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Identification of a Biomarker Associated With Cis-duplication of the SMN1 Gene (BADGES)

This study is currently recruiting participants.
Verified August 2017 by University Hospital, Rouen
Sponsor:
ClinicalTrials.gov Identifier:
NCT02550691
First Posted: September 15, 2015
Last Update Posted: August 30, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Society GENOMIC VISION
Information provided by (Responsible Party):
University Hospital, Rouen
  Purpose

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder characterized by loss of motor neurons in the anterior horn of the spinal cord and leading to muscle atrophy. SMA has an autosomal recessive inheritance and affects 1 in 6000 infants with a carrier frequency of 1 in 40. In most cases, it is caused by homozygous gene deletion or gene conversion of the SMN1 gene (0+0 genotype) on 5q11-q13. This genomic region has been duplicated and inverted during evolution. Thus the SMN1 gene has a very homologous copy, called SMN2. Genetic counseling aim at detecting carriers with only one copy of the SMN1 gene (0+1 genotype). SMA carrier testing relies on total copy number quantification of the SMN1 copies by quantitative PCR methods. Nevertheless, cis-duplication of the SMN1 gene on one allele and deletion on the second allele (2+0 genotype) can lead to a misinterpretation as molecular methods show 2 copies of the SMN1 gene and cannot detect the carrier status.

The aim of the study is the characterization of a biomarker specific of the cis-duplication of the SMN1 gene in order to allow the detection of this 2+0 genotype which constitutes a trap for genetic counseling. We will use molecular combing to identify a genomic morse code (GMC) composed of a combination of probes specific of a structural motif on the cis-duplication chromosome. The characterization of this GMC is based on the comparison of two sample groups:

  • The test group, with a maximum of 137 individuals carrying 3 copies of the SMN1 gene (suggesting a cis-duplication on one allele)
  • The control-1 group, with a maximum of 137 individuals carrying 2 copies of the SMN1 gene

A pilot study performed on 24 samples in the two groups is needed to define the exact sample number necessary for statistical analysis of the study. When the GMC will be characterized, its specificity will be evaluated by testing two sample groups:

  • The test group, with 37 individuals carrying 3 copies of the SMN1 gene
  • The control-2 group, with 37 individuals carrying 3 copies of the SMN2 gene Molecular combing needs long DNA fibers and usual methods for DNA extraction are not appropriate. This project requires new blood samples for specific DNA extraction.

If this project is successful, during a second project, this GMC will be converted into a simple and cheap PCR-based method. We will then evaluate the sensitivity of this method on our sample collection, notably on individuals with the 2+0 genotype defined by familial genotyping.


Condition Intervention
Spinal Muscular Atrophy Procedure: blood sampling

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Identification of a Biomarker Associated With Cis-duplication of the SMN1 Gene Aiming at Improving the Genetic Counseling in Spinal Muscular Atrophy Families

Resource links provided by NLM:


Further study details as provided by University Hospital, Rouen:

Primary Outcome Measures:
  • Identification of a genetic signature indicating the presence of one allele with 2 copies in cis of the SMN1 gene. [ Time Frame: Day 1 ]

Secondary Outcome Measures:
  • Specificity of a genetic signature [ Time Frame: Day 1 ]
    Specificity of a genetic signature will be done using analysis of individual carrying either 3 copies of the SMN1 gene or 3 copies of the SMN2 gene


Estimated Enrollment: 311
Study Start Date: December 2015
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Subject carrying 3 copies of the SMN1 gene
Using blood sampling, use of molecular combing to identify a genomic morse code (GMC) composed of a combination of probes specific of a structural motif on the cis-duplication chromosome.
Procedure: blood sampling
A blood sample will be taken on subject carrying specific genotype
Subject carrying 2 copies of the SMN1 gene
Using blood sampling, use of molecular combing to identify a genomic morse code (GMC) composed of a combination of probes specific of a structural motif on the cis-duplication chromosome.
Procedure: blood sampling
A blood sample will be taken on subject carrying specific genotype
Subject carrying 3 copies of the SMN2 gene
Using blood sampling, use of molecular combing to identify a genomic morse code (GMC) composed of a combination of probes specific of a structural motif on the cis-duplication chromosome.
Procedure: blood sampling
A blood sample will be taken on subject carrying specific genotype

  Eligibility

Information from the National Library of Medicine

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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:

  • Adult individual
  • Individual with either 2 copies of the SMN1 gene (control-1 group), 3 copies of the SMN1 gene (test group), or 3 copies of the SMN2 gene (control-2 group).
  • Individual with a social insurance
  • Signed consent form

Exclusion Criteria:

  • Pregnant women, nursing women
  • Individual without freedom by administrative decision or judicial decision or individual under administrative supervision or legal guardianship
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02550691


Contacts
Contact: Pascale SAUGIER-VEBER, pharm pascale.saugier-veber@chu-rouen.fr
Contact: Julien BLOT julien.blot@chu-rouen.fr

Locations
France
Nantes University Hospital Not yet recruiting
Nantes, France
Principal Investigator: Bertrand ISIDOR, MD         
Rouen University Hospital Recruiting
Rouen, France, 76031
Contact: Thierry FREBOURG, MD         
Sub-Investigator: Sarah GROTTO, MD         
Sponsors and Collaborators
University Hospital, Rouen
Society GENOMIC VISION
Investigators
Principal Investigator: Thierry FREBOURG, MD Rouen University Hospital
  More Information

Responsible Party: University Hospital, Rouen
ClinicalTrials.gov Identifier: NCT02550691     History of Changes
Other Study ID Numbers: 2015/092/HP
First Submitted: September 14, 2015
First Posted: September 15, 2015
Last Update Posted: August 30, 2017
Last Verified: August 2017

Additional relevant MeSH terms:
Atrophy
Muscular Atrophy
Muscular Atrophy, Spinal
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases