The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies
Main Author: | |
---|---|
Publication Date: | 2016 |
Other Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | eng |
Source: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Download full: | http://hdl.handle.net/10400.18/4461 |
Summary: | Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology. |
id |
RCAP_17fdd196d4b0ec6bf21c51dec837d61a |
---|---|
oai_identifier_str |
oai:repositorio.insa.pt:10400.18/4461 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomaliesCytogeneticsStructural VariationBalanced Chromosomal AbnormalityCongenital AnomalyIntellectual DisabilityAutismTranslocationInversionChromothripsisTopologically Associated Domain (TAD)MEF2CCytogenetic AbnormalitiesHuman Congenital AnomaliesDoenças GenómicasDoenças GenéticasDespite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.Nature Publishing GroupRepositório Científico do Instituto Nacional de SaúdeRedin, ClaireBrand, HarrisonCollins, Ryan L.Kammin, TammyMitchell, ElyseHodge, Jennelle C.Hanscom, CarriePillalamarri, VamseeSeabra, Catarina M.Abbott, Mary-AliceAbdul-Rahman, Omar A.de Vries, Bert B A.Earl, Dawn L.Ferguson, Heather L.Harris, David J.Fisher, HeatherFitzPatrick, David R.Gerrol, PamelaGiachino, DanielaGlessner, Joseph T.Gliem, TroyMargolin, LaurenGrady, MargoGraham, Brett H.Griffis, CristinHayden, Mark A.Hill, RosamundHochstenbach, RonHoffman, Jodi D.Hopkin, Robert J.Hubshman, Monika W.Moya, GracielaMason, TamaraInnes, A MicheilIrons, MiraIrving, MelitaJacobsen, Jessie C.Janssens, SandraJewett, TamisonJohnson, John P.Jongmans, Marjolijn C.Kahler, Stephen G.Koolen, David A.Masser-Frye, DianeNieuwint, Aggie W.Korzelius, JeromeKroisel, Peter M.Lacassie, YvesLawless, WilliamLemyre, EmmanuelleLeppig, KathleenLevin, Alex V.Li, HaiboLi, HongParkash, SandhyaLiao, Eric C.Ordulu, ZehraLim, CynthiaLose, Edward J.Lucente, DianeMacera, Michael J.Manavalan, PoornimaMandrile, GiorgiaMarcelis, Carlo L.McClellan, Michael W.Mendoza, Cinthya J. ZepedaMenten, BjörnMiddelkamp, SjorsMikami, Liya R.Moe, EmilyWiley, SusanMohammed, ShehlaMononen, TarjaMortenson, Megan E.Pauker, Susan P.Pereira, ShahrinPerrin, DaniellePhelan, KatyAguilar, Raul E PiñaPoddighe, Pino J.Aberg, ErikaWilson, AnnaPregno, GiuliaRaskin, SalmoReis, LindaRhead, WilliamRita, DebraRenkens, IvoRoelens, FilipRuliera, JaylaRump, PatrickSchilit, Samantha L.P.Yerena-de Vega, Maria de la Concepcion A.Adley, RhettShaheen, RanadSparkes, RebeccaSpiegel, EricaStevens, BlairStone, Matthew R.Tagoe, JuliaThakuria, Joseph V.van Bon, Bregje W.van de Kamp, JiddekeAlkuraya, Fowzan S.van Der Burgt, InekeAlcaraz-Estrada, Sofia L.van Essen, Tonvan Ravenswaaij-Arts, Conny M.van Roosmalen, Markus J.Vergult, SarahVolker-Touw, Catharina M.L.Warburton, Dorothy P.Waterman, Matthew J.Zori, Roberto T.Levy, BrynnBrunner, Han G.de Leeuw, NicoleKloosterman, Wigard P.Thorland, Erik C.Gripp, Karen W.Morton, Cynthia C.Gusella, James F.Talkowski, Michael