1.5 Mb de novo 22q11.21 microduplication in a patient with cognitive deficits and dysmorphic facial features

Abstract

The 22q11.2 microduplication syndrome is caused by non-allelic homologous recombination mediated by misalignments of low copy repeats located in the region deleted in the DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS). The variable phenotype of such condition, consisting in a combination of dysmorphic facial features, cognitive deficits, velopharyngeal insufficiency, congenital heart defects and immunologic derangement, is caused usually in 90% of cases by a 3 Mb deletion or in a minority of cases (7%) by a 1.5 Mb deletion. The most common reciprocal event of deletion is the 3 Mb duplication, reported more recently with a variable phenotype, ranging from multiple defects to normality. In this study, we report a 2.5-year-old girl with cognitive deficits and dysmorphic facial features such as superior placement of eyebrows, upslanting palpebral fissures, widely spaced eyes, broad nasal bridge and epicanthal folds. Fluorescent in situ hybridization for DGS/VCFS region on metaphase chromosomes did not show any apparent anomaly. Subsequent array comparative genomic hybridization study, confirmed by multiplex ligation-dependent probe assay and microsatellite analysis, disclosed a 1.5 Mb de novo 22q11.21 duplication concerning the same chromosomal region deleted in a minority of patients with DGS. These findings identify the minimal duplicated region leading to this emerging syndrome.

Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes

“…Similar findings were reported by Yobb et al 39 who found significant variability among patients with ϳ3-Mb microduplications, with a spectrum of phenotypes, including developmental and speech delay, hearing impairment, failure to thrive, hypotonia, and behavioral abnormalities. The patient with a ϳ1.5-Mb proximal nested duplication reported by Alberti et al 37 has clinical manifestations similar to those observed in the four patients described herein, including developmental delay and dysmorphic features such as narrow forehead, wide nasal bridge, epicanthic folds, upslanting palpebral fissures, and micrognathia. Also, two groups reported finding no individuals with microduplications of 22q11.2 among 372 patients 40 and 295 patients 41 referred for clinical testing because of manifestations consistent with DGS/VCFS, suggesting that the microduplication is only rarely associated with this phenotype.…”

“…4). While this manuscript was in preparation, a single patient with a ϳ1.5 Mb proximal nested microduplication was reported by Alberti et al 37 and a patient mosaic for cell lines containing the reciprocal ϳ1.5-Mb microdeletion and microduplication of this region was reported by Dempsey et al, 38 but to our knowledge, the other atypical duplications have not previously been reported in the literature. The CMA results and high-resolution oligonucleotide array results are consistent with breakpoints of these various rearrangements involving most of the LCR22s that occur in this region.…”

Novel Submicroscopic Chromosomal Abnormalities Detected in Autism Spectrum Disorder

“…However, dup 22q11 and del 16p11.2 have a small number of patients for whom preliminary phenotypic characterization can begin. Currently, one 22q11 duplication has been reported in a single patient with autism (16), while additional subjects have been reported with features characteristic of autism without a formal diagnosis (17,18). The most consistent features of 22q11 duplication subjects were intellectual disability, neuropsychological problems and speech disorder (17).…”

Detailed analysis of 22q11.2 with a high density MLPA probe set

“…Although both deletions and duplications are expected to occur in equal proportions as a result of reciprocal LCR-mediated events, fewer duplications of 22q11.2 have been described, and the phenotype resulting from these duplications is extremely variable [Yobb et al, 2005;Vorstman et al, 2006a;Portnoi et al, 2005;Lindsay et al, 1995b;Hassed et al, 2004;Meins et al, 2003;Ensenauer et al, 2003;de La Rochebrochard et al, 2006;Mukaddes and Herguner, 2007;Alberti et al, 2007]. Further, the breakpoints implicated in generating the cat eye chromosome, a supernumerary inverted duplication of proximal 22q implicated in cat eye syndrome (CES; MIM# 115470), frequently match the proximal LCR or one of the more distal LCRs of the 22q11.2 region [McDermid et al, 1986;Mears et al, 1994].…”