Novel pathogenic variants and genes for myopathies identified by whole exome sequencing

We present four unique childhood myopathy cases characterized by relatively mild muscle weakness, slowly progressing course, mildly elevated creatine phosphokinase (CPK), and contractures. We also present two additional cases characterized by severe prenatal/neonatal myopathy. Prior extensive genetic testing and histology of these cases did not reveal the genetic etiology of disease. Here, we applied whole exome sequencing (WES) and bioinformatics to identify likely causal pathogenic variants in each pedigree. In two cases, we identified novel pathogenic variants in COL6A3. In a third case, we identified novel likely pathogenic variants in COL6A6 and COL6A3. We identified a novel splice variant in EMD in a fourth case. Finally, we classify two cases as calcium channelopathies with identification of novel pathogenic variants in RYR1 and CACNA1S. These are the first cases of myopathies reported to be caused by variants in COL6A6 and CACNA1S. Our results demonstrate the utility and genetic diagnostic value of WES in the broad class of NMD phenotypes. In this article, we describe six diagnostic odyssey cases of myopathy and the novel genetic variants that we identified as the probable cause of neuromuscular disease. In particular we have identified variants in CACNA1S as the cause of a new, severe form of central core disease. In addition, we identify novel pathogenic variants in COL6A3 (images shown above), COL6A6, EMD, and RYR1.
Source: Molecular Genetics & Genomic Medicine - Category: Genetics & Stem Cells Authors: Tags: Original Article Source Type: research