A common molecular basis for rearrangement disorders on chromosome 22q11

Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA,
Human Molecular Genetics (Impact Factor: 6.68). 08/1999; 8(7):1157-67.
Source: PubMed

ABSTRACT The chromosome 22q11 region is susceptible to rearrangements that are associated with congenital anomaly disorders and malignant tumors. Three congenital anomaly disorders, cat-eye syndrome, der() syndrome and velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) are associated with tetrasomy, trisomy or monosomy, respectively, for part of chromosome 22q11. VCFS/DGS is the most common syndrome associated with 22q11 rearrangements. In order to determine whether there are particular regions on 22q11 that are prone to rearrangements, the deletion end-points in a large number of VCFS/DGS patients were defined by haplotype analysis. Most VCFS/DGS patients have a similar 3 Mb deletion, some have a nested distal deletion breakpoint resulting in a 1.5 Mb deletion and a few rare patients have unique deletions or translocations. The high prevalence of the disorder in the population and the fact that most cases occur sporadically suggest that sequences at or near the breakpoints confer susceptibility to chromosome rearrangements. To investigate this hypothesis, we developed hamster-human somatic hybrid cell lines from VCFS/DGS patients with all three classes of deletions and we now show that the breakpoints occur within similar low copy repeats, termed LCR22s. To support this idea further, we identified a family that carries an interstitial duplication of the same 3 Mb region that is deleted in VCFS/DGS patients. We present models to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders. We identified five additional copies of the LCR22 on 22q11 that may mediate other rearrangements leading to disease.

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    • "DS results from a 3-Mb deletion of chromosome 22q11 region spanning LCR22-A to LCR22-D. A minority of cases present either a common approximately 1.5-Mb nested deletion spanning LCR22-A to LCR22-B [Edelmann et al., 1999b]. Deletions distal to 22q11.21 have been reported. "
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    ABSTRACT: The 22q11 chromosomal region contains low copy repeats (LCRs) sequences that mediate non-allelic homologous recombination, which predisposes to copy number variations (CNVs) at this locus. Hemizygous deletions of the proximal 22q11.2 region result in the 22q11.2 deletion syndrome (22q11.2 DS). In addition, 22q11.2 duplications involving the distal LCR22s have been reported. This article describes a patient presenting a 2.5-Mb de novo deletion at proximal 22q11.21 region (between LCRs A-D), combined with a 1.3-Mb maternally inherited duplication at distal 22q11.23 region (between LCRs F-H). The presence of concomitant chromosomal imbalances found in this patient has not been reported previously. Clinical and molecular data were compared with literature, in order to contribute to genotype-phenotype correlation. These findings exemplify the complexity and genetic heterogeneity observed in 22q11.2 deletion syndrome and highlights the difficulty to make genetic counseling and predict phenotypic consequences in these situations. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2015; 167(1). DOI:10.1002/ajmg.a.36809 · 2.05 Impact Factor
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    • "The human 22q11.2 region is susceptible to chromosomal rearrangements because it contains low copy repeats (LCRs) [Edelmann et al., 1999; Babcock et al., 2003]. LCRs constitute $5% of the human genome and are 10–400 kb DNA blocks that show more than 95% identity between copies and can be responsible for genomic instability [Torres-Juan et al., 2007]. "
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    ABSTRACT: We examined a man and his daughter, who both had different jumping translocation karyotypes. The man's wife was pregnant and had been referred for prenatal diagnosis of the fetus. The karyotype of the husband's peripheral blood lymphocytes was 45,XY,der(16)t(16;22)(q24;q11.2), −22 [59]/45,XY,der(1)t(1;22)(p36;q11.2), −22 [11]/45,XY,der(22)t(22;22)(p13;q11.2), −22 [10]. The karyotype of the daughter's peripheral blood lymphocytes was 45,XX,der(16)t(16;22)(q24;q11.2), −22 [45]/45,XX,der(9)t(9;22)(q34;q11.2), −22 [30]/45,XX,der(5)t(5;22)(q35;q11.2), −22 [25]. The wife and the fetus both had a normal karyotype. To the best of our knowledge, the present familial transmitted jumping translocation has not been previously described and the jumping translocation in the husband and daughter did not cause any phenotypic abnormalities. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 08/2014; 164(8). DOI:10.1002/ajmg.a.36560 · 2.05 Impact Factor
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    • "Eight LCRs have been characterized at chromosome 22q11.2, designated 2e8 [7] or AeH [9] (Fig. 1). More than 85% of individuals with 22q11.2 "
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    ABSTRACT: The 22q11.2 Deletion Syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, with a highly variable phenotype. This chromosomal region contains low copy repeat (LCR) sequences that mediate non-allelic homologous recombination which predispose to copy number abnormalities at this locus. This article describes three patients investigated for suspicion of 22q11.2DS presenting atypical copy number abnormalities overlapping or not with the common ∼3Mb deletion. They were investigated by G-banding karyotype, Multiplex-ligation dependent probe amplification (MLPA) and array Genomic Hibridization (aGH). Clinical and molecular data were compared with literature, in order to contribute to genotype-phenotype correlation. Atypical chromosomal abnormalities were detected: 3.6 Mb deletion at 22q11.21-q11.23 between LCRs B-F in patient 1 and approximately 1.5 Mb deletion at 22q11.21-q11.22 between LCRs D-E in patients 2 and 3. The breakpoints detected in patient 1 have not been previously described. These findings exemplify the complexity and genetic heterogeneity observed in 22q11.2 region and corroborates the idea that genetic modifiers contribute to the phenotypic variability observed in proximal and distal 22q11.2 deletion syndromes.
    European journal of medical genetics 07/2013; 56(9). DOI:10.1016/j.ejmg.2013.07.002 · 1.49 Impact Factor
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