Molecular characterisation of patients with subtelomeric 22q abnormalities using chromosome specific array-based comparative genomic hybridisation

Abstract

The 22q13 deletion syndrome is associated with global developmental delay, absent or delayed speech, and generalised hypotonia. In this study, the size and nature of 22q13 deletions (n ¼ 9) were studied in detail by high-resolution chromosome specific array-based comparative genomic hybridisation (array CGH). The deletion sizes varied considerably between the different patients, that is, the largest deletion spanning 8.4 Mb with the breakpoint mapping to 22q13.2 and the smallest deletion spanning 3.3 Mb with the breakpoint mapping to 22q13.31. In one case, a unique subtelomeric 3.9 Mb deletion associated with a 2.0 Mb duplication of 22q13 was observed, adding to a growing number of similar cases identified for other chromosome ends. Remarkably, this patient had signs suggestive of retinitis pigmentosa, which has never been reported before in the 22q13 deletion syndrome. The identification of two pairs of recurrent proximal breakpoints on 22q13 suggests that these specific regions may be prone to recombination, due to yet unknown genome architectural features. In addition to the copy number changes on 22q13, a duplication of B330 kb on 22q11.1 was observed and shown to be a genetic large-scale copy number variation without clinical consequences. The current study failed to reveal relationships between the clinical features and the deletion sizes. Global developmental delay and absent or severely delayed speech were observed in all patients, whereas hypotonia was present in 89% of the cases (8/9). This study underscores the utility of array CGH for characterising the size and nature of subtelomeric deletions, such as monosomy 22q13, and underlines the considerable variability in deletion size in the 22q13 deletion syndrome regardless of the clinical phenotype.

22q13.2q13.32 genomic regions associated with severity of speech delay, developmental delay, and physical features in Phelan–McDermid syndrome

“…The traditional approach would ignore the difference in frequency and identify 22q13.33 as being the only candidate region. In previous works on PMS, there was a general impression that patients with larger deletions were more seriously affected, but genotype-phenotype studies were hampered by small sample size, low resolution genotyping, or reliance on statistical measures of linear association (correlation coefficients, linear regression), 4,8,9,23,24 whereas the present study overcomes these limitations.…”

Phelan–McDermid Syndrome and SHANK3: Implications for Treatment

“…Recurrent infections (ear and upper respiratory tract), allergies (seasonal and food), and asthma are also more common in PMS, although it is unclear if the recurring infections are due to difficulties with maintaining airways because of low muscle tone or a result of underlying immune system dysfunction [51]. Various dysmorphic features are also common in PMS, such as bulbous nose, ear anomalies (prominent and/or poorly formed), long eyelashes, pointed chin, dolichocephaly, hypoplastic/dysplastic nails, and large and fleshy hands [10,58,60,66].…”

Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development

“…1,3,6 Although one study 3 showed the severity of global developmental delay increased with the size of the deletion in 16 patients (plus 17 patients with r(22)), only 4/12 measures of developmental assessment showed some correlation with deletion size in a study of 56 patients. 6 If SHANK3 is responsible for most of the neurological abnormalities in these patients, this would imply that deletion of the region proximal to SHANK3 might have a mild phenotype that is largely masked by the terminal deletion of SHANK3.…”