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Mosaic structural variation in children with developmental disorders

Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2–1.0% of children ascertained for clin...

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Autores principales: King, Daniel A., Jones, Wendy D., Crow, Yanick J., Dominiczak, Anna F., Foster, Nicola A., Gaunt, Tom R., Harris, Jade, Hellens, Stephen W., Homfray, Tessa, Innes, Josie, Jones, Elizabeth A., Joss, Shelagh, Kulkarni, Abhijit, Mansour, Sahar, Morris, Andrew D., Parker, Michael J., Porteous, David J., Shihab, Hashem A., Smith, Blair H., Tatton-Brown, Katrina, Tolmie, John L., Trzaskowski, Maciej, Vasudevan, Pradeep C., Wakeling, Emma, Wright, Michael, Plomin, Robert, Timpson, Nicholas J., Hurles, Matthew E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406290/
https://www.ncbi.nlm.nih.gov/pubmed/25634561
http://dx.doi.org/10.1093/hmg/ddv033
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author King, Daniel A.
Jones, Wendy D.
Crow, Yanick J.
Dominiczak, Anna F.
Foster, Nicola A.
Gaunt, Tom R.
Harris, Jade
Hellens, Stephen W.
Homfray, Tessa
Innes, Josie
Jones, Elizabeth A.
Joss, Shelagh
Kulkarni, Abhijit
Mansour, Sahar
Morris, Andrew D.
Parker, Michael J.
Porteous, David J.
Shihab, Hashem A.
Smith, Blair H.
Tatton-Brown, Katrina
Tolmie, John L.
Trzaskowski, Maciej
Vasudevan, Pradeep C.
Wakeling, Emma
Wright, Michael
Plomin, Robert
Timpson, Nicholas J.
Hurles, Matthew E.
author_facet King, Daniel A.
Jones, Wendy D.
Crow, Yanick J.
Dominiczak, Anna F.
Foster, Nicola A.
Gaunt, Tom R.
Harris, Jade
Hellens, Stephen W.
Homfray, Tessa
Innes, Josie
Jones, Elizabeth A.
Joss, Shelagh
Kulkarni, Abhijit
Mansour, Sahar
Morris, Andrew D.
Parker, Michael J.
Porteous, David J.
Shihab, Hashem A.
Smith, Blair H.
Tatton-Brown, Katrina
Tolmie, John L.
Trzaskowski, Maciej
Vasudevan, Pradeep C.
Wakeling, Emma
Wright, Michael
Plomin, Robert
Timpson, Nicholas J.
Hurles, Matthew E.
author_sort King, Daniel A.
collection PubMed
description Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2–1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case–control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e − 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e − 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic–phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders.
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spelling pubmed-44062902015-04-27 Mosaic structural variation in children with developmental disorders King, Daniel A. Jones, Wendy D. Crow, Yanick J. Dominiczak, Anna F. Foster, Nicola A. Gaunt, Tom R. Harris, Jade Hellens, Stephen W. Homfray, Tessa Innes, Josie Jones, Elizabeth A. Joss, Shelagh Kulkarni, Abhijit Mansour, Sahar Morris, Andrew D. Parker, Michael J. Porteous, David J. Shihab, Hashem A. Smith, Blair H. Tatton-Brown, Katrina Tolmie, John L. Trzaskowski, Maciej Vasudevan, Pradeep C. Wakeling, Emma Wright, Michael Plomin, Robert Timpson, Nicholas J. Hurles, Matthew E. Hum Mol Genet Articles Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2–1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case–control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e − 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e − 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic–phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders. Oxford University Press 2015-05-15 2015-01-29 /pmc/articles/PMC4406290/ /pubmed/25634561 http://dx.doi.org/10.1093/hmg/ddv033 Text en © The Author 2015. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
King, Daniel A.
Jones, Wendy D.
Crow, Yanick J.
Dominiczak, Anna F.
Foster, Nicola A.
Gaunt, Tom R.
Harris, Jade
Hellens, Stephen W.
Homfray, Tessa
Innes, Josie
Jones, Elizabeth A.
Joss, Shelagh
Kulkarni, Abhijit
Mansour, Sahar
Morris, Andrew D.
Parker, Michael J.
Porteous, David J.
Shihab, Hashem A.
Smith, Blair H.
Tatton-Brown, Katrina
Tolmie, John L.
Trzaskowski, Maciej
Vasudevan, Pradeep C.
Wakeling, Emma
Wright, Michael
Plomin, Robert
Timpson, Nicholas J.
Hurles, Matthew E.
Mosaic structural variation in children with developmental disorders
title Mosaic structural variation in children with developmental disorders
title_full Mosaic structural variation in children with developmental disorders
title_fullStr Mosaic structural variation in children with developmental disorders
title_full_unstemmed Mosaic structural variation in children with developmental disorders
title_short Mosaic structural variation in children with developmental disorders
title_sort mosaic structural variation in children with developmental disorders
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406290/
https://www.ncbi.nlm.nih.gov/pubmed/25634561
http://dx.doi.org/10.1093/hmg/ddv033
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