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Up till now more than 50 unrelated cases have been reported with a high frequency of familial duplications.

The age at diagnosis is variable and depends on the clinical manifestations. The clinical presentation of patients shares features with 22q11.2 deletion syndrome (DG/VCFS), including heart defects, velopharyngeal insufficiency with or without cleft palate. The clinical picture is highly variable with incomplete penetrance, ranging from multiple defects with severe intellectual disability to mild learning difficulties with some individuals being essentially normal. Bladder exstrophy, a very rare malformation in the general population, is significantly associated with the duplication. A high rate of autism spectrum disorder is found. Congenital heart defects and urogenital anomalies can be detected in utero, whereas asymptomatic individuals are usually diagnosed after the birth of a severely affected relative.

The basis of this clinical variability remains unclear. The low-copy repeats spanning the region 22q11.2 (LCR22) predispose to homologous recombination events, often nonallelic, that result in rearrangements of 22q11.2. The large majority of affected individuals have identical 3Mb microduplications; however, proximal nested 1.5 Mb duplications or larger duplications are 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 resulting in the same phenotypic spectrum as haploinsufficiency have been observed, and suggests that TBX1 overexpression might be responsible for the 22q11.2 duplication syndrome.

The 22q11.2 duplication is detected by fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification, array comparative genome hybridization (aCGH) or genome-wide SNP (single nucleotide polymorphism) microarrays.

The main differential diagnosis is DG/VCFS.

Detection of the duplication on fetal sample by FISH or a-CGH should be discussed with the parents of an index case during subsequent pregnancies or when a parent carries the microduplication.

Transmission is autosomal dominant. Most cases are inherited from a pauci or asymptomatic parent. An affected individual has a 50% risk of transmitting the duplication.

Symptomatic treatment should be proposed by a multidisciplinary team including pediatricians, child psychiatrists.

Prognosis is variable. Marked inter and intrafamilial variability is observed among patients. Some patients have been reported to have significant cardiovascular malformations leading to early death.