“Neuromuscular diseases (NMDs) encompass a broad spectrum of conditions which vary in their severity and symptoms. Herein, next-generation sequencing (NGS) has had a dramatic role for proper genetic diagnosis even in the case of elusive clinical and histopathological manifestations.
Our group created the first neuromuscular exome-targeted NGS panel, MotorPlex, for the diagnosis of unsolved NMD patients. Although this targeted approach provided a diagnosis for about 43% of patients, many cases remained unsolved, increasing the need for further investigation.
Over the years, technological improvements and the discovery of new disease-causing genes have led to the need for new tools. In this study, 434 unsolved NMD patients with a negative previous test were enrolled. Patients were clinically re-evaluated and the list was cleared of non-monogenic conditions. Our ‘beyond exome’ approach included custom arrays, the latest version of WES, long-read genomic sequencing, RNA-Seq and others. In addition, the old data was re-mapped using new bioinformatics tools. Preliminary data show that we achieved a diagnostic rate of 47% of previously unsolved cases (57%). We calculate a combined success rate of 69% for the original cohort. This was achieved by identifying previously missed variants in new disease-associated genes and in known NMD-associated genes.
Improvements in diagnostic approaches and the implementation of new technologies, combined with continuous follow-up, suggest that re-analysis of unresolved patients is crucial to stop the diagnostic odyssey and provide better counselling and, in some cases, more specific treatments.”