Microduplication and Triplication of 22q11.2: A Highly Variable Syndrome

Department of Biological Sciences, University of Alberta, Edmonton, Canada.
The American Journal of Human Genetics (Impact Factor: 10.93). 06/2005; 76(5):865-76. DOI: 10.1086/429841
Source: PubMed


22q11.2 microduplications of a 3-Mb region surrounded by low-copy repeats should be, theoretically, as frequent as the deletions of this region; however, few microduplications have been reported. We show that the phenotype of these patients with microduplications is extremely diverse, ranging from normal to behavioral abnormalities to multiple defects, only some of which are reminiscent of the 22q11.2 deletion syndrome. This diversity will make ascertainment difficult and will necessitate a rapid-screening method. We demonstrate the utility of four different screening methods. Although all the screening techniques give unique information, the efficiency of real-time polymerase chain reaction allowed the discovery of two 22q11.2 microduplications in a series of 275 females who tested negative for fragile X syndrome, thus widening the phenotypic diversity. Ascertainment of the fragile X-negative cohort was twice that of the cohort screened for the 22q11.2 deletion. We also report the first patient with a 22q11.2 triplication and show that this patient's mother carries a 22q11.2 microduplication. We strongly recommend that other family members of patients with 22q11.2 microduplications also be tested, since we found several phenotypically normal parents who were carriers of the chromosomal abnormality.

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    • "Furthermore, the chromosomal mechanism leading to the transition of a duplication in the father to a triplication in the proband is uncertain. Non-allelic homologous recombination leading to the expansion of a copy number variation during meiosis has already been described [Yobb et al., 2005]. Nevertheless, no low-copy repeats have been found at the 4q31.23 locus, suggesting that this hypothesis is unlikely. "
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    • "Many aspects of the clinical phenotype of this patient, including dysmorphic features [6] [10] [12] [16], congenital heart defects [4] [7], and motor, cognitive, and behavioral disturbances, have been previously described in individuals with 22q11.2 microduplication syndrome. "
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    ABSTRACT: Chromosome 22q11.2 microduplication syndrome is characterized by a variable and usually mild phenotype and by incomplete penetrance. Neurological features of the syndrome may entail intellectual or learning disability, motor delay, and other neurodevelopmental disorders. However, seizures or abnormal EEG are reported in a few cases. We describe a 6-year-old girl with microduplication of chromosome 22q11.2 and epilepsy with continuous spikes and waves during sleep (CSWS). Her behavioral disorder, characterized by hyperactivity, impulsiveness, attention deficit, and aggressiveness, became progressively evident a few months after epilepsy onset, suggesting a link with the interictal epileptic activity characterizing CSWS. We hypothesize that, at least in some cases, the neurodevelopmental deficit seen in the 22q11.2 microduplication syndrome could be the consequence of a disorder of cerebral electrogenesis, suggesting the need for an EEG recording in affected individuals. Moreover, an array-CGH analysis should be performed in all individuals with cryptogenic epilepsy and CSWS.
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    • "microduplication may overlap with that of individuals with the 22q11.2 deletion syndrome and Fragile-X syndrome, this overlap may represent only one part of this syndrome's phenotypic spectrum [5] [13]. "
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