Neurogenetic disorders constitute a large group of genetic and phenotypically heterogenous diseases, making differential diagnosis challenging. The capability of next generation sequencing gene panels to screen hundreds of disease genes concurrently is invaluable for genetic diagnosis of neurogenetic disease patients. The PathWest Neuromuscular disease gene panels are comprised of all known disease genes associated with neurological and muscle disorders amenable to capture with current technologies. Since its initial implementation in 2013, where it consisted of 336 genes, the PathWest neuromuscular gene panel has undergone various updates in chemistries and seen the addition of many new disease genes.
We report the results from the most recent iterations of the panel: Versions 3 and 5. Version 3 included 638 genes and used the Nextera Flex for Enrichment kit. Version 5 included 756 genes and used the Twist Biosciences custom panel. A total 3962 patients were tested across the 20 phenotypic subpanels on versions 3 (n=2740) and 5 (n=1222) of the panel. Overall diagnostic success was 23.5%, with 4.8% of all diagnoses attributed to variants in newly added genes. Diagnostic success varied greatly between the phenotypic subpanels, from 66.7% within the CMD subpanel to 4.8% for the AD/FTD subpanel. The 5 most frequently reported genes were DMD, RYR1, SPG7, SPAST, and PMP22, respectively, accounting for 21.2% of all genetically resolved cases.
The shift in chemistries resulted in greater coverage across complex genes that were previously not well-resolved. This enabled improved copy number variant (CNV) calling with an increased proportion (7.3%) of all genetic diagnoses attributed to CNVs.
This study highlights the benefits of a centralised diagnostic facility. Through the analysis of the data generated we have been able to deduce trends pertaining broadly to the diagnosis of neuromuscular disorders as well as provide key insights into specific phenotypes and genetic associations.