, 34.88% (150/430) harbored more than one variant that was either definitely or likely to be pathogenic. Among the candidate genes, we identified 546 likely pathogenic variants in 47.72% (335/702) of patients. Importantly, we identified 94 loss-of-function (LOF) variants in 45 genes in AD patients, but only five LOF variants in the controls (P=1.34×10−4). With a burden test, we highlighted RNF213 as an important new gene for AD pathogenesis. We also performed transcriptome sequencing of human aorta tissues to evaluate the expression levels of these newly identified genes. Our study has compiled a comprehensive genetic map of sporadic AD in the Han Chinese population. We believe it will facilitate risk predicting and genetic diagnosis of this severe disease in the future.
Keywordsaortic dissection next-generation sequencing genetic diagnosis
This work was supported by National Natural Science Foundation of China (81700413) and National Key Basic Research Program of China (2012CB518004, 2012CB517801).
- Campens, L., Callewaert, B., Muiño Mosquera, L., Renard, M., Symoens, S., De Paepe, A., Coucke, P., and De Backer, J. (2015). Gene panel sequencing in heritable thoracic aortic disorders and related entities— results of comprehensive testing in a cohort of 264 patients. Orphanet J Rare Dis 10, 9.CrossRefGoogle Scholar
- Hoffjan, S. (2012). Genetic dissection of marfan syndrome and related connective tissue disorders: an update 2012. Mol Syndromol 3, 47–58.Google Scholar
- Khau Van Kien, P., Wolf, J.E., Mathieu, F., Zhu, L., Salve, N., Lalande, A., Bonnet, C., Lesca, G., Plauchu, H., Dellinger, A., et al. (2004). Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity. Eur J Hum Genet 12, 173–180.CrossRefGoogle Scholar
- LeMaire, S.A., McDonald, M.L.N., Guo, D.C., Russell, L., Miller, C.C., Johnson, R.J., Bekheirnia, M.R., Franco, L.M., Nguyen, M., Pyeritz, R. E., et al. (2011). Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1. Nat Genet 43, 996–1000.CrossRefGoogle Scholar
- Milewicz, D., Hostetler, E., Wallace, S., Mellor-Crummey, L., Gong, L., Pannu, H., Guo, D.C., and Regalado, E. (2016). Precision medical and surgical management for thoracic aortic aneurysms and acute aortic dissections based on the causative mutant gene. J Cardiovasc Surg (Torino) 57, 172–177.Google Scholar
- Nitschke, Y., Baujat, G., Botschen, U., Wittkampf, T., Moulin, M., Stella, J., Le Merrer, M., Guest, G., Lambot, K., Tazarourte-Pinturier, M.F., et al. (2012). Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet 90, 25–39.CrossRefGoogle Scholar
- Núñez-Gil, I.J., Bautista, D., Cerrato, E., Salinas, P., Varbella, F., Omedè, P., Ugo, F., Ielasi, A., Giammaria, M., Moreno, R., et al. (2015). Incidence, management, and immediate- and long-term outcomes after iatrogenic aortic dissection during diagnostic or interventional coronary procedures. Circulation 131, 2114–2119.CrossRefGoogle Scholar
- Pomianowski, P., and Elefteriades, J.A. (2013). The genetics and genomics of thoracic aortic disease. Ann Cardiothorac Surg 2, 271–279.Google Scholar
- Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W.W., Hegde, M., Lyon, E., Spector, E., et al. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17, 405–423.CrossRefGoogle Scholar
- Sakai, H., Suzuki, S., Mizuguchi, T., Imoto, K., Yamashita, Y., Doi, H., Kikuchi, M., Tsurusaki, Y., Saitsu, H., Miyake, N., et al. (2012). Rapid detection of gene mutations responsible for non-syndromic aortic aneurysm and dissection using two different methods: resequencing microarray technology and next-generation sequencing. Hum Genet 131, 591–599.CrossRefGoogle Scholar
- Smith, L.B., Hadoke, P.W.F., Dyer, E., Denvir, M.A., Brownstein, D., Miller, E., Nelson, N., Wells, S., Cheeseman, M., and Greenfield, A. (2011). Haploinsufficiency of the murine Col3a1 locus causes aortic dissection: a novel model of the vascular type of Ehlers-Danlos syndrome. Cardiovasc Res 90, 182–190.CrossRefGoogle Scholar
- Zhu, L., Vranckx, R., Khau Van Kien, P., Lalande, A., Boisset, N., Mathieu, F., Wegman, M., Glancy, L., Gasc, J.M., Brunotte, F., et al. (2006). Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet 38, 343–349.CrossRefGoogle Scholar