Top

Journal of Cardiovascular Translational Research

Published in:

01-08-2017 | Original Article

Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity

Authors: Benjamin J. Landis, Jeffrey A. Schubert, Dongbing Lai, Anil G. Jegga, Amy R. Shikany, Tatiana Foroud, Stephanie M. Ware, Robert B. Hinton

Published in: Journal of Cardiovascular Translational Research | Issue 4/2017

Abstract

Thoracic aortic aneurysm (TAA) is a genetic disease predisposing to aortic dissection. It is important to identify the genetic modifiers controlling penetrance and expressivity to improve clinical prognostication. Exome sequencing was performed in 27 subjects with syndromic or familial TAA presenting with extreme phenotypes (15 with severe TAA; 12 with mild or absent TAA). Family-based analysis of a subset of the cohort identified variants, genes, and pathways segregating with TAA severity among three families. A rare missense variant in ADCK4 (p.Arg63Trp) segregated with mild TAA in each family. Genes and pathways identified in families were further investigated in the entire cohort using the optimal unified sequence kernel association test, finding significance for the gene COL15A1 (p = 0.025) and the retina homeostasis pathway (p = 0.035). Thus, we identified candidate genetic modifiers of TAA severity by exome-based study of extreme phenotypes, which may lead to improved risk stratification and development of new medical therapies.

Available only for authorised users

Kochanek, K. D., Murphy, S. L., & Xu, J. (2015). Deaths: final data for 2011. National Vital Statistics Reports, 63(3), 1–120.

Hiratzka, L. F., Bakris, G. L., Beckman, J. A., Bersin, R. M., Carr, V. F., Casey Jr., D. E., et al. (2010). 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation, 121(13), e266–e369. doi:10.1161/CIR.0b013e3181d4739e.CrossRefPubMed

Pape, L. A., Tsai, T. T., Isselbacher, E. M., Oh, J. K., O’Gara, P. T., Evangelista, A., et al. (2007). Aortic diameter >or = 5.5 cm is not a good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). Circulation, 116(10), 1120–1127. doi:10.1161/circulationaha.107.702720.CrossRefPubMed

Dietz, H. C., Cutting, G. R., Pyeritz, R. E., Maslen, C. L., Sakai, L. Y., Corson, G. M., et al. (1991). Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature, 352(6333), 337–339. doi:10.1038/352337a0.CrossRefPubMed

Loeys, B. L., Schwarze, U., Holm, T., Callewaert, B. L., Thomas, G. H., Pannu, H., et al. (2006). Aneurysm syndromes caused by mutations in the TGF-beta receptor. The New England Journal of Medicine, 355(8), 788–798. doi:10.1056/NEJMoa055695.CrossRefPubMed

Superti-Furga, A., Steinmann, B., Ramirez, F., & Byers, P. H. (1989). Molecular defects of type III procollagen in Ehlers-Danlos syndrome type IV. Human Genetics, 82(2), 104–108.CrossRefPubMed

Milewicz, D. M., Trybus, K. M., Guo, D. C., Sweeney, H. L., Regalado, E., Kamm, K., et al. (2017). Altered smooth muscle cell force generation as a driver of thoracic aortic aneurysms and dissections. Arteriosclerosis, Thrombosis, and Vascular Biology, 37(1), 26–34. doi:10.1161/atvbaha.116.303229.CrossRefPubMed

Faivre, L., Collod-Beroud, G., Loeys, B. L., Child, A., Binquet, C., Gautier, E., et al. (2007). Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. American Journal of Human Genetics, 81(3), 454–466. doi:10.1086/520125.CrossRefPubMedPubMedCentral

Milewicz, D. M., & Regalado, E. S. (2015). Use of genetics for personalized management of heritable thoracic aortic disease: how do we get there? The Journal of Thoracic and Cardiovascular Surgery, 149(2 Suppl), S3–S5. doi:10.1016/j.jtcvs.2014.07.070.CrossRefPubMed

10.

Landis, B. J., Ware, S. M., James, J., Shikany, A. R., Martin, L. J., & Hinton, R. B. (2015). Clinical stratification of pediatric patients with idiopathic thoracic aortic aneurysm. The Journal of Pediatrics, 167(1), 131–137.e131-135. doi:10.1016/j.jpeds.2015.02.042.CrossRefPubMed

11.

