Skip to main content
SpringerLink
Log in

Postmortem genetic testing should be recommended in sudden cardiac death cases due to thoracic aortic dissection

  • Original Article
  • Published:
International Journal of Legal Medicine Aims and scope Submit manuscript

Abstract

Background

Acute thoracic aortic dissections and ruptures, the main life-threatening complications of the corresponding aneurysms, are an important cause of sudden cardiac death. Despite the usefulness of the molecular diagnosis of these conditions in the clinical setting, the corresponding forensic field remains largely unexplored. The main goal of this study was to explore and validate a new massive parallel sequencing candidate gene​ assay as a diagnostic tool for acute thoracic aortic dissection autopsy cases.

Materials and methods

Massive parallel sequencing of 22 thoracic aortic disease candidate genes performed in 17 cases of thoracic aortic dissection using AmpliSeq and Ion Proton technologies. Genetic variants were filtered by location, type, and frequency at the Exome Aggregation Consortium and an internal database and further classified based on the American College of Medical Genetics and Genomics (ACMG) recommendations published in 2015. All prioritized results were confirmed by traditional sequencing.

Results

From the total of 10 potentially pathogenic genetic variants identified in 7 out of the 17 initial samples, 2 of them were further classified as pathogenic, 2 as likely pathogenic, 1 as possibly benign, and the remaining 5 as variants of uncertain significance, reaching a molecular autopsy yield of 23%, approximately.

Conclusions

This massive parallel sequencing candidate gene approach proved useful for the molecular autopsy of aortic dissection sudden cardiac death cases and should therefore be progressively incorporated into the forensic field, being especially beneficial for the anticipated diagnosis and risk stratification of any other family member at risk of developing the same condition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Montagnana M, Lippi G, Franchini M, Banfi G, Guidi G (2008) Sudden cardiac death in young athletes. Intern Med 47(15):1373–1378

    Article  PubMed  Google Scholar 

  2. Ripperger T, Tröger H, Schmidtke J (2009) The genetic message of a sudden, unexpected death due to thoracic aortic dissection. Forensic Sci Int 187(1–3):1–5. doi:10.1016/j.forsciint.2009.01.020

    Article  PubMed  Google Scholar 

  3. Kuzmik G, Sang A, Elefteriades J (2012) Natural history of thoracic aortic aneurysms. J Vasc Surg 56(2):565–571. doi:10.1016/j.jvs.2012.04.053

    Article  PubMed  Google Scholar 

  4. Prakash S, Kuang S, Investigators GTACR, Regalado E, Guo D, Milewicz D (2016) Recurrent rare genomic copy number variants and bicuspid aortic valve are enriched in early onset thoracic aortic aneurysms and dissections. PLoS One 11(4):e0153543. doi:10.1371/journal.pone.0153543

    Article  PubMed  PubMed Central  Google Scholar 

  5. Elefteriades J (2008) Thoracic aortic aneurysm: reading the enemy’s playbook. Yale J Biol Med 81(4):175–186

    PubMed  PubMed Central  Google Scholar 

  6. Pannu H, Tran-Fadulu V, Milewicz D (2005) Genetic basis of thoracic aortic aneurysms and aortic dissections. Am Mournal Med Genet Part C 139C(1):10–16. doi:10.1002/ajmg.c.30069

    Article  CAS  Google Scholar 

  7. Erbel R, Aboyans V, Boileau C, Bossone E, Di Bartolomeo R, Eggebrecht H et al (2014) ESC guidelines on the diagnosis and treatment of aortic diseases. Eur Heart J 35(41):2873–2926. doi:10.1093/eurheartj/ehu281

    Article  PubMed  Google Scholar 

  8. Milewicz DM, Guo D-C, Tran-Fadulu V, Lafont AL, Papke CL, Inamoto S et al (2008) Genetic basis of thoracic aortic aneurysms and dissections: focus on smooth muscle cell contractile dysfunction. Annu Rev Genomics Hum Genet 9:283–302. doi:10.1146/annurev.genom.8.080706.092303

    Article  CAS  PubMed  Google Scholar 

  9. Cannon Albright L, Camp N, Farnham J, MacDonald J, Abtin K, Rowe KG (2003) A genealogical assessment of heritable predisposition to aneurysms. J Neurosurg 99(4):637–643. doi:10.3171/jns.2003.99.4.0637

