Genomic profile of copy number variants on the short arm of human chromosome 8

Yu, Shihui; Fiedler, Stephanie; Stegner, Andrew L.; Graf, Wilhelm

doi:10.1038/ejhg.2010.66

Cited by 34 publications

(28 citation statements)

References 53 publications

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“…tables 2, 4, 5). This phenomenon was also observed in other genomic regions [Yu et al, 2010]. Although proposed mechanisms are available for explanation of the formation of genomic rearrangements in the human genome [Lupski, 2007;Makoff and Flomen, 2007;de Smith et al, 2008;Gu et al, 2008;Hastings et al, 2009], none of them can fully explain the occurrence of these deletion-or duplicationspecific CNVs observed in this study ( fig.…”

Section: Benign Cnv Profiles On Chromosome 22mentioning

confidence: 44%

Identification of Copy Number Variants on Human Chromosome 22 in Patients with a Variety of Clinical Findings

Graf

Ramalingam

et al. 2011

Cytogenet Genome Res

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The aims of this study were to create a copy number variant (CNV) profile of human chromosome 22 and to establish a genotype-phenotype correlation for patients with genomic abnormalities on chromosome 22. Thus, 1,654 consecutive pediatric patients with a diversity of clinical findings were evaluated by high-resolution chromosomal microarray analysis (CMA). We identified 25 individuals with abnormal CNVs on chromosome 22, representing 1.5% of the cases analyzed in this cohort. Meanwhile, we detected 1,298 benign CNVs on this chromosome in these individuals. Twenty-one of the 25 abnormal CNVs and the majority of the benign CNVs occurred through involvement of the 8 unstable genomic regions enriched with low copy repeats (LCR22A–H). The highly dynamic status of LCR22s within the 22q11 region facilitates the formation of diverse genomic abnormalities. This CNV profile provides a general perspective of the spectrum of chromosome 22 genomic imbalances and subsequently improves the CNV-phenotype correlations.

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Section: Benign Cnv Profiles On Chromosome 22mentioning

confidence: 44%

Identification of Copy Number Variants on Human Chromosome 22 in Patients with a Variety of Clinical Findings

Graf

Ramalingam

et al. 2011

Cytogenet Genome Res

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“…The second was an ∼5-Mb loss on the proximal portion of Chromosome 8 in two brain cells from the same individual and one skin cell from a different individual. This region of Chromosome 8 has previously been identified as a rearrangement hotspot because of an abundance of segmental duplications at chromosome coordinates 0, 1, 7, and 8 Mb that predispose this region to nonallelic homologous recombination (Bailey et al 2002;Yu et al 2010). A study (Yu et al 2010).…”

Section: Characteristics Of Somatic Cnvsmentioning

confidence: 99%

“…This region of Chromosome 8 has previously been identified as a rearrangement hotspot because of an abundance of segmental duplications at chromosome coordinates 0, 1, 7, and 8 Mb that predispose this region to nonallelic homologous recombination (Bailey et al 2002;Yu et al 2010). A study (Yu et al 2010). This region of Chromosome 8 has also been identified as a peak region of deletion across multiple tumor types and contains the tumor suppressor CSMD1 (Ma et al 2009;Midorikawa et al 2009;Zack et al 2013).…”

Section: Characteristics Of Somatic Cnvsmentioning

confidence: 99%

Assessment of megabase-scale somatic copy number variation using single-cell sequencing

