Clinical trial NCT02550691: Identification of a Biomarker Associated With Cis-duplication of the SMN1 Gene
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Spinal Muscular Atrophy
Lead sponsor: University Hospital, Rouen
Sponsor class: OTHER
Collaborators: name: Society GENOMIC VISION
First posted: 2015-09-15
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

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.


Eligibility 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

Primary outcomes:
measure: Identification of a genetic signature indicating the presence of one allele with 2 copies in cis of the SMN1 gene.
timeFrame: Day 1
Secondary outcomes:
measure: Specificity of a genetic signature
timeFrame: Day 1
Other outcomes:
Locations:
city: Nantes
country: France
facility: Nantes University Hospital
city: Rouen
country: France
facility: Rouen University Hospital
Study officials:
affiliation: University Hospital, Rouen
name: Thierry FREBOURG, MD
role: PRINCIPAL_INVESTIGATOR
References: