title: The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States.
abstract: The current study characterizes a cohort of limb-girdle muscular dystrophy (LGMD) in the United States using whole-exome sequencing. Fifty-five families affected by LGMD were recruited using an institutionally approved protocol. Exome sequencing was performed on probands and selected parental samples. Pathogenic mutations and cosegregation patterns were confirmed by Sanger sequencing. Twenty-two families (40%) had novel and previously reported pathogenic mutations, primarily in LGMD genes, and also in genes for Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital myopathy, myofibrillar myopathy, inclusion body myopathy and Pompe disease. One family was diagnosed via clinical testing. Dominant mutations were identified in COL6A1, COL6A3, FLNC, LMNA, RYR1, SMCHD1 and VCP, recessive mutations in ANO5, CAPN3, GAA, LAMA2, SGCA and SGCG, and X-linked mutations in DMD. A previously reported variant in DMD was confirmed to be benign. Exome sequencing is a powerful diagnostic tool for LGMD. Despite careful phenotypic screening, pathogenic mutations were found in other muscle disease genes, largely accounting for the increased sensitivity of exome sequencing. Our experience suggests that broad sequencing panels are useful for these analyses because of the phenotypic overlap of many neuromuscular conditions. The confirmation of a benign DMD variant illustrates the potential of exome sequencing to help determine pathogenicity.
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Hemakumar M
authors.initials: HM
authors.lastname: Reddy
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Cho
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Elicia
authors.initials: E
authors.lastname: Estrella
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
authors.forename: Elise
authors.initials: E
authors.lastname: Valkanas
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Jones
authors.affiliation: Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Satomi
authors.initials: S
authors.lastname: Mitsuhashi
authors.affiliation: Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Basil T
authors.initials: BT
authors.lastname: Darras
authors.affiliation: Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Amato
authors.affiliation: Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Hart Gw
authors.initials: HG
authors.lastname: Lidov
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.|Research Connection and Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Brownstein
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.|Research Connection and Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Margulies
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Yu
authors.affiliation: Department of Pediatrics, Division of Neurology, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Kunkel
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.|Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.|Department of Neurology and Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA.|Genetics Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Kang
mesh_terms: D001483:Base Sequence; D049310:Distal Myopathies / Q000175:diagnosis / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D006009:Glycogen Storage Disease Type II / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D008297:Male; D049288:Muscular Dystrophies, Limb-Girdle / Q000175:diagnosis* / Q000235:genetics*; D020388:Muscular Dystrophy, Duchenne / Q000175:diagnosis / Q000235:genetics; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000175:diagnosis / Q000235:genetics; D009154:Mutation / Q000235:genetics; D020914:Myopathies, Structural, Congenital / Q000175:diagnosis / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D014481:United States