Novel pathogenic variants and genes for myopathies identified by whole exome sequencing. Issue 4 (8th April 2015)

• Record Type: Journal Article
• Authors: Hunter, Jesse M.; Ahearn, Mary Ellen; Balak, Christopher D.; Liang, Winnie S.; Kurdoglu, Ahmet; Corneveaux, Jason J.; Russell, Megan; Huentelman, Matthew J.; Craig, David W.; Carpten, John; Coons, Stephen W.; DeMello, Daphne E.; Hall, Judith G.; Bernes, Saunder M.; Baumbach‐Reardon, Lisa
• Is Part Of: Molecular genetics & genomic medicine. Volume 3:Issue 4(2015:Jul.)
• Page Start: 283
• Page End: 301
• Publication Date: 2015-04-08
• Subjects: Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.142
• Languages: English
• ISSNs: 2324-9269

Abstract

<abstract abstract-type="main" id="mgg3142-abs-0001"> <title>Abstract</title> <p>Neuromuscular diseases (NMD) account for a significant proportion of infant and childhood mortality and devastating chronic disease. Determining the specific diagnosis of NMD is challenging due to thousands of unique or rare genetic variants that result in overlapping phenotypes. 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 <italic>COL6A3</italic>. In a third case, we identified novel likely pathogenic variants in <italic>COL6A6</italic> and <italic>COL6A3</italic>. We identified a novel splice variant in <italic>EMD</italic> in a fourth case. Finally, we classify two cases as calcium channelopathies with identification of novel pathogenic variants in <italic>RYR1</italic> and <italic>CACNA1S</italic>. These are the first cases of myopathies reported to be caused by variants in <italic>COL6A6</italic> and <italic>CACNA1S</italic>. Our results demonstrate the utility and genetic diagnostic value of WES in the broad class of NMD phenotypes.</p> </abstract>