The science

The present challenge lies in increasing detection rate as well as reducing the time-to-diagnosis (down to 72h to one week) for patients and families via characterising all gene mutation types and reducing analyses costs by using platforms with high diagnostic capacities.

These two goals will allow us to characterize the genotype also in rare and atypical phenotypes, in genetically ambiguous sporadic cases and in NMDs whose pathophysiology is multiallelic or multigenic. One must keep in mind that patients with a well characterized pathology, both on clinical and genetic sides, are the only one eligible for clinical trials or protocols, which become more and more numerous. DNA-Chips really correspond to a "one-shot" technology that may considerably reduce both the times and the costs of the whole diagnostic process.

To achieve NMD-Chip aims, we will...
 

1. design specific Sequence Capture DNA arrays containing all the genes already known to be involved in LGMD, CMD and CMT. 
    
2. design a whole gene CGH array containing all the genes already known to be involved in LGMD, CMD and CMT. 
    
3. develop bioinformatic tools to accurately and quickly analyse DNA-Chip data
    
4. assess the quality of the chips. Several hybridisation tests will be performed to assess a good reproducibility and a strong efficiency.
    
5. validate these DNA-arrays on pre-diagnosed patient samples and test their  robustness on undiagnosed samples.
    
6. design distinct candidate genes SC- and CGH-chips for LGMD, CMT and CMD
    

    and finally.. 

7. test patients with unidentified gene mutations with candidate genes chips.

The developed chips will consist first in a series of chips dedicated to sequence capturing of all known genes implied in a given group of NMD. This, coupled with a high throughput sequencing technology (pyrosequencing), will bring a quick molecular diagnosis to patients.

Then, if no deleterious mutation is found with the first run on KG-chips, a second series of chips dedicated to candidate genes will be hybridised with patient's DNA. That means that every gene implied in a given NMD group will be checked at a glance, whereas until now, diagnostic laboratories have 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.