title: Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy.
abstract: Limb-girdle muscular dystrophy primarily affects the muscles of the hips and shoulders (the "limb-girdle" muscles), although it is a heterogeneous disorder that can present with varying symptoms. There is currently no cure. We sought to identify the genetic basis of limb-girdle muscular dystrophy type 1 in an American family of Northern European descent using exome sequencing. Exome sequencing was performed on DNA samples from two affected siblings and one unaffected sibling and resulted in the identification of eleven candidate mutations that co-segregated with the disease. Notably, this list included a previously reported mutation in DNAJB6, p.Phe89Ile, which was recently identified as a cause of limb-girdle muscular dystrophy type 1D. Additional family members were Sanger sequenced and the mutation in DNAJB6 was only found in affected individuals. Subsequent haplotype analysis indicated that this DNAJB6 p.Phe89Ile mutation likely arose independently of the previously reported mutation. Since other published mutations are located close by in the G/F domain of DNAJB6, this suggests that the area may represent a mutational hotspot. Exome sequencing provided an unbiased and effective method for identifying the genetic etiology of limb-girdle muscular dystrophy type 1 in a previously genetically uncharacterized family. This work further confirms the causative role of DNAJB6 mutations in limb-girdle muscular dystrophy type 1D.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Couthouis
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Alya R
authors.initials: AR
authors.lastname: Raphael
authors.affiliation: Neuroscience Center, Stanford Hospital and Clinics, Stanford, CA, USA.
authors.forename: Carly
authors.initials: C
authors.lastname: Siskind
authors.affiliation: Department of Neurology, The Ohio State University, Columbus, OH, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Findlay
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Buenrostro
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Greenleaf
authors.affiliation: Departments of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Departments of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.affiliation: Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Day
authors.affiliation: Department of Neurology, The Ohio State University, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: agitler@stanford.edu.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis / Q000379:methods*; D059472:Exome; D005190:Family; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D044465:White People / Q000235:genetics
chemical_list: C485565:DNAJB6 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins
keywords: DNAJB6; Exome sequencing; Limb-girdle muscular dystrophy