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22q11.2 microduplication syndrome
The newly described 22q11.2 microduplication syndrome (dup22q11 syndrome) is the association of a broad clinical spectrum and a duplication of the region that is deleted in patients with DiGeorge or velocardiofacial syndrome (DG/VCFS; see this term), establishing a complementary duplication syndrome.
ORPHA:1727Classification level: Disorder
Up till now more than 50 unrelated cases of dup22q11 syndrome have been reported with a high frequency of familial duplications.
The clinical presentation of patients is extremely variable and shares features with 22q11.2 deletion syndromes (DG/VCFS), including heart defects, urogenital abnormalities, velopharyngeal insufficiency with or without cleft palate, and ranging from multiple defects to mild learning difficulties with some individuals being essentially normal.
The basis of this clinical variability remains unclear. The low-copy repeats (LCR22) spanning the region predispose to homologous recombination events, and mediate nonallelic homologous recombinations that result in rearrangements of 22q11.2. The large majority of affected individuals have identical 3Mb microduplications identified with high accuracy by interphase fluorescence in situ hybridization (FISH) and other molecular techniques, such as array-comparative genomic hybridization (a-CGH). Proximal nested 1.5 Mb duplications or larger duplications were also reported. The 3Mb duplication encompasses a region containing 40 genes including the TBX1 gene that has been shown to be the major disease gene responsible for DG/VCFS. Interestingly, TBX1 gain-of-function mutations have been observed, resulting in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions, confirming that TBX1 overexpression might be responsible for the dup22q11.2 syndrome.
Management and treatment
Symptomatic treatment should be proposed by a multidisciplinary team and may require medical and/or surgical treatment for cardiac problems.
Prognosis is variable. Marked inter and intrafamilial variability is observed among patients with dup22q11.2. Some patients have been reported to have significant cardiovascular malformations leading to early death.