2016

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Megabase-scale copy number variants (CNVs) can have profound phenotypic consequences. Germline CNVs of this magnitude are associated with disease and experience negative selection. However, it is unknown whether organismal function requires that every cell maintain a balanced genome. It is possible that large somatic CNVs are tolerated or even positively selected. Single-cell sequencing is a useful tool for assessing somatic genomic heterogeneity, but its performance in CNV detection has not been rigorously tested. Here, we develop an approach that allows for reliable detection of megabase-scale CNVs in single somatic cells. We discover large CNVs in 8%-9% of cells across tissues and identify two recurrent CNVs. We conclude that large CNVs can be tolerated in subpopulations of cells, and particular CNVs are relatively prevalent within and across individuals.[Supplemental material is available for this article.]Copy number variants (CNVs) can range in size from hundreds to millions of base pairs. Copy number changes affect approximately seven times as many base pairs as single-nucleotide variants and are major contributors to inter-individual differences (Sudmant et al. 2015). More than 65% of individuals harbor a germline CNV of at least 100 kb, and at least 1% of individuals have a CNV exceeding 1 Mb (Itsara et al. 2009). Although megabase-scale CNVs could be considered collectively common, the specific CNVs themselves are rare and often associated with disease (Girirajan et al. 2011). Not surprisingly, large CNVs experience negative selection, and their existence in a population is largely due to de novo events (Itsara et al. 2010).Although germline, megabase-scale CNVs are found in 1% of individuals, the prevalence of somatic CNVs is only beginning to be investigated. Array-based analyses of populations of cells from many individuals provided initial insight into this question. These studies identified megabase-scale somatic aberrations in up to 4% of individuals; however, the sensitivity was limited to CNVs present in >5% of cells (Forsberg et al. 2012;Jacobs et al. 2012;Laurie et al. 2012). These studies are thus blind to alterations that arise late in development or adversely affect fitness, as this would limit their propagation in a cell population. With the emergence of methods to amplify the genome of a single cell, single-cell sequencing now provides an alternate means of assessing the prevalence of somatic CNVs and offers the advantage of detecting variants that exist in as few as one cell. Recently, two groups performed low-coverage sequencing of single human neurons and reported at least one megabase-scale CNV in >40% of neurons (McConnell et al. 2013;Cai et al. 2014). These findings suggest much greater tolerance of large somatic CNVs compared to germline CNVs and raise the interesting possibility that somatic genomic heterogeneity contributes to phenotypic diversity within a tissue. However, it is still unclear how CNV detection methods perform when applied to individual cells, as single-cell sequ...

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“…Eight patients were found to carry genomic imbalances containing GATA4 of whom 4 were briefly described in our previous study that explored the genomic mechanisms underlying the formation of chromosomal abnormalities on the short arm of chromosome 8. 14 The present study protocol was approved by the Institutional Review Board of Children's Mercy Hospitals and Clinics.…”

Section: Specimensmentioning

confidence: 99%

Cardiac Defects Are Infrequent Findings in Individuals With 8p23.1 Genomic Duplications Containing GATA4

Zhou

Fiedler

et al. 2011

Circ Cardiovasc Genet

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Background-The GATA4 gene is critical to regulating myocardial differentiation and function. Haploinsufficiency of GATA4 is strongly associated with congenital heart defects (CHD). However, it is inconclusive whether duplicated GATA4 causes CHD. Methods and Results-We evaluated 1645 consecutive pediatric patients with various developmental disorders by highresolution microarray-based comparative genomic hybridization and found 8 probands and 2 relatives with pathogenic genomic imbalances containing GATA4. Four probands contain an Ϸ4.0-Mb interstitial duplication of 8p23.1 flanked by the 2 olfactory receptor gene clusters REPD and REPP, representing 0.24% (4/1645) of the patients analyzed. None of the 4 patients has CHD or any other heart diseases and 1 mother who transmitted the duplication to her child has a history of aortic stenosis. Two patients who carry multiple genomic abnormalities, including a duplication containing GATA4, have complex CHD. Only 1 of the 3 individuals carrying genomic deletion containing GATA4 has atrial septal and ventricular septal defects. Conclusions-Cardiac defects are infrequent findings in individuals with 8p23.1 genomic duplications containing GATA4.A 0.24% detection rate of this duplication in this study is significantly higher than previously estimated. Observation in 2 patients with multiple genomic abnormalities and complex CHD is consistent with a 2-hit model that emphasizes accumulative effects of Ͼ1 insult to the genome, leading to a visible or more severe clinical manifestation. Haploinsufficient GATA4 may show variable expressivity with a wide spectrum of clinical findings, including CHD.(Circ Cardiovasc Genet. 2011;4:620-625.)

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Genomic profile of copy number variants on the short arm of human chromosome 8

Cited by 34 publications

References 53 publications

Identification of Copy Number Variants on Human Chromosome 22 in Patients with a Variety of Clinical Findings

Identification of Copy Number Variants on Human Chromosome 22 in Patients with a Variety of Clinical Findings

Assessment of megabase-scale somatic copy number variation using single-cell sequencing

Cardiac Defects Are Infrequent Findings in Individuals With 8p23.1 Genomic Duplications Containing GATA4

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