Modifying Genes in Neurofibromatosis 1 (NFGENMODIF)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
French National Referral Center for Neurofibromatoses
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01650142
First received: May 29, 2012
Last updated: June 13, 2014
Last verified: June 2014
  Purpose

Thanks to the investigators previous study the investigators demonstrated the influence of modifying genes in the phenotypic expression of neurofibromatosis 1 (Hum Mol Genet. 2009; 18 (15) :2768-78). Indeed, analysis of the intra-and inter-family variability performed using the investigators phenotype/genotype database demonstrated a strong genetic component for most clinical features. The investigators results suggest the involvement of genetic factors, not related to the NF1 gene, the modifiers. The objective of this project is to identify the modifiers involved in the variability of clinical expression of NF1. The investigators will focus in particular variants involved in the development and progression of neurofibromas.


Condition Intervention
Neurofibromatosis 1
Other: No intervention

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Study of the Neurofibromatosis 1 Expression: Identification of the Modifying Genes

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Identification of the genetic variants involved in variability of clinical expression of neurofibromatosis 1. [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

Whole blood for DNA samples


Estimated Enrollment: 450
Study Start Date: May 2012
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
NF1GeneModif Cohort
Adult patients with neurofibromatosis 1
Other: No intervention
No intervention

Detailed Description:

Neurofibromatosis 1(NF1) is a rare autosomal dominant disorder with an incidence of one birth out of 3000. NF1 gene is located in 17q11.2. The penetrance is near 100% by the age of 8 and the de novo mutations represent half the cases. The product of NF1 gene is neurofibromin, a protein controlling cellular differentiation and proliferation. Phenotypic expression is variable even in the same family. Neurofibromatosis 1 is characterized by café au lait spots, freckling of the folds, Lisch'nodules (hamartomas of iris) and multiple neurofibromas. Manifestations of neurofibromatosis 1 are pleiotropic, potentially severe and unpredictable. Morbidity and mortality associated to neurofibromatosis 1 are linked with complications, optic pathway gliomas, neurofibromas of the spine or of peripheral nerves, learning disabilities, scoliosis and bone abnormalities and vasculopathy. The investigators already demonstrated the existence of modifiers, genes modifying the phenotypic expression of neurofibromatosis 1 (Hum Mol Genet. 2009;18(15):2768-78). Indeed, a quantitative analysis of inter and intrafamilial variability performed with the data of the investigators phenotype/genotype database showed a strong genetic component for most studied clinical traits with an estimated heritability from 44 and 45% for subcutaneous and plexiform neurofibromas, to 66% for small café au lait spots. The investigators also showed that the NF1 gene had minor effect in the phenotypic variability. The investigators results suggested the implication of genes non linked to NF1 gene. The identification of these variants called modifiers of the phenotype is possible thanks to the investigators vast collection of patients and its statistical power. The aim of the present study is to identify in the human genome genetic variants in the evolving pattern of the most frequent manifestation of neurofibromatosis 1, neurofibromas. The genetic association studies are the most adapted in that purpose. The investigators bank includes at the present time 1099 patients of 575 families with genotypes, phenotypes and DNA samples.

The investigators will include 450 index cases more to have around 1000 independent patients with neurofibromatosis 1 to get a 90% statistical power to detect variants of 30% frequency in the general population and having an effect of odds ratio of 2 for studied trait. The investigators will use Affymetrix® Genechips 6.0 covering well the whole genome.

Identification of the variants will provide new comprehension of pathophysiology and new targets for treatment.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Adult patients with neurofibromatosis 1 according to the NIH criteria followed in NF France network, a national network devoted in to neurofibromatosis 1

Criteria

Inclusion Criteria:

  • Aged of 18 or more
  • Patient with neurofibromatosis 1 according the NIH criteria :
  • Six or more café au lait macules over 15 mm in greatest diameter in postpubertal individuals
  • Two or more neurofibromas of any type or one plexiform neurofibroma
  • Freckling in the axillary or inguinal regions (Crowe´s sign)
  • Optic glioma
  • Two or more Lisch nodules (iris hamartomas)
  • A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis
  • A first-degree relative (parent, sibling, or offspring) with NF1 by the above criteria
  • The criteria are met in an individual if two or more of the features listed are present.

Exclusion Criteria:

  • Children (< 18 year-old)
  • One member of the family already included in the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01650142

Locations
France
Henri Mondor Hospital
Creteil, France, 94010
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
French National Referral Center for Neurofibromatoses
Investigators
Principal Investigator: Pierre Wolkenstein, MD, PhD Assistance Publique - Hôpitaux de Paris
  More Information

Publications:
Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01650142     History of Changes
Other Study ID Numbers: AOM 10 005, 2010-023137-34
Study First Received: May 29, 2012
Last Updated: June 13, 2014
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Neurofibromatosis 1
Phenotype
Modifiers

Additional relevant MeSH terms:
Neurofibromatoses
Neurofibromatosis 1
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Neoplastic Syndromes, Hereditary
Nerve Sheath Neoplasms
Nervous System Diseases
Neurocutaneous Syndromes
Neurodegenerative Diseases
Neurofibroma
Neuromuscular Diseases
Peripheral Nervous System Diseases

ClinicalTrials.gov processed this record on October 21, 2014