Diagnostic Utility of Long-Read Genome Sequencing in a Late-Onset Muscular Dystrophy: A Case of Calpainopathy Revealed by Variant Phasing
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Background: Diagnosing adult-onset muscular dystrophies is often challenging due to phenotypic overlap and the unavailability of parental samples for genetic phasing in recessive disorders.Case Presentation: A 49-year-old man presented with progressive proximal muscle weakness. Initially misdiagnosed as inflammatory myopathy, he did not respond to immunosuppressive treatment. To evaluate a clinical suspicion of facioscapulohumeral muscular dystrophy (FSHD1), long-read genome sequencing was performed using Oxford Nanopore Technology. Surprisingly, the patient was found to harbor compound heterozygous variants in the CAPN3 gene, consistent with calpainopathy (LGMD2A). Phasing by long-read sequencing confirmed trans configuration, enabling a definitive diagnosis without parental DNA. Conclusion: This case illustrates the value of long-read sequencing in resolving phasing in autosomal recessive neuromuscular diseases and enabling diagnosis in the absence of parental samples.
