Alu-mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4

Eur J Hum Genet. 2012 Sep;20(9):990-4. doi: 10.1038/ejhg.2012.29. Epub 2012 Feb 29.


Waardenburg syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15-35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alu Elements*
  • Child, Preschool
  • Chromosome Breakpoints
  • Chromosomes, Human, Pair 22
  • Endothelin-3 / genetics
  • Enhancer Elements, Genetic*
  • Hirschsprung Disease
  • Humans
  • Male
  • Molecular Sequence Data
  • Neural Crest / metabolism
  • Neural Crest / pathology
  • Receptor, Endothelin B / genetics
  • SOXE Transcription Factors / genetics*
  • Sequence Deletion*
  • Waardenburg Syndrome / genetics*
  • Waardenburg Syndrome / pathology


  • Endothelin-3
  • Receptor, Endothelin B
  • SOX10 protein, human
  • SOXE Transcription Factors

Supplementary concepts

  • Waardenburg syndrome, type 4