Mitochondrial disorders, characterized by clinical symptoms and/or OXPHOS deficiencies, are caused by pathogenic variants in mitochondrial genes. However, pathogenic variants in some of these genes can lead to clinical manifestations which overlap with other neuromuscular diseases, which can be caused by pathogenic variants in non-mitochondrial genes as well. Mitochondrial pathogenic variants can be found in the mitochondrial DNA (mtDNA) or in any of the 1,500 nuclear genes with a mitochondrial function. In this study, the authors performed a complete next-generation sequencing strategy, analysing the mtDNA and exome in a cohort of 86 patients with mitochondrial disease (group 1) and 31 neuromuscular patients in whom a pathogenic variant in a mitochondrial gene could possibly be involved (group 2). The latter group includes heterogeneous neuromuscular patients with disease symptoms that are not specific for mitochondrial disease, but in which a mitochondrial genetic cause has been identified in a minority of cases. Patients were screened for pathogenic variants in the mtDNA by next-generation sequencing and, if negative, further analysed by whole exome sequencing (WES). WES-variants were filtered according to the presumed genetic model of disease inheritance, allele frequencies, conservation, and the predicted effect of the variant. With this approach, the authors identified in 68% of their patients, a causative pathogenic variant in new and known disease genes, which were either inherited or de novo.
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