Article

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

ABSTRACT

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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    • "In addition, the same repeat sequence is located in many places throughout the proximal 15q chromosome region (http://www.ncbi.nlm.nih.gov/pubmed/18177502 - 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.
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    • "Five recurrent breakpoints (BP) have been described in most patients of 15 rearrangements, from BP1 to BP5. PWS/AS critical region involves a segment that lies between BP2 and BP3 [Wang et al., 2008]. Each of the common breakpoints harbors transcribed END repeats that are derived from the ancestral HERC2 locus, which is located just proximal to BP3, as well as a number of other low-copy repeat (LCR) elements. "
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