SHORT REPORT

Germline mutation in DOK7 associated with fetal akinesia deformation sequence

J Vogt^1,2, N V Morgan¹, T Marton³, S Maxwell⁴, B J Harrison¹, D Beeson⁴, E R Maher^1,2

¹ Department of Medical and Molecular Genetics and WellChild Paediatric Research Centre, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK
² West Midlands Regional Clinical Genetics Service, Birmingham Women’s Hospital, West Midlands, UK
³ Department of Paediatric Pathology, Birmingham Women’s Hospital, West Midlands, UK
⁴ Neurosciences Group, Weatherall Institute of Molecular Medicine, The John Radcliffe Hospital, Oxford, UK

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}bham.ac.uk

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 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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