G.P.48 Genotype–phenotype correlations in recessive RYR1-related myopathies

BackgroundMutations in RYR1 are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia. Several genotype–phenotype correlations have been identified for these mutations, while less is known about recessive mutations. Thus far, no systematic examinations on recessive mutations have been performed.MethodsA large cohort of 106 recessive RYR1 cases was analyzed in this study. Cases were ascertained in the literature (n=92) and among clinicians (n=14). We also report several new cases identified in Canada.ResultsAmong this cohort, almost 50% of cases were non-core myopathies. Of note, we found enrichment of hypomorphic mutations (mutations expected to diminish RyR1 expression) in patients with severe clinical phenotypes. In addition, hypomorphic mutations were more likely among non-central core myopathies. Analysis of non-hypomorphic mutation location revealed an enrichment of missense mutations in the MH/CCD hotspots and specifically in the selectivity filter of the channel pore.ConclusionsThis study represents the first comprehensive analysis of genotype–phenotype correlations in recessive RYR1-myopathies. These results help in better understanding disease pathogenesis and prognosis. Specifically, the study supports that loss of protein function is predictive of disease severity. In addition, the results suggest that decreased RyR1 expression may dictate non-core related pathology; though, confirmation in a larger cohort should be performed since data on protein expression was limited. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis of recessive core myopathies.