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: 2.05). 03/2011; 155A(3):548-54. DOI: 10.1002/ajmg.a.33861
Source: PubMed

ABSTRACT 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: Background The rearrangements in the 22q11.2 chromosomal region, responsible for the 22q11.2 deletion and microduplication syndromes, are frequently associated with congenital heart disease (CHD). The present work aimed to identify the genetic basis of CHD in 87 patients from the São Miguel Island, Azores, through the detection of copy number variants (CNVs) in the 22q11.2 region. These structural variants were searched using multiplex ligation-dependent probe amplification (MLPA). In patients with CNVs, we additionally performed fluorescent in situ hybridization (FISH) for the assessment of the exact number of 22q11.2 copies among each chromosome, and array comparative genomic hybridization (array-CGH) for the determination of the exact length of CNVs.ResultsWe found that four patients (4.6%; A to D) carried CNVs. Patients A and D, both affected with a ventricular septal defect, carried a de novo 2.5 Mb deletion of the 22q11.2 region, which was probably originated by inter-chromosomal (inter-chromatid) non-allelic homologous recombination (NAHR) events in the regions containing low-copy repeats (LCRs). Patient C, with an atrial septal defect, carried a de novo 2.5 Mb duplication of 22q11.2 region, which could have been probably generated during gametogenesis by NAHR or by unequal crossing-over; additionally, this patient presented a benign 288 Kb duplication, which included the TOP3B gene inherited from her healthy mother. Finally, patient B showed a 3 Mb triplication associated with dysmorphic facial features, cognitive deficit and heart defects, a clinical feature not reported in the only case described so far in the literature. The evaluation of patient B¿s parents revealed a 2.5 Mb duplication in her father, suggesting a paternal inheritance with an extra copy.Conclusions This report allowed the identification of rare deletion and microduplication syndromes in Azorean CHD patients. Moreover, we report the second patient with a 22q11.2 triplication, and we suggest that patients with triplications of chromosome 22q11.2, although they share some characteristic features with the deletion and microduplication syndromes, present a more severe phenotype probably due to the major dosage of implicated genes.
    BMC Genetics 11/2014; 15(1):115. DOI:10.1186/s12863-014-0115-6 · 2.36 Impact Factor
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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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    American Journal of Medical Genetics Part A 08/2013; 161(8):1992-8. DOI:10.1002/ajmg.a.35918 · 2.05 Impact Factor