22q13.3 deletion syndrome: clinical and molecular analysis using array CGH

Abstract

The 22q13.3 deletion syndrome results from loss of terminal segments of varying sizes at 22qter. Few genotype-phenotype correlations have been found but all patients have mental retardation and severe delay, or absence of, expressive speech. We carried out clinical and molecular characterization of 13 patients. Developmental delay and speech abnormalities were common to all and comparable in frequency and severity to previously reported cases. Array-based comparative genomic hybridization showed the deletions to vary from 95 kb to 8.5 Mb. We also carried out high-resolution 244K array comparative genomic hybridization in 10 of 13 patients, that defined the proximal and distal breakpoints of each deletion and helped determine the size, extent, and gene content within the deletion. Two patients had a smaller 95 kb terminal deletion with breakpoints within the SHANK3 gene while three other patients had a similar 5.5 Mb deletion implying the recurrent nature of these deletions. The two largest deletions were found in patients with ring chromosome 22. No correlation could be made with deletion size and phenotype although complete/partial SHANK3 was deleted in all patients. There are very few reports on array comparative genomic hybridization analysis on patients with the 22q13.3 deletion syndrome, and we aim to accurately characterize these patients both clinically and at the molecular level, to pave the way for further genotype-phenotype correlations. (c) 2010 Wiley-Liss, Inc.

FIG. 1

A: Representation of the clinical array CGH data in Patient 3 indicating a loss in copy number (red circle). Below is shown the size and extent of deletions at 22q13 and the genes involved in the region. B: FISH analysis using a cosmid clone (n66c4) as a target probe labeled in red indicating a deletion involving the SHANK3 gene while RP11-316L10 is labeled in green and serves as a control probe. C: Physical map of 22q13.3 region representing SHANK3 and its neighboring genes ACR and RABL2B, the latter toward the telomere. FISH probes (COSMIDS) used in the hybridizations are indicated in the green bar below.

FIG. 2

Molecular data mapping the deletions in 10 patients on the 244K oligoarray which include the estimated proximal breakpoint and the distal breakpoint and the size of the deletion. Note: the deletion disrupts the SHANK3 gene in Patients 1 and 2.

FIG. 3

Facial features of six 22q13.3 deletion syndrome patients from this cohort. Photographs of Patients 2, 4, 5, 7, 8, and 10 from left to right then bottom left to right, respectively. The common features are listed in Table II. Individual features include: Patient 2: full cheeks; Patient 4: mild ptosis and long eyelashes with thick, bushy eyebrows; Patient 5: upslanting palpebral fissures with flat nasal bridge and long philtrum; Patient 7: bitemporal narrowing, thick bushy eyebrows, and low set ears; Patient 8: flat nasal bridge; Patient 10: bitemporal narrowing, upslanting palpebral fissures, and long eyelashes.