Genetic Profile in Patients With Aortic Syndrome

NCT04751058 | Completed DMC

• 1 other identifier: HU Virgen Rocio
• Study Type: observational
• Target: 73
• Locations: 1 country
• Sites: 2

Brief Summary

The overall prevalence has increased significantly in the general population, which may be due in part to advances in diagnostic techniques, such as improved imaging techniques. Aortic dissection (AD) can cause sudden cardiac death (SCD). Approximately 95% of thoracic AAS are clinically "silent" until a life-threatening complication arises in an unpredictable manner and presents as sudden cardiac death. The peak incidence of death caused by aortic dissection occurs within 48 hours, therefore, timely diagnosis is essential and saves lives. We have traditionally associated as risk factors in patients with ASA long-term arterial hypertension, present in 66-75% of cases, smoking, dyslipidemia or atherosclerotic disease. Likewise, any condition that alters the structure of the aorta such as: collagen diseases, aneurysms, bicuspid aorta, and manipulation of the thoracic aorta (cardiac surgery, 18%, or percutaneous intervention that can injure the intima) is involved in ASA. In addition to the well-known hereditary syndromes that affect collagen (Marfan, Elher-Danlos ...) there is a clear familial aggregation: 13-19% of patients without identifiable syndrome have first-degree relatives with thoracic aortic aneurysms or ICD, something that has been called "thoracic aortic dissection and familial aneurysm syndrome." Notable achievements have been made in the discovery of genetic mutations associated with SAA and key regulatory molecules involved, including the extracellular matrix (ECM), cytoskeletal proteins, and the TGF-β signaling pathway. Identification of the causative gene is advantageous for both patients and their families, especially those who do not show symptoms. The specific underlying genotype could benefit the process of diagnosis, surveillance and surgery, with the aim of reducing morbidity and mortality

Conditions

Gene Abnormality; Acute Aortic Syndrome

Outcome Measures

Primary Outcomes (4)

• % of patients with presence of Missense mutations

  massive sequencing

  post-treatment

• % of patients with presence of splicing mutations

  massive sequencing

  post-treatment

• % of patients with presence of frameshift mutations

  massive sequencing

  post-treatment

• % of patients with presence of nonframeshift mutations

  massive sequencing

  post-treatment

Interventions

genetic analysis GENETIC

Intervention details: sampling in peripheral blood for the Methodology: 1. Automatic DNA extraction (ChemagicTM 360) 2. Mass sequencing using SeqCap EZ Choice Library capture technology (NimbleGen) and NextSeq sequencer (Illumina). 3. Bioinformatic analysis:. * Identification of point mutations and small deletions or insertions * Analysis of CNVs using the BEDtools program package * Search of the identified variants in the following public databases: 1000G, dbSNP, ExAC, EVS, GenomADm CSVS and DGV. Those with a MAF\> 1% have been considered benign, in public or private databases of our population. The analysis process has focused exclusively on the genes described to date as associated with the pathology under study and included in the panel used. The reference sequences used for these genes are: determination of possible mutations, nucleotics, etc.

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study includes all patients who are admitted with the diagnosis of Acute Aortic Syndrome verified by imaging techniques (CT Angiography) in the Intensive Care Unit of a tertiary Hospital with a 24-hour Cardiac and Vascular Surgery Service

You may qualify if:

• Patient older than 16 years
• Patients admitted alive with a diagnosis of acute aortic syndrome
• Written consent to be DNA analysis and conservation in the DNA bank

You may not qualify if:

• Refusal to participate in the study and , or analysis of their DNA.
• Without life expectancy and , or Income without life.

Sponsors & Collaborators

• Hospitales Universitarios Virgen del Rocío: lead

Study Sites (2)

Hospital Universitario Virgen del Rocio

Seville, Andalusia, 41012, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, 41012, Spain

Location

Related Publications (22)

• Bravo-Gil N, Gonzalez-Del Pozo M, Martin-Sanchez M, Mendez-Vidal C, Rodriguez-de la Rua E, Borrego S, Antinolo G. Unravelling the genetic basis of simplex Retinitis Pigmentosa cases. Sci Rep. 2017 Feb 3;7:41937. doi: 10.1038/srep41937.

  PMID: 28157192 BACKGROUND

• Lopez-Domingo FJ, Florido JP, Rueda A, Dopazo J, Santoyo-Lopez J. ngsCAT: a tool to assess the efficiency of targeted enrichment sequencing. Bioinformatics. 2014 Jun 15;30(12):1767-8. doi: 10.1093/bioinformatics/btu108. Epub 2014 Feb 26.

  PMID: 24578402 BACKGROUND

• Biddinger A, Rocklin M, Coselli J, Milewicz DM. Familial thoracic aortic dilatations and dissections: a case control study. J Vasc Surg. 1997 Mar;25(3):506-11. doi: 10.1016/s0741-5214(97)70261-1.

