Digenic inheritance of variants in RYR1 and PLEC causing myopathy with tubular aggregates

Despite the advances in genetic testing, a significant proportion of patients with suspected genetic myopathies remain undiagnosed. In these patients, the standard patterns of transmission of single gene disorders which include autosomal dominant, autosomal recessive or X-linked are investigated. However, an under recognized phenomenon that could be considered is digenic inheritance in which variants in two separate genes established to cause myopathy result in the phenotype. We report a 53-year-old man who had complaints of fatigability and weakness. Following neurological examination and electrophysiological testing he was diagnosed with a myopathy. Muscle biopsy confirmed the presence of a myopathy with tubular aggregates without inflammatory features, and a genetic etiology was suspected. There was no family history to suggest an autosomal dominant pattern of inheritance and no family members available for further study. Whole exome sequencing was performed and revealed variants in multiple genes including the ryanodine receptor 1 (RYR1) gene, Kelch repeat and BTB (POZ) domain containing 13, (KBTBD13) gene, spectrum repeat containing nuclear envelope protein 1 (SYNE1) gene and plectin (PLEC) gene. These variants were further analyzed for available published research papers and databases reporting pathogenicity, and frequency. In addition, we performed modeling for possible pathogenicity and protein/protein interactions for each of the variants. We hypothesize that in this patient, the ryanodine receptor 1 (RYR1) gene variant, c.1598 G>A, and plectin (PLEC) gene variant, c.2144 C>T following digenic inheritance are the cause of his genetic myopathy. Our study demonstrates that genetic diagnosis can be facilitated by recognition of digenic inheritance in patients with undiagnosed myopathies and the utility of the tools to analyze variants even if family members are not available for study.