Clinical Variability in Marfan Syndrome

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

Conditions
-----------------
Marfan Syndrome

Intervention / Treatment
-----------------
* Procedure: skin punch biopsy and molecular biology
* Other: fibroblast culture and molecular biology


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Marfan patients<br>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<br> <br> |
| Other: control patients<br>Fibroblasts were obtained from non Marfan patients (cell bank). We determineed mRNA level for FBN1 for each allele. | Other: fibroblast culture and molecular biology<br> <br> |

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Marfan syndrome, Variability, Fibrillin 1, clinical expression