title: Targeted sequencing and identification of genetic variants in sporadic inclusion body myositis.
abstract: Sporadic inclusion body myositis (sIBM) has clinical, pathologic and pathomechanistic overlap with some inherited muscle and neurodegenerative disorders. In this study, DNA from 79 patients with sIBM was collected and the sequencing of 38 genes associated with hereditary inclusion body myopathy (IBM), myofibrillar myopathy, Emery-Dreifuss muscular dystrophy, distal myopathy, amyotrophic lateral sclerosis and dementia along with C9orf72 hexanucleotide repeat analysis was performed. No C9orf72 repeat expansions were identified, but; 27 rare (minor allele frequency <1%) missense coding variants in several other genes were identified. One patient carried a p.R95C missense mutation in VCP and another carried a previously reported p.I27V missense mutation in VCP. Mutations in VCP cause IBM associated with Paget's disease of the bone (PDB) and fronto-temporal dementia (IBMPFD). Neither patient had a family history of weakness or manifested other symptoms reported with VCP mutations such as PDB or dementia. In vitro analysis of these VCP variants found that they both disrupted autophagy similar to other pathogenic mutations. Although no clear genetic etiology has been implicated in sIBM pathogenesis, our study suggests that genetic evaluation in sIBM may be clinically meaningful and lend insight into its pathomechanism.
authors.affiliation: Department of Neurology, Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO 63110, United States. Electronic address: weihlc@neuro.wustl.edu.
authors.forename: Conrad C
authors.initials: CC
authors.lastname: Weihl
authors.affiliation: Department of Neurology, Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8730 Alden Drive, Los Angeles, CA 90048, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
authors.affiliation: Department of Neurology, Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Centre, Los Angeles Biomedical Research Institute, Torrance, CA 90502, United States.
authors.forename: Tsui-Fen
authors.initials: TF
authors.lastname: Chou
authors.affiliation: Department of Neurology, Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Sara K
authors.initials: SK
authors.lastname: Pittman
authors.affiliation: Department of Neurology, Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Glenn
authors.initials: G
authors.lastname: Lopate
authors.affiliation: Department of Neurology, Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8730 Alden Drive, Los Angeles, CA 90048, United States.
authors.forename: Peggy
authors.initials: P
authors.lastname: Allred
authors.affiliation: Department of Neurology, Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jockel-Balsarotti
authors.affiliation: Department of Neurology, Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.affiliation: Department of Neurology, Hope Center for Neurologic Disorders, Washington University School of Medicine, Saint Louis, MO 63110, United States.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Harms
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000073885:C9orf72 Protein; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D003704:Dementia / Q000235:genetics; D049310:Distal Myopathies / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics; D020914:Myopathies, Structural, Congenital / Q000235:genetics; D018979:Myositis, Inclusion Body / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D000074405:Valosin Containing Protein
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D018797:Cell Cycle Proteins; D011506:Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: Amyotrophic lateral sclerosis; Hereditary inclusion body myopathy; Inclusion body myositis; Myofibrillar myopathy; VCP