Genome-wide Epistasis for Cardiovascular Severity in Marfan Study

NCT06257004 | Unknown

• 3 other identifiers: 20/08/0871S81820NB3002021000292
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Marfan Syndrome; FBN1 Mutation

Keywords

p.Ile2585Thr;c.7754T>C; Rare disease; Aortopathies; TAAD; Congenital abnormalities; Genetic modifiers; Thoracic aortic disease; Thoracic aortic rupture

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (3)

• Omics integration for modifier identification in the 5% extreme ends of the cohort (UMC and AMC)

  September 2023

• Functional validation of the modifiers.

  2024

• Replication of the identified modifiers in a large MFS cohort Time frame: December 2024

  2024

Study Arms (2)

AMC (Affected Mutation Carrier)

FBN1 mutation (Marfan Syndrome) - Phenotype cardiovascular severe outcome

Genetic: Saliva collection (screening of all participants); Genetic: Bloodsampling

UMC (Unaffected Mutation Carrier)

FBN1 mutation (Marfan Syndrome) - Phenotype cardiovascular mild outcome

Genetic: Saliva collection (screening of all participants); Genetic: Bloodsampling

Interventions

Saliva collection (screening of all participants) GENETIC

All participants will give a salive sample (self-sampling kit) - selection of 25% extremes (UMC and AMC) participants for WGS and linkage analysis

AMC (Affected Mutation Carrier); UMC (Unaffected Mutation Carrier)

Bloodsampling GENETIC

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

AMC (Affected Mutation Carrier); UMC (Unaffected Mutation Carrier)

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

participants with Marfan syndrom

You may qualify if:

• Participants with proven mutation (p.Ile2585Thr;c.7754C\>T) in the FBN1 gene

Sponsors & Collaborators

• University Hospital, Antwerp: lead
• University Hospital, Ghent: collaborator

Study Sites (1)

University Hospital Antwerp

Edegem, Prins Boudewijnlaan 43/6, 2650, Belgium

RECRUITING

Related Publications (9)

• 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.

  PMID: 28102232 BACKGROUND

• 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.

  PMID: 26124674 BACKGROUND

• 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.

  PMID: 25812041 BACKGROUND

• 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.

  PMID: 20591885 BACKGROUND

• 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.

  PMID: 23260459 BACKGROUND

• 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.

  PMID: 17718856 BACKGROUND

• 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.

  PMID: 28468757 BACKGROUND

• 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.

  PMID: 28708846 BACKGROUND

• 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.

  PMID: 27893734 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

1. saliva collection (screening all subjects) 2. bloodsampling (5% most extremes UMC and AMC participants)

MeSH Terms

Conditions

Marfan Syndrome; Rare Diseases; Congenital Abnormalities

Condition Hierarchy (Ancestors)

Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Abnormalities, Multiple; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Bart Loeys, Prof,MD,PhD

  University Hospital, Antwerp

  PRINCIPAL INVESTIGATOR

• Paul Coucke, Prof,MD,Ing

  University Hospital, Ghent

  STUDY CHAIR

Central Study Contacts

Bart Loeys, Prof,MD,PhD

CONTACT

++32-3-2759768; bart.loeys@uantwerpen.be

Paul Coucke, Prof,PhD,Ing

CONTACT

++32-9-3323634; paul.coucke@ugent.be

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2024
• First Posted: February 13, 2024
• Study Start: November 30, 2020
• Primary Completion: October 31, 2025
• Study Completion: October 31, 2025
• Last Updated: February 13, 2024

Record last verified: 2024-01

Locations

BE (1)