    Article  PubMed  Google Scholar 

  10. Isselbacher E (2005) Thoracic and abdominal aortic aneurysms. Circulation 111(6):816–828. doi:10.1161/01.CIR.0000154569.08857.7A

    Article  PubMed  Google Scholar 

  11. Li Y, Li L, Mu H, Fan S, He F, Wang Z (2015) Aortic dissection and sudden unexpected deaths: a retrospective study of 31 forensic autopsy cases. J Forensic Sci 60(5):1206–1211. doi:10.1111/1556-4029.12768

    Article  PubMed  Google Scholar 

  12. Bisleri G, Bagozzi L, Muneretto C (2013) Current evidence and insights about genetics in thoracic aorta disease. Sci World J 2013:e962097. doi:10.1155/2013/962097

    Article  Google Scholar 

  13. Coady MA, Davies RR, Roberts M, Goldstein LJ, Rogalski MJ, Rizzo JA et al (1999) Familial patterns of thoracic aortic aneurysms. Arch Surg 134(4):361–367

    Article  CAS  PubMed  Google Scholar 

  14. Poninska J, Bilinska Z, Franaszczyk M, Michalak E, Rydzanicz M, Szpakowski E et al (2016) Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations. J Transl Med 14(1):115. doi:10.1186/s12967-016-0870-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gillis E, Van Laer L, Loeys B (2013) Genetics of thoracic aortic aneurysm: at the crossroad of transforming growth factor-β signaling and vascular smooth muscle cell contractility. Circ Res 113(3):327–340. doi:10.1161/CIRCRESAHA.113.300675

    Article  CAS  PubMed  Google Scholar 

  16. Bowdin S, Laberge A, Verstraeten A, Loeys B (2016) Genetic testing in thoracic aortic disease-when, why, and how? Can J Cardiol 32(1):131–134. doi:10.1016/j.cjca.2015.09.018

    Article  PubMed  Google Scholar 

  17. Campens L, Renard M, Callewaert B, Coucke P, De Backer J, De Paepe A (2013) New insights into the molecular diagnosis and management of heritable thoracic aortic aneurysms and dissections. Pol Arch Med Wewn 123(12):693–700

    PubMed  Google Scholar 

  18. Hannuksela M, Stattin E, Nyberg P, Carlberg B (2014) Familial thoracic aortic aneurysms and dissections can be divided into three different main categories. Lakartidningen 111(9–10):399–403

    PubMed  Google Scholar 

  19. Saratzis A, Bown M (2014) The genetic basis for aortic aneurysmal disease. Heart 100(12):916–922. doi:10.1136/heartjnl-2013-305130

    Article  CAS  PubMed  Google Scholar 

  20. Halushka M, Angelini A, Bartoloni G, Basso C, Batoroeva L, Bruneval P et al (2016) Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: II. Noninflammatory degenerative diseases—nomenclature and diagnostic criteria. Cardiovasc Pathol 25(3):247–257. doi:10.1016/j.carpath.2016.03.002

    Article  PubMed  Google Scholar 

  21. Hasham S, Lewin M, Tran V, Pannu H, Muilenburg A, Willing M et al (2004) Nonsyndromic genetic predisposition to aortic dissection: a newly recognized, diagnosable, and preventable occurrence in families. Ann Emerg Med 43(1):79–82. doi:10.1016/S0196064403008187

    Article  PubMed  Google Scholar 

  22. Guo D, Hasham S, Kuang S, Vaughan C, Boerwinkle E, Chen H et al (2001) Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13-14. Circulation 103(20):2461–2468

    Article  CAS  PubMed  Google Scholar 

  23. Jondeau G, Boileau C (2012) Genetics of thoracic aortic aneurysms. Curr Atheroscler Rep 14(3):219–226. doi:10.1007/s11883-012-0241-4

    Article  CAS  PubMed  Google Scholar 

  24. Andelfinger G, Loeys B, Dietz H (2016) A decade of discovery in the genetic understanding of thoracic aortic disease. Can J Cardiol 32(1):13–25. doi:10.1016/j.cjca.2015.10.017

    Article  PubMed  Google Scholar 

  25. Wooderchak-Donahue W, Vansant-Webb C, Tvrdik T, Plant P, Lewis T, Stocks J et al (2015) Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. Am J Med Genet Part A 167A(8):1747–1757. doi:10.1002/ajmg.a.37085

