Scientific background

While the microdeletion 22q11.2 occurs with a prevalence of up to 1:4,000, microduplications of the same region are only observed in about half as many cases. Due to the underlying mechanism (NAHR: non-allelic homologous recombination in the region of low copy repeats), microduplications of the same region would be expected to occur as frequently. This may be partly due to the highly variable or mild phenotype which only leads to a diagnosis in a few cases. Furthermore, in the usual FISH analysis on metaphases, a duplication (two close signals) is more difficult to detect than a deletion (missing signal). For duplication diagnostics, FISH analysis on interphase cell nuclei is more suitable. Alternatively, MLPA and CMA (chromosomal microarray) may be considered. Most patients have a duplication of about 1.5 to 3 Mb which is often already present in one parent who is usually clinically inconspicuous.


The clinical symptoms are also intrafamilial highly variable, partly overlapping with the microdeletion 22q11.2, and range from cardiac and urogenital malformations, velopharyngeal insufficiency, mild learning difficulties, autism spectrum disorders to asymptomatic duplication carriers. In terms of external features, high-set eyebrows, wide interocular distance with an outward downward eyelid axis position, mild micro/retrognathia, and minor auricular dysplasia are observed. Hearing impairment is present in almost half of the patients. The duplicated region contains the TBX1 gene. In microdeletion, the loss of TBX1 is responsible for most of the symptoms. In the mouse model, it has been shown that overexpression of TBX1 as a result of a duplication also causes similar symptomatology to haploinsufficiency. This may explain the overlap of symptoms between microdeletion and microduplication 22q11.2.



Goldenberg P 2018, Pediatr Ann 47(5):e198 / Portnoi 2009, Eur J Med Genet 52 :88 / de La Rochebrochard et al. 2006, Am J Med Genet 114:1608 / Yobb et al. 2005, Am J Hum Genet 76:865 / Portnoi et al. 2005, Am J Med Genet 137A:47 / Ensenauer et al. 2003, Am J Hum Genet 73:1027




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