  PMID: 9081132 BACKGROUND

• Albornoz G, Coady MA, Roberts M, Davies RR, Tranquilli M, Rizzo JA, Elefteriades JA. Familial thoracic aortic aneurysms and dissections--incidence, modes of inheritance, and phenotypic patterns. Ann Thorac Surg. 2006 Oct;82(4):1400-5. doi: 10.1016/j.athoracsur.2006.04.098.

  PMID: 16996941 BACKGROUND

• Coady MA, Davies RR, Roberts M, Goldstein LJ, Rogalski MJ, Rizzo JA, Hammond GL, Kopf GS, Elefteriades JA. Familial patterns of thoracic aortic aneurysms. Arch Surg. 1999 Apr;134(4):361-7. doi: 10.1001/archsurg.134.4.361.

  PMID: 10199307 BACKGROUND

• Milewicz D, Hostetler E, Wallace S, Mellor-Crummey L, Gong L, Pannu H, Guo DC, Regalado E. Precision medical and surgical management for thoracic aortic aneurysms and acute aortic dissections based on the causative mutant gene. J Cardiovasc Surg (Torino). 2016 Apr;57(2):172-7. Epub 2016 Feb 2.

  PMID: 26837258 BACKGROUND

• Elefteriades JA, Farkas EA. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J Am Coll Cardiol. 2010 Mar 2;55(9):841-57. doi: 10.1016/j.jacc.2009.08.084.

  PMID: 20185035 BACKGROUND

• Milewicz DM, Chen H, Park ES, Petty EM, Zaghi H, Shashidhar G, Willing M, Patel V. Reduced penetrance and variable expressivity of familial thoracic aortic aneurysms/dissections. Am J Cardiol. 1998 Aug 15;82(4):474-9. doi: 10.1016/s0002-9149(98)00364-6.

  PMID: 9723636 BACKGROUND

• Robertson EN, van der Linde D, Sherrah AG, Vallely MP, Wilson M, Bannon PG, Jeremy RW. Familial non-syndromal thoracic aortic aneurysms and dissections - Incidence and family screening outcomes. Int J Cardiol. 2016 Oct 1;220:43-51. doi: 10.1016/j.ijcard.2016.06.086. Epub 2016 Jun 23.

  PMID: 27372041 BACKGROUND

• Renner S, Schuler H, Alawi M, Kolbe V, Rybczynski M, Woitschach R, Sheikhzadeh S, Stark VC, Olfe J, Roser E, Seggewies FS, Mahlmann A, Hempel M, Hartmann MJ, Hillebrand M, Wieczorek D, Volk AE, Kloth K, Koch-Hogrebe M, Abou Jamra R, Mitter D, Altmuller J, Wey-Fabrizius A, Petersen C, Rau I, Borck G, Kubisch C, Mir TS, von Kodolitsch Y, Kutsche K, Rosenberger G. Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients. Genet Med. 2019 Aug;21(8):1832-1841. doi: 10.1038/s41436-019-0435-z. Epub 2019 Jan 24.

  PMID: 30675029 BACKGROUND

• Poninska JK, Bilinska ZT, Franaszczyk M, Michalak E, Rydzanicz M, Szpakowski E, Pollak A, Milanowska B, Truszkowska G, Chmielewski P, Sioma A, Janaszek-Sitkowska H, Klisiewicz A, Michalowska I, Makowiecka-Ciesla M, Kolsut P, Stawinski P, Foss-Nieradko B, Szperl M, Grzybowski J, Hoffman P, Januszewicz A, Kusmierczyk M, Ploski R. Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations. J Transl Med. 2016 May 4;14(1):115. doi: 10.1186/s12967-016-0870-4.

  PMID: 27146836 BACKGROUND

• Proost D, Vandeweyer G, Meester JA, Salemink S, Kempers M, Ingram C, Peeters N, Saenen J, Vrints C, Lacro RV, Roden D, Wuyts W, Dietz HC, Mortier G, Loeys BL, Van Laer L. Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes. Hum Mutat. 2015 Aug;36(8):808-14. doi: 10.1002/humu.22802. Epub 2015 Jun 13.

  PMID: 25907466 BACKGROUND

• Arslan-Kirchner M, Arbustini E, Boileau C, Charron P, Child AH, Collod-Beroud G, De Backer J, De Paepe A, Dierking A, Faivre L, Hoffjan S, Jondeau G, Keyser B, Loeys B, Mayer K, Robinson PN, Schmidtke J. Clinical utility gene card for: Hereditary thoracic aortic aneurysm and dissection including next-generation sequencing-based approaches. Eur J Hum Genet. 2016 Jan;24(1):e1-5. doi: 10.1038/ejhg.2015.225. Epub 2015 Oct 28. No abstract available.

