Why the study?
Next generation sequencing has identified numerous rare RYR1 variants, complicating the correlation between phenotype and genotype.
Cohort (n=33)
No
Answers are grounded in this paper and cite their sources.
Clinical diversity of RYR1-related myopathy is impacted by inheritance mode, variation type, and variant location, with recessive variants causing more severe early bulbar and respiratory involvement.
Introduction Next generation sequencing results in an explosive identification of rare variants of RYR1, making the correlation between phenotype and genotype complicated. We analyzed the data of 33 patients with RYR1-related myopathy, attempting to elucidate correlations between phenotype, genotype, and protein structure of RyR1. Methods Clinical, histopathologic, and genetic data were evaluated, and variants were mapped to the cryo-EM RyR1 structure. The three-dimensional structure of the variant on RyR1 was analyzed. Results The clinical spectrum was highly variable regardless of the mode of inheritance. Recessive variations were associated with more severe feeding problems and respiratory insufficiency in infancy (p < 0.05). Forty pathogenic and likely pathogenic variations were identified, and 14 of them were novel. Missense was the most common variation type regardless of inheritance mode. Arginine (15/45) was the most frequently involved residue. All but one dominant variation clustered in Pore forming and pVSD domains, while recessive variations enriched in Bsol (7/25) and SPRYs (6/25) domains. Analysis of the spatial structure of variants showed that dominant variants may impact RyR1 mainly by breaking down hydrogen or electrovalent bonds (10/21); recessive variants located in different domains may impact the function of RyR1 through different pathways. Variants located in RyR1 coupling sites (PY1&2 and the outermost of Bsol) may cause the most severe clinical manifestation. Conclusion Clinical diversity of RYR1-related myopathy was impacted by the inheritance mode, variation type, and variant location. Dominant and recessive variants have different sensitive domains impacting the function of RyR1 through different pathways.
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Chang et al. (2022) conducted a cohort in RYR1-related myopathy (n=33). Recessive RYR1 variations vs. Dominant RYR1 variations was evaluated on Respiratory insufficiency (p=<0.05).
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