    Article  PubMed  Google Scholar 

  26. Braverman AC (2015) Heritable thoracic aortic aneurysm disease. Recognizing phenotypes, exploring genotypes. J Am Coll Cardiol 65(13):1337–1339. doi:10.1016/j.jacc.2014.12.056

    Article  PubMed  Google Scholar 

  27. Arslan-Kirchner M, Arbustini E, Boileau C, Charron P, Child A, Collod-Beroud G et al (2016) Clinical utility gene card for: hereditary thoracic aortic aneurysm and dissection including next-generation sequencing-based approaches. Eur J Hum Genet 24(1):e1–e5. doi:10.1038/ejhg.2015.225

    Article  PubMed  Google Scholar 

  28. Hiratzka L, Bakris G, Beckman J, Bersin R, Carr V, Casey D 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. J Am Coll Cardiol 55(14):e27–129. doi:10.1016/j.jacc.2010.02.015

    Article  PubMed  Google Scholar 

  29. Klintschar M, Bilkenroth U, Arslan-Kirchner M, Schmidtke J, Stiller D (2009) Marfan syndrome: clinical consequences resulting from a medicolegal autopsy of a case of sudden death due to aortic rupture. Int J Legal Med 123(1):55–58. doi:10.1007/s00414-008-0288-5

    Article  CAS  PubMed  Google Scholar 

  30. Proost D, Vandeweyer G, Meester J, Salemink S, Kempers M, Ingram C et al (2015) Performant mutation identification using targeted next-generation sequencing of 14 thoracic aortic aneurysm genes. Hum Mutat 36(8):808–814. doi:10.1002/humu.22802

    Article  CAS  PubMed  Google Scholar 

  31. Hirschhorn JN, Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6(2):95–108. doi:10.1038/nrg1521

    Article  CAS  PubMed  Google Scholar 

  32. Brion M, Sobrino B, Martinez M, Blanco-Verea A, Carracedo A (2015) Massive parallel sequencing applied to the molecular autopsy in sudden cardiac death in the young. Forensic Sci Int Genet 18:160–170. doi:10.1016/j.fsigen.2015.07.010

    Article  CAS  PubMed  Google Scholar 

  33. Yang H, Wang K (2015) Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR. Nat Protoc 10(10):1556–1566. doi:10.1038/nprot.2015.105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Exome Aggregation Consortium (ExAC), available from exac.broadinstitute.org/, and accessed [2016 Oct 10]

  35. Robinson J, Thorvaldsdóttir H, Winckler W, Guttman M, Lander E, Getz G et al (2011) Integrative Genomics Viewer. Nat Biotechnol 29(1):24–26. doi:10.1038/nbt.1754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Thorvaldsdóttir H, Robinson J, Mesirov J (2013) Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform 14(2):178–192. doi:10.1093/bib/bbs017

    Article  PubMed  Google Scholar 

  37. Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA (URL: http://evs.gs.washington.edu/EVS/) [Aug. 2016 accessed].

  38. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291. doi:10.1038/nature19057

  39. Adzhubei I, Schmidt S, Peshkin L, Ramensky V, Gerasimova A, Bork P et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249. doi:10.1038/nmeth0410-248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schwarz J, Cooper D, Shuelke M, Seelow D (2014) MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods 11(4):361–362. doi:10.1038/nmeth.2890

    Article  CAS  PubMed  Google Scholar 

  41. Kumar P, Henikoff S, Ng P (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4(8):1073–1082. doi:10.1038/nprot.2009.86

    Article  CAS  PubMed  Google Scholar 

  42. Kircher M, Witten D, Jain P, O’Roak B, Cooper G, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46(3):310–315. doi:10.1038/ng.2892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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. Genet Med 17(5):405–424. doi:10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  44. Halliday D, Hutchinson S, Lonie L, Hurst J, Firth H, Handford P (2002) Twelve novel FBN1 mutations in Marfan syndrome and Marfan related phenotypes test the feasibility of FBN1 mutation testing in clinical practice. J Med Genet 39(8):589–593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. van de Luijtgaarden K, Heijsman D, Maugeri A, Weiss M, Verhagen H, Ijpma A et al (2015) First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm. Hum Genet 134(8):881–893. doi:10.1007/s00439-015-1567-0

