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


CONCLUSIONS
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.
Wilson
H L
HL
Department of Biological Sciences, University of Alberta, Edmonton, Alberta T6G 2E9, Canada.
Wong
A C C
AC
Shaw
S R
SR
Tse
W-Y
WY
Stapleton
G A
GA
Phelan
M C
MC
Hu
S
S
Marshall
J
J
McDermid
H E
HE
D001483:Base Sequence; D002352:Carrier Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D002872:Chromosome Deletion; D002874:Chromosome Mapping / Q000379:methods; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D020732:Cytogenetic Analysis; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D007805:Language Development Disorders / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D010330:Patents as Topic; D010641:Phenotype; D013577:Syndrome
D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C492357:SHANK3 protein, human