Clinical Variability in Marfan Syndrome (Variarfan)

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Marfan Syndrome	Procedure: skin punch biopsy and molecular biology; Other: fibroblast culture and molecular biology	Not Applicable

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 Design

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	160 participants
Allocation:	Non-Randomized
Intervention Model:	Factorial Assignment
Masking:	None (Open Label)
Primary Purpose:	Basic Science
Official Title:	Correlations' Study Between Variability of Expression in FBN1 Gene and Clinical Features in Marfan Patients.
Study Start Date :	January 2009
Actual Primary Completion Date :	June 2011
Actual Study Completion Date :	January 2012

Arms and Interventions

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Arm	Intervention/treatment
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
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

Outcome Measures

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. FBN1 expression level [ Time Frame: 6 months ]
   Evaluation in Marfan patients, of FBN1 expression level (non-mutated or mutated allele) compared to the clinical expression of the disease in idividuals

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

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.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

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

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Hospices Civils de Lyon

Banque de cellules cochin

Investigators

Principal Investigator:	Chantal Stheneur, PHD, MD	Hôpital Bichat, AP-HP

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:	NCT01707563 History of Changes
Other Study ID Numbers:	P071009
First Posted:	October 16, 2012
Last Update Posted:	November 6, 2014
Last Verified:	December 2010

Keywords provided by Assistance Publique - Hôpitaux de Paris:

Marfan syndrome; Variability; Fibrillin 1; clinical expression

Additional relevant MeSH terms:

Marfan Syndrome; Arachnodactyly; Syndrome; Disease; Pathologic Processes; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Heart Defects, Congenital	Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Abnormalities, Multiple; Congenital Abnormalities; Genetic Diseases, Inborn; Connective Tissue Diseases; Limb Deformities, Congenital; Musculoskeletal Abnormalities