Colan, S. D., McElhinney, D. B., Crawford, E. C., Keane, J. F., & Lock, J. E. (2006). Validation and re-evaluation of a discriminant model predicting anatomic suitability for biventricular repair in neonates with aortic stenosis. Journal of the American College of Cardiology, 47(9), 1858–1865. doi:10.1016/j.jacc.2006.02.020.CrossRefPubMed

12.

Lopez, L., Colan, S. D., Frommelt, P. C., Ensing, G. J., Kendall, K., Younoszai, A. K., et al. (2010). Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. Journal of the American Society of Echocardiography, 23(5), 465–495; quiz 576-467. doi:10.1016/j.echo.2010.03.019.CrossRefPubMed

13.

Chen, J., Bardes, E. E., Aronow, B. J., & Jegga, A. G. (2009). ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Research, 37(Web Server issue), W305–W311. doi:10.1093/nar/gkp427.CrossRefPubMedPubMedCentral

14.

Lee, S., Emond, M. J., Bamshad, M. J., Barnes, K. C., Rieder, M. J., Nickerson, D. A., et al. (2012). Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. American Journal of Human Genetics, 91(2), 224–237. doi:10.1016/j.ajhg.2012.06.007.CrossRefPubMedPubMedCentral

15.

Farlow, J. L., Robak, L. A., Hetrick, K., Bowling, K., Boerwinkle, E., Coban-Akdemir, Z. H., et al. (2016). Whole-exome sequencing in familial Parkinson disease. JAMA Neurology, 73(1), 68–75. doi:10.1001/jamaneurol.2015.3266.CrossRefPubMedPubMedCentral

16.

Loeys, B. L., Dietz, H. C., Braverman, A. C., Callewaert, B. L., De Backer, J., Devereux, R. B., et al. (2010). The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics, 47(7), 476–485. doi:10.1136/jmg.2009.072785.CrossRefPubMed

17.

Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., 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. Genetics in Medicine, 17(5), 405–424. doi:10.1038/gim.2015.30.CrossRefPubMedPubMedCentral

18.

Schubert, J. A., Landis, B. J., Shikany, A. R., Hinton, R. B., & Ware, S. M. (2016). Clinically relevant variants identified in thoracic aortic aneurysm patients by research exome sequencing. American Journal of Medical Genetics. Part A, 170(5), 1288–1294. doi:10.1002/ajmg.a.37568.CrossRef

19.

Halme, T., Savunen, T., Aho, H., Vihersaari, T., & Penttinen, R. (1985). Elastin and collagen in the aortic wall: changes in the Marfan syndrome and annuloaortic ectasia. Experimental and Molecular Pathology, 43(1), 1–12.CrossRefPubMed

20.

Wang, X., LeMaire, S. A., Chen, L., Shen, Y. H., Gan, Y., Bartsch, H., et al. (2006). Increased collagen deposition and elevated expression of connective tissue growth factor in human thoracic aortic dissection. Circulation, 114(1 Suppl), I200–I205. doi:10.1161/circulationaha.105.000240.PubMedPubMedCentral

21.

Maleszewski, J. J., Miller, D. V., Lu, J., Dietz, H. C., & Halushka, M. K. (2009). Histopathologic findings in ascending aortas from individuals with Loeys-Dietz syndrome (LDS). The American Journal of Surgical Pathology, 33(2), 194–201. doi:10.1097/PAS.0b013e31817f3661.CrossRefPubMed

22.

Marneros, A. G., & Olsen, B. R. (2001). The role of collagen-derived proteolytic fragments in angiogenesis. Matrix Biology, 20(5–6), 337–345.CrossRefPubMed

23.

Ware, S. M., Shikany, A., Landis, B. J., James, J. F., & Hinton, R. B. (2014). Twins with progressive thoracic aortic aneurysm, recurrent dissection and ACTA2 mutation. Pediatrics, 134(4), e1218–e1223. doi:10.1542/peds.2013-2503.CrossRefPubMed

24.

Korkmaz, E., Lipska-Zietkiewicz, B. S., Boyer, O., Gribouval, O., Fourrage, C., Tabatabaei, M., et al. (2016). ADCK4-associated glomerulopathy causes adolescence-onset FSGS. Journal of the American Society of Nephrology, 27(1), 63–68. doi:10.1681/asn.2014121240.CrossRefPubMed

25.

Duvvari, M. R., van de Ven, J. P., Geerlings, M. J., Saksens, N. T., Bakker, B., Henkes, A., et al. (2016). Whole exome sequencing in patients with the cuticular drusen subtype of age-related macular degeneration. PloS One, 11(3), e0152047. doi:10.1371/journal.pone.0152047.CrossRefPubMedPubMedCentral

26.

