J Med Genet 40:575-584 doi:10.1136/jmg.40.8.575
  • Original article

Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms

  1. H L Wilson1,*,
  2. A C C Wong1,,
  3. S R Shaw2,
  4. W-Y Tse1,
  5. G A Stapleton3,
  6. M C Phelan4,
  7. S Hu1,
  8. J Marshall1,
  9. H E McDermid1
  1. 1Department of Biological Sciences, University of Alberta, Edmonton, Alberta T6G 2E9, Canada
  2. 2Department of Developmental Pediatrics, The Children’s Hospital, Greenville, SC 29615, USA
  3. 3Greenwood Genetic Center, Greenwood, SC 29646, USA
  4. 4TC Thompson Children’s Hospital, Chattanooga, TN 37403, USA
  1. Correspondence to:
 Dr H E McDermid, Department of Biological Sciences, University of Alberta, Edmonton, Alberta T6G 2E9, Canada; 
  • Accepted 23 April 2003
  • Revised 18 April 2003


Methods: The 22q13 deletion syndrome (MIM 606232) is characterised by moderate to profound mental retardation, delay/absence of expressive speech, hypotonia, normal to accelerated growth, and mild dysmorphic features. We have determined the deletion size and parent of origin in 56 patients with this syndrome.

Results: Similar to other terminal deletion syndromes, there was an overabundance of paternal deletions. The deletions vary widely in size, from 130 kb to over 9 Mb; however all 45 cases that could be specifically tested for the terminal region at the site of SHANK3 were deleted for this gene. The molecular structure of SHANK3 was further characterised. Comparison of clinical features to deletion size showed few correlations. Some measures of developmental assessment did correlate to deletion size; however, all patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size.

Conclusion: Our analysis therefore supports haploinsufficiency of the gene SHANK3, which codes for a structural protein of the postsynaptic density, as a major causative factor in the neurological symptoms of 22q13 deletion syndrome.


  • * Present address: Center for Neuroscience, University of Pittsburgh, PA 15260, USA

  • Present address: Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA