Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study

Abstract

Mutations in the RYR1 gene, encoding ryanodine receptor 1 (RyR1), are a well-known cause of Central Core Disease (CCD) and Multi-minicore Disease (MmD). We screened a cohort of 153 patients carrying an histopathological diagnosis of core myopathy (cores and minicores) for RYR1 mutation. At least one RYR1 mutation was identified in 69 of them and these patients were further studied. Clinical and histopathological features were collected. Clinical phenotype was highly heterogeneous ranging from asymptomatic or paucisymptomatic hyperCKemia to severe muscle weakness and skeletal deformity with loss of ambulation. Sixty-eight RYR1 mutations, generally missense, were identified, of which 16 were novel. The combined analysis of the clinical presentation, disease progression and the structural bioinformatic analyses of RYR1 allowed to associate some phenotypes to mutations in specific domains. In addition, this study highlighted the structural bioinformatics potential in the prediction of the pathogenicity of RYR1 mutations. Further improvement in the comprehension of genotype–phenotype relationship of core myopathies can be expected in the next future: the actual lack of the human RyR1 crystal structure paired with the presence of large intrinsically disordered regions in RyR1, and the frequent presence of more than one RYR1 mutation in core myopathy patients, require designing novel investigation strategies to completely address RyR1 mutation effect.

Using Cluster Analysis to Overcome the Limits of Traditional Phenotype–Genotype Correlations: The Example of RYR1-Related Myopathies

“…That said, we also attempted to apply the same cluster analysis also to RYR1-related cohorts with cores described in the recent literature [28][29][30]. Other patients [28][29][30] (Figure S4) with more specific features of core/multicore myopathy were found to fall only within our clusters 3 and, in part, 4. This is not surprising given the more stringent and homogeneous criteria adopted in previous studies.…”

“…Several studies have been published reporting case series carrying various RYR1 mutations. Some of these have recently identified homogenous groups of patients in a bid to better define specific phenotypes [28][29][30]. In the present study, using extensive clinical, morphological, genetic, and biochemical information from a large cohort of index cases harboring variants in RYR1, we attempted an innovative clustering of data to establish more precise correlations and similarities between patients.…”

“…The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/genes14020298/s1, Figure S1: Breakdown of muscle strength (measured using MRC scores) in various affected patients at the first and at the last available visit; Figure S2: Stress plot of the nMDS model applied to clinical characteristics and biopsy findings of proband patients; Figure S3: Elbow method: the 4-cluster solution suggested. We used the k-means clustering algorithm and determined the optimal number of clusters by plotting the total withincluster sum of squares for different numbers of clusters; Figure S4: The cluster analysis applied to RYR1-related cohorts with cores described in the recent literature [28][29][30]; Table S1: Clinical, histopathological, and genetic features of the sample. NA= not available, LGMW= limb girdle muscle weakness; Table S2: Clinical, histopathological, and genetic features of the familial cases; Table S3: This table shows the distance of the clusters (in the nMDS model of the patients) from the clusters' centroids.…”