E.An, YuAnderson, Mary-AnneAntolik, CarolineAnyane-Yeboa, KwameAtkin, Joan F.Bartell, TinaBernstein, Jonathan A.Gropman, Andrea L.Beyer, ElizabethBlumenthal, IanBongers, Ernie M.H.F.Brilstra, Eva H.Brown, Chester W.Brüggenwirth, Hennie T.Callewaert, BertChiang, ColbyCorning, KenCox, HelenHanson-Kahn, AndreaCuppen, EdwinCurrall, Benjamin B.Cushing, TomDavid, DezsőDeardorff, Matthew A.Dheedene, AnneliesD'Hooghe, Marc2017-03-03T17:09:28Z2016-11-142016-11-14T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/4461engNat Genet. 2017 Jan;49(1):36-45. doi: 10.1038/ng.3720. Epub 2016 Nov 14.1061-403610.1038/ng.3720info:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:40:22Zoai:repositorio.insa.pt:10400.18/4461Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:39:18.657655Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies |
title |
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies |
spellingShingle |
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin, Claire Cytogenetics Structural Variation Balanced Chromosomal Abnormality Congenital Anomaly Intellectual Disability Autism Translocation Inversion Chromothripsis Topologically Associated Domain (TAD) MEF2C Cytogenetic Abnormalities Human Congenital Anomalies Doenças Genómicas Doenças Genéticas |
title_short |
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies |
title_full |
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies |
title_fullStr |
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies |
title_full_unstemmed |
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies |
title_sort |
The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies |
author |
Redin, Claire |
author_facet |
Redin, Claire Brand, Harrison Collins, Ryan L. Kammin, Tammy Mitchell, Elyse Hodge, Jennelle C. Hanscom, Carrie Pillalamarri, Vamsee Seabra, Catarina M. Abbott, Mary-Alice Abdul-Rahman, Omar A. de Vries, Bert B A. Earl, Dawn L. Ferguson, Heather L. Harris, David J. Fisher, Heather FitzPatrick, David R. Gerrol, Pamela Giachino, Daniela Glessner, Joseph T. Gliem, Troy Margolin, Lauren Grady, Margo Graham, Brett H. Griffis, Cristin Hayden, Mark A. Hill, Rosamund Hochstenbach, Ron Hoffman, Jodi D. Hopkin, Robert J. Hubshman, Monika W. Moya, Graciela Mason, Tamara Innes, A Micheil Irons, Mira Irving, Melita Jacobsen, Jessie C. Janssens, Sandra Jewett, Tamison Johnson, John P. Jongmans, Marjolijn C. Kahler, Stephen G. Koolen, David A. Masser-Frye, Diane Nieuwint, Aggie W. Korzelius, Jerome Kroisel, Peter M. Lacassie, Yves Lawless, William Lemyre, Emmanuelle Leppig, Kathleen Levin, Alex V. Li, Haibo Li, Hong Parkash, Sandhya Liao, Eric C. Ordulu, Zehra Lim, Cynthia Lose, Edward J. Lucente, Diane Macera, Michael J. Manavalan, Poornima Mandrile, Giorgia Marcelis, Carlo L. McClellan, Michael W. Mendoza, Cinthya J. Zepeda Menten, Björn Middelkamp, Sjors Mikami, Liya R. Moe, Emily Wiley, Susan Mohammed, Shehla Mononen, Tarja Mortenson, Megan E. Pauker, Susan P. Pereira, Shahrin