Germline mutation in DOK7 associated with fetal akinesia deformation sequence

J Med Genet. 2009 May;46(5):338-40. doi: 10.1136/jmg.2008.065425. Epub 2009 Mar 3.

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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Alternative Splicing / genetics
  • Base Sequence
  • Child
  • Consanguinity
  • DNA Mutational Analysis
  • Developmental Disabilities / pathology
  • Female
  • Germ-Line Mutation*
  • Humans
  • India
  • Male
  • Muscle Proteins / genetics*
  • RNA Splice Sites / genetics
  • Syndrome

Substances

  • DOK7 protein, human
  • Muscle Proteins
  • RNA Splice Sites