title: Novel pathogenic variants and genes for myopathies identified by whole exome sequencing.
abstract: 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 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.
authors.affiliation: Integrated Cancer Genomics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Hunter
authors.affiliation: Integrated Cancer Genomics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Ahearn
authors.affiliation: Integrated Cancer Genomics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Balak
authors.affiliation: Collaborative Sequencing Center, Translational Genomics Research Institute (TGen) Phoenix, Arizona.
authors.forename: Winnie S
authors.initials: WS
authors.lastname: Liang
authors.affiliation: Center for Bioinformatics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kurdoglu
authors.affiliation: Neurogenomics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.affiliation: Center for Bioinformatics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.
authors.forename: Megan
authors.initials: M
authors.lastname: Russell
authors.affiliation: Neurogenomics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.affiliation: Neurogenomics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.affiliation: Integrated Cancer Genomics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.
authors.forename: John
authors.initials: J
authors.lastname: Carpten
authors.affiliation: Section of Neuropathology, Barrow Neurological Institute Phoenix, Arizona.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Coons
authors.affiliation: Division of Neurology, Phoenix Children's Hospital Phoenix, Arizona.
authors.forename: Daphne E
authors.initials: DE
authors.lastname: DeMello
authors.affiliation: Departments of Medical Genetics and Pediatrics, University of British Columbia Vancouver, British Columbia, Canada.
authors.forename: Judith G
authors.initials: JG
authors.lastname: Hall
authors.affiliation: Division of Neurology, Phoenix Children's Hospital Phoenix, Arizona.
authors.forename: Saunder M
authors.initials: SM
authors.lastname: Bernes
authors.affiliation: Integrated Cancer Genomics, Translational Genomics Research Institute (TGen) Phoenix, Arizona.
authors.forename: Lisa
authors.initials: L
authors.lastname: Baumbach-Reardon
keywords: Arthrogryposis; CACNA1S; COL6A3; COL6A6; EMD; RYR1; central core disease; exome; muscular dystrophy; myopathy