Multiple forms of atypical rearrangements generating supernumerary derivative chromosome 15

Nemours Biomedical Research, Alfred I, duPont Hospital for Children, Wilmington, Delaware, 19803, USA.
BMC Genetics (Impact Factor: 2.4). 02/2008; 9(1):2. DOI: 10.1186/1471-2156-9-2
Source: PubMed


Maternally-derived duplications that include the imprinted region on the proximal long arm of chromosome 15 underlie a complex neurobehavioral disorder characterized by cognitive impairment, seizures and a substantial risk for autism spectrum disorders1. The duplications most often take the form of a supernumerary pseudodicentric derivative chromosome 15 [der(15)] that has been called inverted duplication 15 or isodicentric 15 [idic(15)], although interstitial rearrangements also occur. Similar to the deletions found in most cases of Angelman and Prader Willi syndrome, the duplications appear to be mediated by unequal homologous recombination involving low copy repeats (LCR) that are found clustered in the region. Five recurrent breakpoints have been described in most cases of segmental aneuploidy of chromosome 15q11-q13 and previous studies have shown that most idic(15) chromosomes arise through BP3:BP3 or BP4:BP5 recombination events.
Here we describe four duplication chromosomes that show evidence of atypical recombination events that involve regions outside the common breakpoints. Additionally, in one patient with a mosaic complex der(15), we examined homologous pairing of chromosome 15q11-q13 alleles by FISH in a region of frontal cortex, which identified mosaicism in this tissue and also demonstrated pairing of the signals from the der(15) and the normal homologues.
Involvement of atypical BP in the generation of idic(15) chromosomes can lead to considerable structural heterogeneity.

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Article: Multiple forms of atypical rearrangements generating supernumerary derivative chromosome 15

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    • "In addition, the same repeat sequence is located in many places throughout the proximal 15q chromosome region ( - bib18). Five breakpoints were identified within the 15q proximal region and named BP1 to BP5 [12]. The critical region for the Prader-Willi and Angelman Syndromes has been determined to lie between BP2 and BP3 [13]. "
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    ABSTRACT: Background Complex small supernumerary marker chromosomes (sSMCs) consist of chromosomal material derived from more than one chromosome and have been implicated in reproductive problems such as recurrent pregnancy loss. They may also be associated with congenital abnormalities in the offspring of carriers. Due to its genomic architecture, chromosome 15 is frequently associated with rearrangements and the formation of sSMCs. Recently, several different CNVs have been described at 16p11.2, suggesting that this region is prone to rearrangements. Results We detected the concomitant occurrence of partial trisomy 15q and 16p, due to a complex sSMC, in a 6-year-old girl with clinical phenotypic. The karyotype was analyzed by G and C banding, NOR staining, FISH and SNP array and defined as 47,XX,+der(15)t(15;16)(q13;p13.2)mat. The array assay revealed an unexpected complex sSMC containing material from chromosomes 15 and 16, due to an inherited maternal translocation (passed along over several generations). The patient’s phenotype included microsomia, intellectual disability, speech delay, hearing impairment, dysphagia and other minor alterations. Discussion This is the first report on the concomitant occurrence of partial trisomy 15q and 16p. The wide range of phenotypes associated with complex sSMCs represents a challenge for genotype-phenotype correlation studies, accurate clinical assessment of patients and genetic counseling.
    Molecular Cytogenetics 04/2014; 7(1):29. DOI:10.1186/1755-8166-7-29 · 2.14 Impact Factor
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    • "A second limitation of aCGH in diagnostic settings is the inability to detect imbalances reproducibly when the tumor burden is below 20% [5,6,44]. Problems detecting low-level clonality were observed in four different clinical situations: 1) a normal aCGH result in a patient with a karyotypic-aberrant clone in the absence of morphologic disease; 2) low-level clonality in low-grade MDS, in particular with del(20q) or loss/rearrangement of a sex chromosome; 3) detection of the dominant clone only in a co-morbid patient; and 4) difficulty interpreting emerging subclones associated with clonal evolution of disease. "
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    ABSTRACT: Recent genome-wide microarray-based research investigations have revealed a high frequency of submicroscopic copy number alterations (CNAs) in the myelodysplastic syndromes (MDS), suggesting microarray-based comparative genomic hybridization (aCGH) has the potential to detect new clinically relevant genomic markers in a diagnostic laboratory. We performed an exploratory study on 30 cases of MDS, myeloproliferative neoplasia (MPN) or evolving acute myeloid leukemia (AML) (% bone marrow blasts ≤ 30%, range 0-30%, median, 8%) by aCGH, using a genome-wide bacterial artificial chromosome (BAC) microarray. The sample data were compared to corresponding cytogenetics, fluorescence in situ hybridization (FISH), and clinical-pathological findings. Previously unidentified imbalances, in particular those considered submicroscopic aberrations (< 10 Mb), were confirmed by FISH analysis. CNAs identified by aCGH were concordant with the cytogenetic/FISH results in 25/30 (83%) of the samples tested. aCGH revealed new CNAs in 14/30 (47%) patients, including 28 submicroscopic or hidden aberrations verified by FISH studies. Cryptic 344-kb RUNX1 deletions were found in three patients at time of AML transformation. Other hidden CNAs involved 3q26.2/EVI1, 5q22/APC, 5q32/TCERG1,12p13.1/EMP1, 12q21.3/KITLG, and 17q11.2/NF1. Gains of CCND2/12p13.32 were detected in two patients. aCGH failed to detect a balanced translocation (n = 1) and low-level clonality (n = 4) in five karyotypically aberrant samples, revealing clinically important assay limitations. The detection of previously known and unknown genomic alterations suggests that aCGH has considerable promise for identification of both recurring microscopic and submicroscopic genomic imbalances that contribute to myeloid disease pathogenesis and progression. These findings suggest that development of higher-resolution microarray platforms could improve karyotyping in clinical practice.
    Molecular Cytogenetics 11/2010; 3(1):23. DOI:10.1186/1755-8166-3-23 · 2.14 Impact Factor
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    • "DNA was extracted from peripheral blood leukocytes and LCL using the Gentra Puregene DNA extraction kit (Qiagen, Valencia CA) per the manufacturer's instructions. Genotyping was performed using 29 short tandem repeat polymorphism (STRP) markers from chromosome 15q and 19 from chromosome 9 (Tables 1 and 2) [24]. Methylation analyses at exon alpha of the SNRPN locus was examined by Southern blot and densitometry [25] and methylation specific PCR [26]. "
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    ABSTRACT: Autism spectrum disorders have been associated with maternally derived duplications that involve the imprinted region on the proximal long arm of chromosome 15. Here we describe a boy with a chromosome 15 duplication arising from a 3:1 segregation error of a paternally derived translocation between chromosome 15q13.2 and chromosome 9q34.12, which led to trisomy of chromosome 15pter-q13.2 and 9q34.12-qter. Using array comparative genome hybridization, we localized the breakpoints on both chromosomes and sequence homology suggests that the translocation arose from non-allelic homologous recombination involving the low copy repeats on chromosome 15. The child manifests many characteristics of the maternally-derived duplication chromosome 15 phenotype including developmental delays with cognitive impairment, autism, hypotonia and facial dysmorphisms with nominal overlap of the most general symptoms found in duplications of chromosome 9q34. This case suggests that biallelically expressed genes on proximal 15q contribute to the idic(15) autism phenotype.
    Molecular Cytogenetics 12/2009; 2(1):27. DOI:10.1186/1755-8166-2-27 · 2.14 Impact Factor
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