Genotype-phenotype correlations in recessive RYR1-related myopathies

Abstract

Background: RYR1 mutations are typically associated with core myopathies and are the most common overall cause of congenital myopathy. Dominant mutations are most often associated with central core disease and malignant hyperthermia, and genotype-phenotype patterns have emerged from the study of these mutations that have contributed to the understanding of disease pathogenesis. The recent availability of genetic testing for the entire RYR1 coding sequence has led to a dramatic expansion in the identification of recessive mutations in core myopathies and other congenital myopathies. To date, no clear patterns have been identified in these recessive mutations, though no systematic examination has yet been performed.

Methods: In this study, we investigated genotype-phenotype correlations in a large combined cohort of unpublished (n = 14) and previously reported (n = 92) recessive RYR1 cases.

Results: Overall examination of this cohort revealed nearly 50% of cases to be non-core myopathy related. Our most significant finding was that hypomorphic mutations (mutations expected to diminish RyR1 expression) were enriched in patients with severe clinical phenotypes. We also determined that hypomorphic mutations were more likely to be encountered in non-central core myopathies. With analysis of the location of non-hypomorphic mutations, we found that missense mutations were generally enriched in the MH/CCD hotspots and specifically enriched in the selectivity filter of the channel pore.

Conclusions: These results support a hypothesis that loss of protein function is a key predictive disease parameter. In addition, they suggest that decreased RyR1 expression may dictate non-core related pathology though, data on protein expression was limited and should be confirmed in a larger cohort. Lastly, the results implicate abnormal ion conductance through the channel pore in the pathogenesis in recessive core myopathies. Overall, our findings represent a comprehensive analysis of genotype-phenotype associations in recessive RYR1-myopathies.

Figure 1

Breakdown of hispathologic diagnosis. Percentage breakdown of cases in the combined cohort by their predominant histopathologic pattern on muscle biopsy. Exceptions included are King Denborough Syndrome (KDS), which is a clinical diagnosis based primarily on specific dysmorphic features, and congenital myopathy plus malignant hyperthermia (MH), where individuals had non-specific biopsy features plus a history of MH. Abbreviations: multimincore disease (MmD), central core disease (CCD), centronuclear myopathy (CNM), congenital fiber type disproportion (CFTD), RYR1-related myopathy (RRM), autosomal recessive muscular dystrophy (AR MD).

Figure 2

Assessment of associations with mutation type. (A) Mutation types among histopalogic diagnosis. Abbreviations: multimincore disease (MmD), central core disease (CCD), centronuclear myopathy (CNM), RYR1-related myopathy (RRM), congenital fiber type disproportion (CFTD). (B) Mutation types among severity groups. Clinical severity scores of 0–4 were considered mild, while scores of 5–8 were considered severe based on the criteria listed in Additional file 3: Table S3.

Figure 3

Assessment of associations with mutation type. Each mutation is represented by a shape which corresponds to the mutation type and color which corresponds to the diagnosis. Superscripts correspond to the number of times the mutation has been reported in separate families. Several regions of RYR1 have been highlighted, including the mutation hotspots (Regions I-III) and domains. Abbreviations: multimincore disease (MmD), central core disease (CCD), centronuclear myopathy (CNM), congenital fiber type disproportion (CFTD), RYR1-related myopathy (RRM), King Denborough syndrome (KDS), malignant hyperthermia (MH), autosomal recessive muscular dystrophy (AR MD).

Figure 4

Assessment of associations with ophthalmoparesis. (A) Ophthalmoparesis among hispathologic diagnosis. Abbreviations: multimincore disease (MmD), centronuclear myopathy (CNM), RYR1-related myopathy (RRM), congenital fiber type disproportion (CFTD). (B) Ophthalmoparesis among mutation types.