Molecular and phenotypic characterization of ring chromosome 22.

We performed a phenotype study of 35 individuals (19 males, 16 females) with ring chromosome 22 or r(22) with a mean age of 10 years. In common with other studies, a phenotype of moderate-to-profound learning difficulties and delay or absence of speech affected all individuals with the exception of the case with the smallest deletion. Autistic traits were significantly associated with r(22), as shown by an autism screening questionnaire. Mild and variable dysmorphic features, predominantly craniofacial and distal limb, were observed. Internal organ involvement was uncommon. Even though ring chromosomes are reportedly associated with growth abnormalities, only 2 out of 24 individuals showed evidence of growth failure, while 2 showed accelerated growth. Chromosome 22 long arm deletions, as determined by hemizygosity for informative microsatellite markers, varied from <67 kb to 10.2 Mb in size (or <0.15 to 21% of total chromosome length), with no significant differences in the parental origin of the ring chromosome. Few phenotypic features correlated with deletion size suggesting a critical gene, or genes, of major effect lies close to the telomere. Loss of the SHANK3/PROSAP2 gene has been proposed to be responsible for the main neurological developmental deficits observed in 22q13 monosomies. This study supports this candidate gene by identifying a phenotypically normal r(22) individual whose ring chromosome does not disrupt SHANK3. All other r(22) individuals were hemizygous for SHANK3, and we propose it to be a candidate gene for autism or abnormal brain development.