    Article  PubMed  PubMed Central  Google Scholar 

  46. Harakalova M, van der Smagt J, de Kovel C, Van’t Slot R, Poot M, Nijman I et al (2013) Incomplete segregation of MYH11 variants with thoracic aortic aneurysms and dissections and patent ductus arteriosus. Eur J Hum Genet 21(5):487–493. doi:10.1038/ejhg.2012.206

    Article  CAS  PubMed  Google Scholar 

  47. Imai Y, Morita H, Takeda N, Miya F, Hyodo H, Fujita D et al (2015) A deletion mutation in myosin heavy chain 11 causing familial thoracic aortic dissection in two Japanese pedigrees. Int J Cardiol 195:290–292. doi:10.1016/j.ijcard.2015.05.178

    Article  PubMed  Google Scholar 

  48. Meder B, Haas J, Keller A, Heid C, Just S, Borries A et al (2011) Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies. Circ Cardiovasc Genet 4(2):110–122. doi:10.1161/CIRCGENETICS.110.958322

    Article  CAS  PubMed  Google Scholar 

  49. Hertz C, Christiansen S, Ferrero-Miliani L, Fordyce S, Dahl M, Holst A et al (2015) Next-generation sequencing of 34 genes in sudden unexplained death victims in forensics and in patients with channelopathic cardiac diseases. Int J Legal Med 129(4):793–800. doi:10.1007/s00414-014-1105-y

    Article  CAS  PubMed  Google Scholar 

  50. Pua C, Bhalshankar J, Miao K, Walsh R, John S, Lim S et al (2016) Development of a comprehensive sequencing assay for inherited cardiac condition genes. J Cardiovasc Transl Res 9(1):3–11. doi:10.1007/s12265-016-9673-5

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work has been supported by Plan Estatal de I+D+i 2008-2011 and 2013-2016, Subdirección General de Evaluación y Fomento de la Investigación (ISCIII-SGEFI) from Instituto de Salud Carlos III (ISCIII), and Fondo Europeo de Desarrollo Regional (FEDER) [grant numbers PI13/00933, RD12/0042/0037, RD12/0042/0029, and CD13/0005].

Author information

Authors and Affiliations

  1. Xenética de Enfermidades Cardiovasculares e Oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain

    Marina Gago-Díaz, Eva Ramos-Luis, Silvia Zoppis, Alejandro Blanco-Verea & María Brion

  2. Grupo de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela, Universidade de Santiago de Compostela, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain

    Marina Gago-Díaz, Eva Ramos-Luis, Silvia Zoppis, Beatriz Sobrino, Jorge Amigo, Alejandro Blanco-Verea, Ángel Carracedo & María Brion

  3. Laboratorio di Genetica Forense, Sezione di Medicina Legale, Dipartimento S.A.I.M.L.A.L., Università di Roma Sapienza, Rome, Italy

    Silvia Zoppis

  4. Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Valencia, Spain

    Esther Zorio

  5. Servicio de Patología, Instituto de Medicina Legal de Valencia, Valencia, Spain

    Pilar Molina

  6. Instituto de Investigación Sanitaria La Fe, Valencia, Spain

    Aitana Braza-Boïls

  7. Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia

    Juan Giner & Ángel Carracedo

  8. Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Laboratorio 1, Travesía de Choupana S/N, CP: 15706, Santiago de Compostela, Spain

    María Brion

Authors
  1. Marina Gago-Díaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eva Ramos-Luis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia Zoppis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Esther Zorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pilar Molina
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aitana Braza-Boïls
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juan Giner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Beatriz Sobrino
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jorge Amigo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alejandro Blanco-Verea
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ángel Carracedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. María Brion
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to María Brion.

Ethics declarations

All samples were processed and preserved by Biobanco La Fe (PT13/0010/0026), integrated in the Plataforma Nacional de Biobancos, with the approval of the corresponding Scientific and Ethics Committees. Furthermore, the corresponding informed consent, signed by either the individual or legal representative, was approved by Comité Ético de Investigación Clínica de Galicia. All procedures were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

ESM 1

(DOCX 17 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gago-Díaz, M., Ramos-Luis, E., Zoppis, S. et al. Postmortem genetic testing should be recommended in sudden cardiac death cases due to thoracic aortic dissection. Int J Legal Med 131, 1211–1219 (2017). https://doi.org/10.1007/s00414-017-1583-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00414-017-1583-9

Keywords

Search

Navigation