Perrin, Danielle Phelan, Katy Aguilar, Raul E Piña Poddighe, Pino J. Aberg, Erika Wilson, Anna Pregno, Giulia Raskin, Salmo Reis, Linda Rhead, William Rita, Debra Renkens, Ivo Roelens, Filip Ruliera, Jayla Rump, Patrick Schilit, Samantha L.P. Yerena-de Vega, Maria de la Concepcion A. Adley, Rhett Shaheen, Ranad Sparkes, Rebecca Spiegel, Erica Stevens, Blair Stone, Matthew R. Tagoe, Julia Thakuria, Joseph V. van Bon, Bregje W. van de Kamp, Jiddeke Alkuraya, Fowzan S. van Der Burgt, Ineke Alcaraz-Estrada, Sofia L. van Essen, Ton van Ravenswaaij-Arts, Conny M. van Roosmalen, Markus J. Vergult, Sarah Volker-Touw, Catharina M.L. Warburton, Dorothy P. Waterman, Matthew J. Zori, Roberto T. Levy, Brynn Brunner, Han G. de Leeuw, Nicole Kloosterman, Wigard P. Thorland, Erik C. Gripp, Karen W. Morton, Cynthia C. Gusella, James F. Talkowski, Michael E. An, Yu Anderson, Mary-Anne Antolik, Caroline Anyane-Yeboa, Kwame Atkin, Joan F. Bartell, Tina Bernstein, Jonathan A. Gropman, Andrea L. Beyer, Elizabeth Blumenthal, Ian Bongers, Ernie M.H.F. Brilstra, Eva H. Brown, Chester W. Brüggenwirth, Hennie T. Callewaert, Bert Chiang, Colby Corning, Ken Cox, Helen Hanson-Kahn, Andrea Cuppen, Edwin Currall, Benjamin B. Cushing, Tom David, Dezső Deardorff, Matthew A. Dheedene, Annelies D'Hooghe, Marc |
author_role |
author |
author2 |
Brand, Harrison Collins, Ryan L. Kammin, Tammy Mitchell, Elyse Hodge, Jennelle C. Hanscom, Carrie Pillalamarri, Vamsee Seabra, Catarina M. Abbott, Mary-Alice Abdul-Rahman, Omar A. de Vries, Bert B A. Earl, Dawn L. Ferguson, Heather L. Harris, David J. Fisher, Heather FitzPatrick, David R. Gerrol, Pamela Giachino, Daniela Glessner, Joseph T. Gliem, Troy Margolin, Lauren Grady, Margo Graham, Brett H. Griffis, Cristin Hayden, Mark A. Hill, Rosamund Hochstenbach, Ron Hoffman, Jodi D. Hopkin, Robert J. Hubshman, Monika W. Moya, Graciela Mason, Tamara Innes, A Micheil Irons, Mira Irving, Melita Jacobsen, Jessie C. Janssens, Sandra Jewett, Tamison Johnson, John P. Jongmans, Marjolijn C. Kahler, Stephen G. Koolen, David A. Masser-Frye, Diane Nieuwint, Aggie W. Korzelius, Jerome Kroisel, Peter M. Lacassie, Yves Lawless, William Lemyre, Emmanuelle Leppig, Kathleen Levin, Alex V. Li, Haibo Li, Hong Parkash, Sandhya Liao, Eric C. Ordulu, Zehra Lim, Cynthia Lose, Edward J. Lucente, Diane Macera, Michael J. Manavalan, Poornima Mandrile, Giorgia Marcelis, Carlo L. McClellan, Michael W. Mendoza, Cinthya J. Zepeda Menten, Björn Middelkamp, Sjors Mikami, Liya R. Moe, Emily Wiley, Susan Mohammed, Shehla Mononen, Tarja Mortenson, Megan E. Pauker, Susan P. Pereira, Shahrin Perrin, Danielle Phelan, Katy Aguilar, Raul E Piña Poddighe, Pino J. Aberg, Erika Wilson, Anna Pregno, Giulia Raskin, Salmo Reis, Linda Rhead, William Rita, Debra Renkens, Ivo Roelens, Filip Ruliera, Jayla Rump, Patrick Schilit, Samantha L.P. Yerena-de Vega, Maria de la Concepcion A. Adley, Rhett Shaheen, Ranad Sparkes, Rebecca Spiegel, Erica Stevens, Blair Stone, Matthew