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

NCT02550691 | Terminated

• 1 other identifier: 2015/092/HP
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Spinal Muscular Atrophy

Outcome Measures

Primary Outcomes (1)

• Identification of a genetic signature indicating the presence of one allele with 2 copies in cis of the SMN1 gene.

  Day 1

Secondary Outcomes (1)

• Specificity of a genetic signature

  Day 1

Study Arms (3)

Subject carrying 3 copies of the SMN1 gene

EXPERIMENTAL

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

Subject carrying 2 copies of the SMN1 gene

OTHER

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

Subject carrying 3 copies of the SMN2 gene

OTHER

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

Interventions

blood sampling PROCEDURE

A blood sample will be taken on subject carrying specific genotype

Subject carrying 2 copies of the SMN1 gene; Subject carrying 3 copies of the SMN1 gene; Subject carrying 3 copies of the SMN2 gene

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Pregnant women, nursing women
• Individual without freedom by administrative decision or judicial decision or individual under administrative supervision or legal guardianship

Sponsors & Collaborators

• University Hospital, Rouen: lead
• Society GENOMIC VISION: collaborator

Study Sites (2)

Nantes University Hospital

Nantes, France

Location

Rouen University Hospital

Rouen, 76031, France

Location

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Thierry FREBOURG, MD

  University Hospital, Rouen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2015
• First Posted: September 15, 2015
• Study Start: December 15, 2015
• Primary Completion: July 4, 2016
• Study Completion: July 4, 2016
• Last Updated: July 24, 2019

Record last verified: 2019-07

Locations

FR (2)