PracticeUpdate

Next-Generation Sequencing Leads to Diagnosis in About Half of Cases of Suspected Neuromuscular Disease Next-generation sequencing improves the diagnosis of neuromuscular disease substantially

T he cases of approximately half of individuals with suspected neuromuscular disease are solved using next-generation sequencing, according to a retrospective study presented at ICNMD 2018. Daniel Natera de Benito, MD, of the Hospital Sant Joan de Déu in Barcelona, Spain, and colleagues described results obtained in an extensive study of 151 genetically undiagnosed individuals who presented clinical signs of muscular dystrophies, congenital myopathies, or other neuromuscular conditions. Dr. Natera de Benito told Elsevier’s PracticeUpdate , “We wanted to measure the real usefulness of these new tools in our patients, and studies analyzing the diagnostic yield of next-generation sequencing in patients with neuromuscular disease are relatively scarce.” They reported a huge improvement observed after the application of next-generation sequencing into the field of neuromuscular disease management. Participants who met clinical criteria of a neuro- muscular disease and whose condition had been studied using different strategies of next-gen- eration sequencing were collected. The 151 participants had been evaluated using three dif- ferent methodologies, due to the rapid evolution of next-generation sequencing. The first group of participants (n=58) was studied using a custom panel. The investigators sequenced 4813 genes in the second group (n=40).

Dr. Natera de Benito’s team analyzed the entire exome of the third group (n=53). After sequencing and bioinformatics analysis, they studied only 169 genes associated with neuromuscular disorders to check for candidate mutations. In cases and progenitors, Sanger sequencing was performed in cases of strong candidates. Participants were classified according to clinical phenotype as affected by congenital myopathy (52%), muscular dystrophies (29%), congenital myasthenic syndromes (6%), neuropathies (5%), and other clinical conditions (8%). These other clin- ical conditions included, among others, metabolic myopathy and hereditary spastic paraplegia. Most participants displayed sporadic disease. The majority of samples collected had been previously tested without success, according to the observed phenotype. A total of 80 cases (53%) were diagnosed with known disease-associated variants or with variants of a likely pathogenicity, or variants predicted to affect function in genes corresponding to clinical suspicions. The genetic cause of disease was elucidated in 24 of 40 samples (60%) according to the clinical exome, in 30 of 58 samples (51%) by the custom panel, and in 26 of 53 samples (49%) by selected whole exome sequencing. Dr. Natera de Benito explained that inherited neu- romuscular disorders are chronic genetic diseases

Dr. Daniel Natera de Benito

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PRACTICEUPDATE CONFERENCE SERIES • ICNMD 2018