Dataset Information

Copy number changes and methylation patterns in an isodicentric and a ring chromosome of 15q11-q13: report of two cases and review of literature.

ABSTRACT: BACKGROUND:The low copy repeats (LCRs) in chromosome 15q11-q13 have been recognized as breakpoints (BP) for not only intrachromosomal deletions and duplications but also small supernumerary marker chromosomes 15, sSMC(15)s, in the forms of isodicentric chromosome or small ring chromosome. Further characterization of copy number changes and methylation patterns in these sSMC(15)s could lead to better understanding of their phenotypic consequences. METHODS:Routine G-band karyotyping, fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH) analysis and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay were performed on two Chinese patients with a sSMC(15). RESULTS:Patient 1 showed an isodicentric 15, idic(15)(q13), containing symmetrically two copies of a 7.7 Mb segment of the 15q11-q13 region by a BP3::BP3 fusion. Patient 2 showed a ring chromosome 15, r(15)(q13), with alternative one-copy and two-copy segments spanning a 12.3 Mb region. The defined methylation pattern indicated that the idic(15)(q13) and the r(15)(q13) were maternally derived. CONCLUSIONS:Results from these two cases and other reported cases from literature indicated that combined karyotyping, aCGH and MS-MLPA analyses are effective to define the copy number changes and methylation patterns for sSMC(15)s in a clinical setting. The characterized genomic structure and epigenetic pattern of sSMC(15)s could lead to further gene expression profiling for better phenotype correlation.

SUBMITTER: Wang Q

PROVIDER: S-EPMC4687147 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Copy number changes and methylation patterns in an isodicentric and a ring chromosome of 15q11-q13: report of two cases and review of literature.

Wang Qin Q Wu Weiqing W Xu Zhiyong Z Luo Fuwei F Zhou Qinghua Q Li Peining P Xie Jiansheng J

Molecular cytogenetics 20151221

<h4>Background</h4>The low copy repeats (LCRs) in chromosome 15q11-q13 have been recognized as breakpoints (BP) for not only intrachromosomal deletions and duplications but also small supernumerary marker chromosomes 15, sSMC(15)s, in the forms of isodicentric chromosome or small ring chromosome. Further characterization of copy number changes and methylation patterns in these sSMC(15)s could lead to better understanding of their phenotypic consequences.<h4>Methods</h4>Routine G-band karyotyping ...[more]

PMID: 26697114

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Project description:Background:Small supernumerary marker chromosomes (sSMCs) are common structurally abnormal chromosomes that occur in 0.288% of cases of mental retardation. Isodicentric 15 (idic(15)) is common in sSMCs and usually leads to a rare chromosome disorder with distinctive clinical phenotypes, including early central hypotonia, developmental delay, epilepsy, and autistic behavior. It was previously shown that the partial tetrasomy 15q and partial hexasomy 15q syndromes are usually caused by one and two extra idic(15), respectively. Karyotypes containing a mosaic partial octosomy 15q resulting from three extra idic(15) have rarely been reported. Case presentation:Two patients with profound intellectual impairment, development delay and hyperpigmentation were recruited for this study. The phenotype was relatively more severe in patient 1 than in patient 2. Conventional cytogenetic analysis of peripheral blood obtained from patients 1 and 2 revealed rare mosaic karyotypes containing sSMCs, i.e., mos 49,XX,+mar?×?3[83]/48,XX,+mar?×?2[7]/46,XX[10] and mos 48,XX,+mar?×?2[72]/47,XX,+mar[28], respectively. The results of analyses of copy number variation (CNV) and fluorescence in situ hybridization (FISH) analyses, showed that the sSMCs were found to be idic(15) involving the Prader-Willi/Angelman Syndrome Critical Region (PWACR) genes and the P gene, with duplication sizes of 6.3 Mb and 9.7 Mb, respectively. DNA fingerprinting analysis of patient 1 showed a maternal origin for the idic(15). Both patients had mosaic idic(15) karyotypes: patient 1 had cells with a 15q partial octosomy (83%), and patient 2 had cells with a 15q partial hexasomy (72%). Conclusions:We detected two rare mosaic idic(15) karyotypes that were associated with congenital abnormalities, including a rare mosaic octosomy of 15q11-q13. Our cases further validate the notion that the phenotypic severity is correlated with the level of mosaicism and the dosage effect of related genes in the proximal 15q.

Project description:Duplications of the chromosome 15q11-q13.1 region are associated with an estimated 1 to 3% of all autism cases, making this copy number variation (CNV) one of the most frequent chromosome abnormalities associated with autism spectrum disorder (ASD). Several genes located within the 15q11-q13.1 duplication region including ubiquitin protein ligase E3A (UBE3A), the gene disrupted in Angelman syndrome (AS), are involved in neural function and may play important roles in the neurobehavioral phenotypes associated with chromosome 15q11-q13.1 duplication (Dup15q) syndrome.We have generated induced pluripotent stem cell (iPSC) lines from five different individuals containing CNVs of 15q11-q13.1. The iPSC lines were differentiated into mature, functional neurons. Gene expression across the 15q11-q13.1 locus was compared among the five iPSC lines and corresponding iPSC-derived neurons using quantitative reverse transcription PCR (qRT-PCR). Genome-wide gene expression was compared between neurons derived from three iPSC lines using mRNA-Seq.Analysis of 15q11-q13.1 gene expression in neurons derived from Dup15q iPSCs reveals that gene copy number does not consistently predict expression levels in cells with interstitial duplications of 15q11-q13.1. mRNA-Seq experiments show that there is substantial overlap in the genes differentially expressed between 15q11-q13.1 deletion and duplication neurons, Finally, we demonstrate that UBE3A transcripts can be pharmacologically rescued to normal levels in iPSC-derived neurons with a 15q11-q13.1 duplication.Chromatin structure may influence gene expression across the 15q11-q13.1 region in neurons. Genome-wide analyses suggest that common neuronal pathways may be disrupted in both the Angelman and Dup15q syndromes. These data demonstrate that our disease-specific stem cell models provide a new tool to decipher the underlying cellular and genetic disease mechanisms of ASD and may also offer a pathway to novel therapeutic intervention in Dup15q syndrome.

Dataset Information

Copy number changes and methylation patterns in an isodicentric and a ring chromosome of 15q11-q13: report of two cases and review of literature.

Publications

Copy number changes and methylation patterns in an isodicentric and a ring chromosome of 15q11-q13: report of two cases and review of literature.

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