title: Whole Exome Sequencing RevealsDYSF,FKTN, andISPDMutations in Congenital Muscular Dystrophy Without Brain or Eye Involvement.
abstract: BACKGROUND
  Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of neuromuscular disorders. Several genes encoding extracellular matrix, nuclear envelope, sarcolemmal proteins and glycosylation enzymes have been implicated in CMDs. The large overlap of clinical presentations due to mutations in different genes poses a challenge for clinicians in determining disease etiology for each patient.
  
  
  OBJECTIVE
  We investigated the use of whole exome sequencing (WES) in identifying the genetic cause of disease in 5 CMD patients from 3 families who presented with highly similar clinical features, including early-onset rapidly progressive weakness without brain or eye abnormalities.
  
  
  METHODS
  Whole exome sequencing was performed on DNA from affected individuals. Potential functional impacts of mutations were investigated by immunostaining on available muscle biopsies.
  
  
  RESULTS
  Pathogenic mutations in 3 different genes,DYSF,FKTN, andISPDwere identified in each family. Mutation inDYSFled to absence of dysferlin protein in patient muscle. Mutations inISPDled to impaired ISDP function, as demonstrated by deficiency of α-dystroglycan glycosylation in patient muscle.
  
  
  CONCLUSIONS
  This study highlights the benefit of unbiased genomic approaches in molecular diagnosis of neuromuscular disorders with high clinical heterogeneity, such as the phenotypes observed in our patients. Our results suggest that dysferlin deficiency should be in the differential diagnosis of congenital and rapidly progressive muscular dystrophy, and therefore dysferlin antibody should be in the standard immunohistochemistry panel for muscle biopsies in cases with suspected CMD.
authors.affiliation: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Ozge
authors.initials: O
authors.lastname: Ceyhan-Birsoy
authors.affiliation: Department of Pediatrics, Pathology Unit, Hacettepe University Children's Hospital, Ankara, Turkey.
authors.forename: Beril
authors.initials: B
authors.lastname: Talim
authors.affiliation: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Swanson
authors.affiliation: Department of Pediatrics, Neurology Unit, Hacettepe University Children's Hospital, Ankara, Turkey.
authors.forename: Mert
authors.initials: M
authors.lastname: Karakaya
authors.affiliation: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Graff
authors.affiliation: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.affiliation: Department of Pediatrics, Neurology Unit, Hacettepe University Children's Hospital, Ankara, Turkey.
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloglu
keywords: DYSF protein human; Dysferlinopathy; FKTN protein human; ISPD protein human; Muscular dystrophies; genetic testing; neuromuscular diseases
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