title: Germline mutation in DOK7 associated with fetal akinesia deformation sequence.
abstract: BACKGROUND
  Fetal akinesia deformation sequence syndrome (FADS) is a heterogeneous disorder characterised by fetal akinesia and developmental defects including, in some case, pterygia. Multiple pterygium syndromes (MPS) are traditionally divided into prenatally lethal and non-lethal (such as Escobar) types. Previously, we and others reported that homozygous mutations in the fetal acetylcholine receptor gamma subunit (CHRNG) can cause both lethal and non-lethal MPS, demonstrating that pterygia resulted from fetal akinesia, and that mutations in the acetylcholine receptor subunits CHRNA1, CHRND, and Rapsyn (RAPSN) can also result in a MPS/FADS phenotype.
  
  
  METHODS
  We hypothesised that mutations in other acetylcholine receptor related genes may interfere with neurotransmission at the neuromuscular junction and so we analysed 14 cases of lethal MPS/FADS without CHRNG, CHRNA1, CHRNB1, CHRND, or RAPSN mutations for mutations in DOK7.
  
  
  RESULTS
  A homozygous DOK7 splice site mutation, c.331+1G>T, was identified in a family with three children affected with lethal FADS. Previously DOK7 mutations have been reported to underlie a congenital myaesthenic syndrome with a characteristic "limb girdle" pattern of muscle weakness.
  
  
  CONCLUSIONS
  This finding is consistent with the hypothesis that whereas incomplete loss of DOK7 function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype.
authors.affiliation: Department of Medical and Molecular Genetics and WellChild Paediatric Research Centre, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: J
authors.initials: J
authors.lastname: Vogt
authors.forename: N V
authors.initials: NV
authors.lastname: Morgan
authors.forename: T
authors.initials: T
authors.lastname: Marton
authors.forename: S
authors.initials: S
authors.lastname: Maxwell
authors.forename: B J
authors.initials: BJ
authors.lastname: Harrison
authors.forename: D
authors.initials: D
authors.lastname: Beeson
authors.forename: E R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D017398:Alternative Splicing / Q000235:genetics; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000473:pathology; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007194:India; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D013577:Syndrome
chemical_list: C511692:DOK7 protein, human; D009124:Muscle Proteins; D022821:RNA Splice Sites