Clinical Variability in Marfan Syndrome (Variarfan)

Correlations' Study Between Variability of Expression in FBN1 Gene and Clinical Features in Marfan Patients.

Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1). Penetrance of FBN1 mutations is complete but intra and inter familial clinical expressivity is extremely variable. The underlying mechanisms for variability are not understood. An interesting mechanism is that the expression level of the wild type and/or mutated allele may play a role in the determination of variability.

Principal objective: To evaluate in Marfan patients, if FBN1 expression level (non-mutated or mutated allele) modulates the clinical expression of the disease.

Judgment criteria : Correlation allelic expression level-phenotype Perspectives : To search the predictive factors of severity in order to ameliorate precocity of taking care.

Study Overview

• Status: Completed
• Conditions: Marfan Syndrome
• Intervention / Treatment: Procedure: skin punch biopsy and molecular biology; Other: fibroblast culture and molecular biology

Detailed Description

Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1). Penetrance of FBN1 mutations is complete but intra and inter familial clinical expressivity is extremely variable. The underlying mechanisms for variability are not understood. An interesting mechanism is that the expression level of the wild type and/or mutated allele may play a role in the determination of variability.

Principal objective : To evaluate in Marfan patients, if FBN1 expression level (non-mutated or mutated allele) modulates the clinical expression of the disease in individuals from families with clinical variability (intrafamilial) and in independant probands (interfamilial).

Judgment criteria : Correlation allelic expression level-phenotype Method : In Marfan patients with a FBN1 nul allele, FBN1 RNA will be extracted from a fibroblast culture. Allelic FBN1 expression level will be performed by quantitative RT-PCR and then compared with clinical evaluation.

Number of subjects : 160 subjects, 45 Marfan patients in 15 independent families, 5 patients with the same mutation, 30 with a private mutation leading to a nul allele and 80 non Marfan subjects.

Perspectives : To search the predictive factors of severity in order to ameliorate precocity of taking care.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Ile de France
    • Paris, Ile de France, France, 75018
      • Centre de Reference Maladie de Marfan Et Apparente

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Man or woman > 18 years old
• With a mutation in FBN1 gene
• Has signed an informed consent form

Exclusion Criteria:

-No affiliated to a Healthcare System.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Marfan patients; Study participants were recruited between 11/2009 and 10/2011, among adult patients consulting in the Multidisciplinary Marfan Clinic of our University Hospital, and having a known mutation in the FBN1 gene. There, patients are evaluated by geneticists, rheumatologists, cardiologists, and ophthalmologists. Systematic slit-lamp examination, cardiac ultrasonography, and radiological investigations are also performed. A skin punch biopsy was used to establish a fibroblast cell culture. We determined mRNA levels for FBN1 and compared it to the clinical involvement.	Procedure: skin punch biopsy and molecular biology
Other: control patients; Fibroblasts were obtained from non Marfan patients (cell bank). We determineed mRNA level for FBN1 for each allele.	Other: fibroblast culture and molecular biology

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
FBN1 expression level	Evaluation in Marfan patients, of FBN1 expression level (non-mutated or mutated allele) compared to the clinical expression of the disease in idividuals	6 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Hospices Civils de Lyon; Banque de cellules cochin
• Investigators: Principal Investigator: Chantal Stheneur, PHD, MD, Hôpital Bichat, AP-HP

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): January 1, 2012

Study Registration Dates

• First Submitted: October 12, 2012
• First Submitted That Met QC Criteria: October 12, 2012
• First Posted (Estimate): October 16, 2012

Study Record Updates

• Last Update Posted (Estimate): November 6, 2014
• Last Update Submitted That Met QC Criteria: November 5, 2014
• Last Verified: December 1, 2010

More Information

Terms related to this study

• Keywords: Marfan syndrome; Variability; Fibrillin 1; clinical expression
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Bone Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Musculoskeletal Abnormalities; Abnormalities, Multiple; Bone Diseases, Developmental; Limb Deformities, Congenital; Syndrome; Marfan Syndrome; Arachnodactyly
• Other Study ID Numbers: P071009