The science

The challenge facing the NMD-CHIP team  lies in increasing the rate of detection of genetic mutations as well as reducing the time taken for diagnosis (down to within 1 week) for patients and families affected by NMDs. This will be done by characterising the gene mutations involved in the NMDs under study and by using bioinformatics tools to reduce the cost of the analyses.

These goals will also allow us to characterize the genotype in rare and atypical phenotypes, in genetically ambiguous sporadic cases and in NMDs whose pathophysiology is multiallelic or multigenic. This is of huge significance because only those patients with a well characterized pathology, both clinical and genetic, are eligible for clinical trials. DNA-Chips represent a "one-shot" technology that may considerably reduce the time and the cost of the whole diagnostic process so increasing the number of patients with a confirmed genetic diagnosis.

To achieve its aims, NMD-Chip will:
 

• Design specific Sequence Capture DNA arrays containing all the genes already known to be involved in LGMD, CMD and CMT. 
• Design a whole gene CGH array containing all the genes already known to be involved in LGMD, CMD and CMT. 
• Develop bioinformatic tools to accurately and quickly analyse DNA-Chip data.
• Assess the quality of the chips. Several hybridisation tests will be performed to assess the reproducibility and efficiency.
• Validate these DNA-arrays on pre-diagnosed patient samples and test their  robustness on undiagnosed samples.
• Design distinct candidate genes SC- and CGH-chips for LGMD, CMT and CMD.
• Test patients with unidentified gene mutations with candidate genes chips.

The first chips to be developed will be dedicated to sequence capturing of all the known genes implied in a given group of NMDs. This, coupled with a high throughput sequencing technology (pyrosequencing), will speed up genetic diagnosis.

This means that every gene implied in a given NMD group will be checked at a glance. Until now diagnostic laboratories have had to sequence one gene after another until the mutation is found. If deleterious mutations are identified in known genes, the delay to diagnosis will be reduced to less than a week.

The next step will be to develop a second series of chips dedicated to candidate genes. If no deleterious mutation is found, these will be hybridised with patients’ DNA to identify previously unknown genetic mutations involved in NMDs.