260P NEUROMYODredger – 3 billion megaproject: expanding the accessibility of exome sequencing for the diagnosis of neurodevelopmental and neuromuscular disorders in nine countries

• Published in: Neuromuscular disorders : NMD Vol. 43; p. 104441
• Main Authors: Malfatti, E., Caramizaru, A., Lee, H., Kim, J., Shoaito, H., Pennisi, A., Fahmi, N., Escobar-Cedillo, R., Miranda-Duarte, A., Nouioua, S., Benchaabi, O., Martinez, P., Castiglioni, C., Dobrescu, A., Tajsharghi, H.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-10-2024
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.477

Over recent years, there has been a significant advancement in the field of genetic testing for neurologic and neuromuscular disorders in both technique refinement and accessibility. However, despite this progress, various issues still prevent patients from accessing genetic tests, leading to delays in diagnosis, effective treatments and preventive measures through genetic counselling. Sources of disparity include a lack of education, costs and insurance differences, and the isolation of certain communities. On the grounds of a tight international collaboration, the NEUROMYODredger-3billion Megaproject aimed to provide free access to whole exome sequencing for individual patients with uncharacterized neurodevelopmental and neuromuscular disorders in nine countries: Algeria, Chile, Egypt, France, Iran, Mexico, Peru, Romania, and Sweden. DNA samples were collected from a total of 257 patients, comprising both children (N=176) and adults (N=81), with clinical and/or paraclinical evidence of neurodevelopmental or neuromuscular disorders. We identified pathogenic variants (SNVs, indels, CNVs) in 79 samples, resulting in a diagnostic yield of 30.73%. Additionally, 49 patients (19.06%) were found to harbour variants of uncertain significance (VUS), requiring further genetic investigations and functional validation. Furthermore, 111 samples yielded negative results, while 18 are still pending. Currently, raw sequencing data are being analysed to refine or degrade the VUS, further explore negative cases, and perform epidemiological studies, genotype-phenotype correlations, and investigations into novel causative genes. NEUROMYODredger, linking together higher and lower income countries, has expanded the availability of free genetic testing for neurologic/neuromuscular patients. Moreover, and it has increased the diagnostic yield, facilitated international collaborations, and set the bases for the development of official testing strategies that consider the unique circumstances of each country while prioritising patient perspectives.