Genetic Dosage Compensation in a Family with Velo-Cardio-Facial/DiGeorge/22q11.2 Deletion Syndrome
Department of Obstetrics and Gynecology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.American Journal of Medical Genetics Part A (Impact Factor: 2.16). 03/2011; 155A(3):548-54. DOI: 10.1002/ajmg.a.33861
Cytogenetic studies of a male child carrying the 22q11.2 deletion common in patients with velo-cardio-facial/DiGeorge syndrome showed an unexpected rearrangement of the 22q11.2 region in his normal appearing mother. The mother carried a 3 Mb deletion on one copy and a reciprocal, similar sized duplication on the other copy of chromosome 22q11.2 as shown by fluorescence in situ hybridization and array comparative genome hybridization analyses. The most parsimonious mechanism for the rearrangement is a mitotic non-allelic homologous recombination event in a cell in the early embryo soon after fertilization. The normal phenotype of the mother can be explained by the theory of genetic dosage compensation. This is the second documented case of such an event for this or any genomic disorder. This finding helps to reinforce this phenomenon in a human model, and has significant implications for recurrence risks for the dose-compensated mother.
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ABSTRACT: An array-CGH on 19-year-old male showed a proximal 1.11 Mb duplication and a distal 1.7 Mb deletion of 22q11.2 regions flanking the Velocardiofacial/DiGeorge syndrome region that remained intact. FISH analyses revealed both abnormalities to be on the same homolog 22. This double rearrangement lead to the co-existence of two syndromes: Cat eye and distal 22q11.2 microdeletion syndromes with a rare associated phenotype of oculo-auriculo-vertebral spectrum (OAVS). A review of the literature indicates that this is the second report of a proximal duplication and the fifth report of a distal deletion and OAVS suggestive of a possible OAVS candidate gene in this region. © 2013 Wiley Periodicals, Inc.
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ABSTRACT: Background We and others have previously reported that familial cytogenetic studies in apparently de novo genomic imbalances may reveal complex or uncommon inheritance mechanisms.MethodsA familial, combined genomic and cytogenetic approach was systematically applied to the parents of all patients with unbalanced genome copy number changes.ResultsDiscordant array-CGH and FISH results in the mother of a child with a prenatally detected 16p13.11 interstitial microduplication disclosed a balanced uncommon rearrangement in this chromosomal region. Further dosage and haplotype familial studies revealed that both the maternal grandfather and uncle had also the same 16p duplication as the proband. Genomic compensation observed in the mother probably occurred as a consequence of interchromosomal postzygotic nonallelic homologous recombination.Conclusions We emphasize that such a dualistic strategy is essential for the full characterization of genomic rearrangements as well as for appropriate genetic counseling.
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