22q11.2 Distal Deletion: A Recurrent Genomic Disorder Distinct from DiGeorge Syndrome and Velocardiofacial Syndrome

Shay Ben-Shachar, Zhishuo Ou, Chad A. Shaw, John W. Belmont, Millan S. Patel, Marybeth Hummel, Stephen Amato, Nicole Tartaglia, Jonathan Berg, V. Reid Sutton, Seema R. Lalani, A.  Craig Chinault, Sau W. Cheung, James R. Lupski, Ankita Patel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Microdeletions within chromosome 22q11.2 cause a variable phenotype, including DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). About 97% of patients with DGS/VCFS have either a common recurrent ∼3 Mb deletion or a smaller, less common, ∼1.5 Mb nested deletion. Both deletions apparently occur as a result of homologous recombination between nonallelic flanking low-copy repeat (LCR) sequences located in 22q11.2. Interestingly, although eight different LCRs are located in proximal 22q, only a few cases of atypical deletions utilizing alternative LCRs have been described. Using array-based comparative genomic hybridization (CGH) analysis, we have detected six unrelated cases of deletions that are within 22q11.2 and are located distal to the ∼3 Mb common deletion region. Further analyses revealed that the rearrangements had clustered breakpoints and either a ∼1.4 Mb or ∼2.1 Mb recurrent deletion flanked proximally by LCR22-4 and distally by either LCR22-5 or LCR22-6, respectively. Parental fluorescence in situ hybridization (FISH) analyses revealed that none of the available parents (11 out of 12 were available) had the deletion, indicating de novo events. All patients presented with characteristic facial dysmorphic features. A history of prematurity, prenatal and postnatal growth delay, developmental delay, and mild skeletal abnormalities was prevalent among the patients. Two patients were found to have a cardiovascular malformation, one had truncus arteriosus, and another had a bicuspid aortic valve. A single patient had a cleft palate. We conclude that distal deletions of chromosome 22q11.2 between LCR22-4 and LCR22-6, although they share some characteristic features with DGS/VCFS, represent a novel genomic disorder distinct genomically and clinically from the well-known DGS/VCF deletion syndromes.

Original languageEnglish
Pages (from-to)214-221
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number1
StatePublished - 10 Jan 2008
Externally publishedYes


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