NCT06257004|Unknown
Genome-wide Epistasis for Cardiovascular Severity in Marfan Study
GEMS
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GEMS
Sponsor study identifier
Secondary identifiers
OTHER_GRANT · FWO (Foundation for national research Belgium)
OTHER · Belgian number
observational
200
1 country
1
Study Start
November 30, 2020
Actual (reported)Primary Completion
October 31, 2025
Estimated (date passed)This estimate has passed. The registry has not confirmed an actual date for this milestone.
Study Completion
October 31, 2025
Estimated (date passed)This estimate has passed. The registry has not confirmed an actual date for this milestone.
Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with pleiotropic manifestations in the ocular, skeletal and cardiovascular systems. Morbidity and mortality are mostly determined by aortic root aneurysm dissection and rupture. Although mutations in FBN1, the gene coding for the extracellular matrix protein fibrillin-1, are the well-established genetic cause of this condition, there is a very poor correlation between the nature or location of the causal FBN1 mutation and the phenotypical outcome. Indeed, wide intra- and interfamilial phenotypical variability is observed. So, even with an identical primary mutation in all family members, the clinical spectrum varies widely, from completely asymptomatic to sudden death due to aortic dissection at a young age. The precise mechanisms underlying this variability remain largely elusive. Consequently, a better understanding of the functional effects of the primary mutation is highly needed and the identification of genetic variation that modifies these effects is becoming increasingly important. In this project, we have carefully selected different innovative strategies to discover mother nature's own modifying capabilities with respect to Marfan syndrome aortopathy.
Registry-reported information. Elapsed time and enrollment totals alone do not measure study progress or recruitment pace.
October 31, 2025
Estimated (date passed)This estimate has passed. The registry has not confirmed an actual date for this milestone.
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Dates and qualifiers reported by the registry. Estimated dates do not confirm that a milestone has occurred.
November 30, 2020
Actual (reported)February 5, 2024
Actual (reported)February 13, 2024
Actual (reported)October 31, 2025
Estimated (date passed)This estimate has passed. The registry has not confirmed an actual date for this milestone.
October 31, 2025
Estimated (date passed)This estimate has passed. The registry has not confirmed an actual date for this milestone.
Molecular characterization of the assembled 25% extreme ends cohort (UMC and AMC).
Whole Genome Sequencing (WGS) and linkage analysis will be used for this purpose
September 2023
Omics integration for modifier identification in the 5% extreme ends of the cohort (UMC and AMC)
September 2023
Functional validation of the modifiers.
2024
FBN1 mutation (Marfan Syndrome) - Phenotype cardiovascular severe outcome
FBN1 mutation (Marfan Syndrome) - Phenotype cardiovascular mild outcome
All participants will give a salive sample (self-sampling kit) - selection of 25% extremes (UMC and AMC) participants for WGS and linkage analysis
Based on the results of the WGS, a selection will be made of the 5% most extremes (UMC and AMC) participants for the iPSC-VSMC generation
participants with Marfan syndrom
Contact the study team to confirm eligibility.
University Hospital Antwerp
Edegem, Prins Boudewijnlaan 43/6, 2650, Belgium
Verstraeten A, Luyckx I, Loeys B. Aetiology and management of hereditary aortopathy. Nat Rev Cardiol. 2017 Apr;14(4):197-208. doi: 10.1038/nrcardio.2016.211. Epub 2017 Jan 19.
von Kodolitsch Y, De Backer J, Schuler H, Bannas P, Behzadi C, Bernhardt AM, Hillebrand M, Fuisting B, Sheikhzadeh S, Rybczynski M, Kolbel T, Puschel K, Blankenberg S, Robinson PN. Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome. Appl Clin Genet. 2015 Jun 16;8:137-55. doi: 10.2147/TACG.S60472. eCollection 2015.
1. saliva collection (screening all subjects) 2. bloodsampling (5% most extremes UMC and AMC participants)
Bart Loeys, Prof,MD,PhD
University Hospital, Antwerp
Paul Coucke, Prof,MD,Ing
University Hospital, Ghent
First Submitted
February 5, 2024
First Posted
February 13, 2024
Study Start
November 30, 2020
Actual (reported)Primary Completion
October 31, 2025
Estimated (date passed)This estimate has passed. The registry has not confirmed an actual date for this milestone.
Effect on the Quality of Life of a Therapeutic Education Program in Patients With Marfan Syndrome
Replication of the identified modifiers in a large MFS cohort Time frame: December 2024
2024
Registry-reported names are shown in full. Names without a link have not yet been matched to a Syfrah profile.
Groth KA, Gaustadnes M, Thorsen K, Ostergaard JR, Jensen UB, Gravholt CH, Andersen NH. Difficulties in diagnosing Marfan syndrome using current FBN1 databases. Genet Med. 2016 Jan;18(1):98-102. doi: 10.1038/gim.2015.32. Epub 2015 Mar 26.
Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476-85. doi: 10.1136/jmg.2009.072785.
Braverman AC. Medical management of thoracic aortic aneurysm disease. J Thorac Cardiovasc Surg. 2013 Mar;145(3 Suppl):S2-6. doi: 10.1016/j.jtcvs.2012.11.062. Epub 2012 Dec 20.
De Backer J, Loeys B, Leroy B, Coucke P, Dietz H, De Paepe A. Utility of molecular analyses in the exploration of extreme intrafamilial variability in the Marfan syndrome. Clin Genet. 2007 Sep;72(3):188-98. doi: 10.1111/j.1399-0004.2007.00845.x.
Franken R, Teixido-Tura G, Brion M, Forteza A, Rodriguez-Palomares J, Gutierrez L, Garcia Dorado D, Pals G, Mulder BJ, Evangelista A. Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome. Heart. 2017 Nov;103(22):1795-1799. doi: 10.1136/heartjnl-2016-310631. Epub 2017 May 3.
Renard M, Muino-Mosquera L, Manalo EC, Tufa S, Carlson EJ, Keene DR, De Backer J, Sakai LY. Sex, pregnancy and aortic disease in Marfan syndrome. PLoS One. 2017 Jul 14;12(7):e0181166. doi: 10.1371/journal.pone.0181166. eCollection 2017.
Granata A, Serrano F, Bernard WG, McNamara M, Low L, Sastry P, Sinha S. An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death. Nat Genet. 2017 Jan;49(1):97-109. doi: 10.1038/ng.3723. Epub 2016 Nov 28.
Study Completion
October 31, 2025
Estimated (date passed)This estimate has passed. The registry has not confirmed an actual date for this milestone.
Last Updated
February 13, 2024
Record last verified: 2024-01
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