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Germline mutation in DOK7 associated with fetal akinesia deformation sequence
  1. J Vogt1,2,
  2. N V Morgan1,
  3. T Marton3,
  4. S Maxwell4,
  5. B J Harrison1,
  6. D Beeson4,
  7. E R Maher1,2
  1. 1
    Department of Medical and Molecular Genetics and WellChild Paediatric Research Centre, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK
  2. 2
    West Midlands Regional Clinical Genetics Service, Birmingham Women’s Hospital, West Midlands, UK
  3. 3
    Department of Paediatric Pathology, Birmingham Women’s Hospital, West Midlands, UK
  4. 4
    Neurosciences Group, Weatherall Institute of Molecular Medicine, The John Radcliffe Hospital, Oxford, UK
  1. Professor E R Maher, Department of Medical and Molecular Genetics, University of Birmingham, Institute of Biomedical Research, Edgbaston, Birmingham B15 2TT, UK; E.R.Maher{at}


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 γ 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.

Conclusion: 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.

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  • Competing interests: None declared.

  • Patient consent: Obtained.