“Primary muscle disorders are clinically and genetically heterogeneous. The achievement of a reliable molecular diagnosis can improve clinical management, provides appropriate genetic counseling and testing of relatives, and enables potential therapeutic options.
We reviewed the molecular findings obtained by using diagnostic next generation sequencing protocols at Dino Ferrari Center. In the last 5 years, 183 patients with the suspect of primary muscle disease underwent NGS-based molecular testing consisting of i) custom targeted gene panels or ii) clinical exome sequencing followed by diagnostic interpretation of variants in genes associated with matched clinical phenotypes.
Disease-causing variants were identified in 74 patients (40%: definitive diagnosis). Furthermore, likely pathogenic variants and/or variants of uncertain significance with positive functional and/or segregation analysis were found in 21 additional patients (11.5%: probable diagnosis).
Diagnostic yield of the two approaches was similar (50% versus 51.6%). This rate tends to increase in patients affected with muscular dystrophies (55%), congenital myopathies (57%) or muscle channelopathies (65%) while it falls to 36% in patients with a suspect of metabolic myopathy. Clinical exome sequencing allowed the analysis of other OMIM genes leading to unexpected diagnosis or the enlargement of the clinical spectrum of known disease-related genes. Full exome sequencing contributed to identify 3 novel disease genes in the last two years. The simultaneous analysis of two affected members from the same family facilitated the establishment of a diagnosis (88%). Muscle biopsy was available for 123 patients (47% presenting a positive genetic report) and it resulted crucial for the interpretation of uncertain results.”