  PMID: 26508578 BACKGROUND

• Renard M, Francis C, Ghosh R, Scott AF, Witmer PD, Ades LC, Andelfinger GU, Arnaud P, Boileau C, Callewaert BL, Guo D, Hanna N, Lindsay ME, Morisaki H, Morisaki T, Pachter N, Robert L, Van Laer L, Dietz HC, Loeys BL, Milewicz DM, De Backer J. Clinical Validity of Genes for Heritable Thoracic Aortic Aneurysm and Dissection. J Am Coll Cardiol. 2018 Aug 7;72(6):605-615. doi: 10.1016/j.jacc.2018.04.089.

  PMID: 30071989 BACKGROUND

• Zheng J, Guo J, Huang L, Wu Q, Yin K, Wang L, Zhang T, Quan L, Zhao Q, Cheng J. Genetic diagnosis of acute aortic dissection in South China Han population using next-generation sequencing. Int J Legal Med. 2018 Sep;132(5):1273-1280. doi: 10.1007/s00414-018-1890-9. Epub 2018 Jul 28.

  PMID: 30056620 BACKGROUND

• Arnaud P, Hanna N, Benarroch L, Aubart M, Bal L, Bouvagnet P, Busa T, Dulac Y, Dupuis-Girod S, Edouard T, Faivre L, Gouya L, Lacombe D, Langeois M, Leheup B, Milleron O, Naudion S, Odent S, Tchitchinadze M, Ropers J, Jondeau G, Boileau C. Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD). Genet Med. 2019 Sep;21(9):2015-2024. doi: 10.1038/s41436-019-0444-y. Epub 2019 Feb 11.

  PMID: 30739908 BACKGROUND

• Clouse WD, Hallett JW Jr, Schaff HV, Spittell PC, Rowland CM, Ilstrup DM, Melton LJ 3rd. Acute aortic dissection: population-based incidence compared with degenerative aortic aneurysm rupture. Mayo Clin Proc. 2004 Feb;79(2):176-80. doi: 10.4065/79.2.176.

  PMID: 14959911 BACKGROUND

• Meszaros I, Morocz J, Szlavi J, Schmidt J, Tornoci L, Nagy L, Szep L. Epidemiology and clinicopathology of aortic dissection. Chest. 2000 May;117(5):1271-8. doi: 10.1378/chest.117.5.1271.

  PMID: 10807810 BACKGROUND

• Kuzmik GA, Sang AX, Elefteriades JA. Natural history of thoracic aortic aneurysms. J Vasc Surg. 2012 Aug;56(2):565-71. doi: 10.1016/j.jvs.2012.04.053.

  PMID: 22840907 BACKGROUND

• Gago-Diaz M, Ramos-Luis E, Zoppis S, Zorio E, Molina P, Braza-Boils A, Giner J, Sobrino B, Amigo J, Blanco-Verea A, Carracedo A, Brion M. Postmortem genetic testing should be recommended in sudden cardiac death cases due to thoracic aortic dissection. Int J Legal Med. 2017 Sep;131(5):1211-1219. doi: 10.1007/s00414-017-1583-9. Epub 2017 Apr 8.

  PMID: 28391405 BACKGROUND

• Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, Evangelista A, Falk V, Frank H, Gaemperli O, Grabenwoger M, Haverich A, Iung B, Manolis AJ, Meijboom F, Nienaber CA, Roffi M, Rousseau H, Sechtem U, Sirnes PA, Allmen RS, Vrints CJ; ESC Committee for Practice Guidelines. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2014 Nov 1;35(41):2873-926. doi: 10.1093/eurheartj/ehu281. Epub 2014 Aug 29. No abstract available.

  PMID: 25173340 BACKGROUND

• Puppo Moreno AM, Bravo-Gil N, Mendez-Vidal C, Adsuar Gomez A, Gomez Ruiz FT, Jimenez De Juan C, Fernandez Garcia RM, Martin Bermudez R, Lopez Sanchez JM, Martin Sastre S, Fernandez Caro M, Gallego P, Borrego S. Genetic profile in patients with complicated acute aortic syndrome: the GEN-AOR study. Rev Esp Cardiol (Engl Ed). 2023 Jun;76(6):434-443. doi: 10.1016/j.rec.2022.10.005. Epub 2022 Oct 25. English, Spanish.

  PMID: 36307044 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

peripheral blood samples

MeSH Terms

Conditions

Acute Aortic Syndrome

Interventions

Genetic Testing

Condition Hierarchy (Ancestors)

Aortic Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Study Officials

• Antonio M Puppo Moreno, MD;PhD

  Andaluz Health Service

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 21, 2020
• First Posted: February 11, 2021
• Study Start: February 27, 2021
• Primary Completion: March 30, 2022
• Study Completion: March 30, 2022
• Last Updated: April 22, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

ES (2)