Chromosome 22 band q11.2 has been recognized to be highly susceptible to subtle microdeletions and microduplications, which have been attributed to the presence of several large segmental duplications; also known as low copy repeats (LCRs). These LCRs function as mediators of non-allelic homologous recombination (NAHR), which results in these chromosomal rearrangements as a result of unequal crossover. The four centromeric LCRs at proximal 22q11.2 have been previously implicated in recurrent chromosomal rearrangements including the DiGeorge/Velocardiofacial syndrome (DG/VCFs) microdeletion and its reciprocal microduplication. Recently, we and others have demonstrated that the four telomeric LCRs at distal 22q11.2 are causally implicated in a newly recognized recurrent distal 22q11.2 microdeletion syndrome in the region immediately telomeric to the DG/VCFs typically deleted region. Here we report on the clinical, cytogenetic, and array CGH studies of a 4.5-year-old girl with history of failure to thrive, developmental delay (DD), and relative macrocephaly. She carries a paternally inherited approximately 2.1 Mb microduplication at distal 22q11.2, which spans approximately 34 annotated genes, and is flanked by two of the four telomeric 22q11.2 LCRs. We conclude that the four telomeric LCRs at distal 22q11.2 can mediate both deletions and duplications in this genomic region. Both deletions and duplication of this region present with subtle clinical features including mild to moderate mental retardation, DD, and mild dysmorphic features.
"As there is a history of hearing loss in the father of patient 4, another etiology cannot be excluded but disruption of gene expression of a gene in the D–E region is possible. Duplications involving LCR22 E–H and F–H have been reported to have a variable phenotype with little correlation with size of the abnormality but features include microcephaly, seizures, hypotonia, developmental delay, and neuropsychiatric issues (Descartes et al. 2008; Ou et al. 2008; Coppinger et al. 2009; Wincent et al. 2010; Shimojima et al. 2010). Neither patient 5 nor 6 had gross motor delay or any distinguishing physical characteristics except obesity in patient 5. Of note, one of this patient's siblings who tested negative for the duplication is also obese, suggesting a possible unrelated familial susceptibility or environmental factors. "
[Show abstract][Hide abstract] ABSTRACT: We describe six individuals with microdeletions and microduplications in the distal 22q11.2 region detected by microarray. Five of the abnormalities have breakpoints in the low-copy repeats (LCR) in this region and one patient has an atypical rearrangement. Two of the six patients with abnormalities in the region between LCR22 D–E have hearing loss, which has previously been reported only once in association with these abnormalities. We especially note the behavioral/neuropsychiatric problems, including the severity and early onset, in patients with distal 22q11.2 rearrangements. Our patients add to the genotype–phenotype correlations which are still being generated for these chromosomal anomalies.
"Duplications of 22q11.2 involving the distal LCR22s have also been reported [Descartes et al., 2008; Ou et al., 2008; Coppinger et al., 2009; Wincent et al., 2010; Tan et al., 2011; Ribeiro-Bicudo et al., 2013]. Similar to the proximal duplications, they appear to have a high rate of familial transmission and phenotypes vary among family members carrying this chromosomal abnormality [Portnoı¨et al., 2009; Ou et al., 2008; Coppinger et al., 2009; Wincent et al., 2010]. "
"More than 50 index cases with 22q11.2 duplications involving the distal LCR22s have been reported so far [Descartes et al., 2008; Ou et al., 2008; Lundin et al., 2010; Shimojima et al., 2010; Tan et al., 2011; Wincent et al., 2011]. Similar to the proximal duplications , there seems to be a high rate of familial transmission [Ensenauer et al., 2003; Hassed et al., 2004; Portnoi et al., 2005; Ou et al., 2008], and the phenotypes vary among family members carrying the duplications [Descartes et al., 2008; Wincent et al., 2011]. "
[Show abstract][Hide abstract] ABSTRACT: The 22q11.2 duplication syndrome has been recently characterized as a new entity with features overlapping the 22q11.2 deletion syndrome. Most 22q11.2 duplications represent reciprocal events of the typical 3-Mb deletions extending between low copy repeat (LCR) 22-A and LCR22-D. It has been suggested that the clinical manifestations observed in patients with 22q11.2 microduplications may range from milder phenotypes to multiple severe defects, and this variability could be responsible for many undetected cases. Here, we report on a patient with a 1.2-Mb microduplication at 22q11.2 spanning LCR22-F and LCR22-H which harbor the SMARCB1 and SNRPD3 genes. The patient presented healed cleft lip, mild facial dysmorphism, cognitive deficit, and delayed language development associated with severe behavioral problems including learning difficulties and aggressive behavior.
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