Brunetti-Pierri, N., Pignatelli, R., Fouladi, N., Towbin, J. A., Belmont, J. W., Craigen, W. J., et al. (2011). Dilation of the aortic root in mitochondrial disease patients. Molecular Genetics and Metabolism, 103(2), 167–170. doi:10.1016/j.ymgme.2011.02.007.CrossRefPubMed

27.

Emrich, F. C., Okamura, H., Dalal, A. R., Penov, K., Merk, D. R., Raaz, U., et al. (2015). Enhanced caspase activity contributes to aortic wall remodeling and early aneurysm development in a murine model of Marfan syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology, 35(1), 146–154. doi:10.1161/atvbaha.114.304364.CrossRefPubMed

28.

Kuang, S. Q., Medina-Martinez, O., Guo, D. C., Gong, L., Regalado, E. S., Reynolds, C. L., et al. (2016). FOXE3 mutations predispose to thoracic aortic aneurysms and dissections. The Journal of Clinical Investigation, 126(3), 948–961. doi:10.1172/jci83778.CrossRefPubMedPubMedCentral

29.

Yang, H. H., van Breemen, C., & Chung, A. W. (2010). Vasomotor dysfunction in the thoracic aorta of Marfan syndrome is associated with accumulation of oxidative stress. Vascular Pharmacology, 52(1–2), 37–45. doi:10.1016/j.vph.2009.10.005.CrossRefPubMed

30.

Branchetti, E., Poggio, P., Sainger, R., Shang, E., Grau, J. B., Jackson, B. M., et al. (2013). Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm. Cardiovascular Research, 100(2), 316–324. doi:10.1093/cvr/cvt205.CrossRefPubMedPubMedCentral

31.

Lee, Y. C., Huang, H. Y., Chang, C. J., Cheng, C. H., & Chen, Y. T. (2010). Mitochondrial GLUT10 facilitates dehydroascorbic acid import and protects cells against oxidative stress: mechanistic insight into arterial tortuosity syndrome. Human Molecular Genetics, 19(19), 3721–3733. doi:10.1093/hmg/ddq286.CrossRefPubMed

32.

Ashraf, S., Gee, H. Y., Woerner, S., Xie, L. X., Vega-Warner, V., Lovric, S., et al. (2013). ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. The Journal of Clinical Investigation, 123(12), 5179–5189. doi:10.1172/jci69000.CrossRefPubMedPubMedCentral

33.

Harper, A. R., Nayee, S., & Topol, E. J. (2015). Protective alleles and modifier variants in human health and disease. Nature Reviews. Genetics, 16(12), 689–701. doi:10.1038/nrg4017.CrossRefPubMed

34.

Zilberberg, L., Phoon, C. K., Robertson, I., Dabovic, B., Ramirez, F., & Rifkin, D. B. (2015). Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome. Proceedings of the National Academy of Sciences of the United States of America, 112(45), 14012–14017. doi:10.1073/pnas.1507652112.CrossRefPubMedPubMedCentral

35.

Miles, L. A., Garippa, R. J., & Poirier, J. T. (2016). Design, execution, and analysis of pooled in vitro CRISPR/Cas9 screens. The FEBS Journal, 283(17), 3170–3180. doi:10.1111/febs.13770.CrossRefPubMed

Title: Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity
Authors: Benjamin J. Landis
Jeffrey A. Schubert
Dongbing Lai
Anil G. Jegga
Amy R. Shikany
Tatiana Foroud
Stephanie M. Ware
Robert B. Hinton
Publication date: 01-08-2017
Publisher: Springer US
Published in: Journal of Cardiovascular Translational Research / Issue 4/2017
Print ISSN: 1937-5387
Electronic ISSN: 1937-5395
DOI: https://doi.org/10.1007/s12265-017-9753-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2017

Development and Characterization of a Porcine Mitral Valve Scaffold for Tissue Engineering

Disaggregation Following Agonist-Induced Platelet Activation in Patients on Dual Antiplatelet Therapy

Thoracic Aneurysms and Dissections: Towards a Further and Better Knowledge

The Notch Ligands DLL1 and Periostin Are Associated with Symptom Severity and Diastolic Function in Dilated Cardiomyopathy

Severity of Hypertension Correlates with Risk of Thromboembolic Stroke

Erratum to: Various Regulatory Modes for Circadian Rhythmicity and Sexual Dimorphism in the Non-Neuronal Cardiac Cholinergic System