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

Abstract

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 approximately 3 Mb deletion or a smaller, less common, approximately 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 approximately 3 Mb common deletion region. Further analyses revealed that the rearrangements had clustered breakpoints and either a approximately 1.4 Mb or approximately 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.

The recurrent distal 22q11.2 microdeletions are often de novo and do not represent a single clinical entity: a proposed categorization system

“…8,9,12,15,17,18 A similar frequency of cardiac defects was noted in our study, with five patients (~42%) presenting with a history of a cardiac defect, including patent ductus arteriosus, atrial and ventricular septal defects, and bicuspid aortic…”

“…MAPK1 encodes mitogen-activated protein kinase 1 and has been proposed to be a candidate for the prematurity and/ or low birth weight in distal 22q11.2 microdeletions due to the fact that it is involved in placental development. 12 These data suggest that pre-and postnatal growth restriction with short stature are common features of the distal 22q11.2 deletions that span the LCR22-D to -E interval but not of those that span the LCR22-E to -F interval.…”

“…DD and/or ID have been reported in more than 80% of distal 22q11.2 microdeletion patients described in the literature to date and tend to be relatively mild to moderate in severity. [7][8][9][10][11][12][13][14][15][16][17][18] Taken together, global DD and ID seem to be key components of the distal 22q11.2 microdeletions phenotype irrespective of the size and position of the deletion. Behavioral and neurological problems were also quite common in our patients in all deletion types.…”

“…[7][8][9][10][11][12][13][14][15][16][17][18] These deletions are mediated by nonallelic homologous recombination between the five telomeric LCR22s (LCR22-D to -H) in the distal portion of the 22q11.2 region (Figure 2). 10 Distal 22q11.2 microdeletions that span the LCR22-F to -G interval encompassing the tumor suppressor SMARCB1 gene (also called INI1) have been reported to manifest many of the presenting features mentioned above but also have high incidence of malignant rhabdoid tumors in infancy and early childhood, predominantly in the kidneys and central nervous system, which necessitates tumor surveillance in these patients.…”

“…6 Recently, others and we demonstrated that the five telomeric LCR22s, namely LCR22-D to H, at the distal portion of 22q11.2 are causally implicated in the recurrent distal 22q11.2 microdeletion-associated phenotype(s) (OMIM 611867), and their reciprocal microduplications in the region immediately distal to the DG/VCFs typically deleted region (Figure 2). [7][8][9][10][11][12][13][14][15][16][17][18] The structure of the LCR22-D, -E, and -F has been studied and was shown to contain the BCRL module in each LCR22, suggesting that the distal 22q11.2 microdeletions/microduplications are mediated by nonallelic homologous recombination. 10 To date, the distal 22q11.2 microdeletions have been grouped together as a single clinical entity despite the fact that these deletions are variable in size and position depending on the Purpose: The five segmental duplications (LCR22-D to -H) at the distal region of chromosome 22 band q11.2 in the region immediately distal to the DiGeorge/velocardiofacial syndrome deleted region have been implicated in the recurrent distal 22q11.2 microdeletions.…”