Novel Variants in Individuals with -Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings.

The ryanodine receptor 1-related congenital myopathies (-RM) comprise a spectrum of slow, rare neuromuscular diseases. Affected individuals present with a mild-to-severe symptomatology ranging from proximal muscle weakness, hypotonia and joint contractures to scoliosis, ophthalmoplegia, and respiratory involvement. Although there is currently no FDA-approved treatment for RM, our group recently conducted the first clinical trial in this patient population (NCT02362425). This study aimed to characterize novel variants with regard to genetic, laboratory, muscle magnetic resonance imaging (MRI), and clinical findings. Genetic and histopathology reports were obtained from participant's medical records. Alamut Visual Software was used to determine if participant's variants had been previously reported and to assess predicted pathogenicity. Physical exams, pulmonary function tests, T1-weighted muscle MRI scans, and blood measures were completed during the abovementioned clinical trial. Six novel variants (two , three dominant, and one recessive) were identified in individuals with -RM. Consistent with established -RM histopathology, cores were observed in all biopsies, except Case 6 who exhibited fiber-type disproportion. Muscle atrophy and impaired mobility with Trendelenburg gait were the most common clinical symptoms and were identified in all cases. Muscle MRI revealed substantial inter-individual variation in fatty infiltration corroborating the heterogeneity of the disease. Two individuals with dominant variants exhibited respiratory insufficiency: a clinical symptom more commonly associated with recessive -RM cases. This study demonstrates that a genetics-led approach is suitable for the diagnosis of suspected -RM which can be corroborated through histopathology, muscle MRI and clinical examination.