R. Tagoe, Julia Thakuria, Joseph V. van Bon, Bregje W. van de Kamp, Jiddeke Alkuraya, Fowzan S. van Der Burgt, Ineke Alcaraz-Estrada, Sofia L. van Essen, Ton van Ravenswaaij-Arts, Conny M. van Roosmalen, Markus J. Vergult, Sarah Volker-Touw, Catharina M.L. Warburton, Dorothy P. Waterman, Matthew J. Zori, Roberto T. Levy, Brynn Brunner, Han G. de Leeuw, Nicole Kloosterman, Wigard P. Thorland, Erik C. Gripp, Karen W. Morton, Cynthia C. Gusella, James F. Talkowski, Michael E. An, Yu Anderson, Mary-Anne Antolik, Caroline Anyane-Yeboa, Kwame Atkin, Joan F. Bartell, Tina Bernstein, Jonathan A. Gropman, Andrea L. Beyer, Elizabeth Blumenthal, Ian Bongers, Ernie M.H.F. Brilstra, Eva H. Brown, Chester W. Brüggenwirth, Hennie T. Callewaert, Bert Chiang, Colby Corning, Ken Cox, Helen Hanson-Kahn, Andrea Cuppen, Edwin Currall, Benjamin B. Cushing, Tom David, Dezső Deardorff, Matthew A. Dheedene, Annelies D'Hooghe, Marc |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
Redin, Claire Brand, Harrison Collins, Ryan L. Kammin, Tammy Mitchell, Elyse Hodge, Jennelle C. Hanscom, Carrie Pillalamarri, Vamsee Seabra, Catarina M. Abbott, Mary-Alice Abdul-Rahman, Omar A. de Vries, Bert B A. Earl, Dawn L. Ferguson, Heather L. Harris, David J. Fisher, Heather FitzPatrick, David R. Gerrol, Pamela Giachino, Daniela Glessner, Joseph T. Gliem, Troy Margolin, Lauren Grady, Margo Graham, Brett H. Griffis, Cristin Hayden, Mark A. Hill, Rosamund Hochstenbach, Ron Hoffman, Jodi D. Hopkin, Robert J. Hubshman, Monika W. Moya, Graciela Mason, Tamara Innes, A Micheil Irons, Mira Irving, Melita Jacobsen, Jessie C. Janssens, Sandra Jewett, Tamison Johnson, John P. Jongmans, Marjolijn C. Kahler, Stephen G. Koolen, David A. Masser-Frye, Diane Nieuwint, Aggie W. Korzelius, Jerome Kroisel, Peter M. Lacassie, Yves Lawless, William Lemyre, Emmanuelle Leppig, Kathleen Levin, Alex V. Li, Haibo Li, Hong Parkash, Sandhya Liao, Eric C. Ordulu, Zehra Lim, Cynthia Lose, Edward J. Lucente, Diane Macera, Michael J. Manavalan, Poornima Mandrile, Giorgia Marcelis, Carlo L. McClellan, Michael W. Mendoza, Cinthya J. Zepeda Menten, Björn Middelkamp, Sjors Mikami, Liya R. Moe, Emily Wiley, Susan Mohammed, Shehla Mononen, Tarja Mortenson, Megan E. Pauker, Susan P. Pereira, Shahrin Perrin, Danielle Phelan, Katy Aguilar, Raul E Piña Poddighe, Pino J. Aberg, Erika Wilson, Anna Pregno, Giulia Raskin, Salmo Reis, Linda Rhead, William Rita, Debra Renkens, Ivo Roelens, Filip Ruliera, Jayla Rump, Patrick Schilit, Samantha L.P. Yerena-de Vega, Maria de la Concepcion A. Adley, Rhett Shaheen, Ranad Sparkes, Rebecca Spiegel, Erica Stevens, Blair Stone, Matthew R. Tagoe, Julia Thakuria, Joseph V. van Bon, Bregje W. van de Kamp, Jiddeke Alkuraya, Fowzan S. van Der Burgt, Ineke Alcaraz-Estrada, Sofia L. van Essen, Ton van Ravenswaaij-Arts, Conny M. van Roosmalen, Markus J. Vergult, Sarah Volker-Touw, Catharina M.L. Warburton, Dorothy P. Waterman, Matthew J. Zori, Roberto T. Levy, Brynn Brunner, Han G. de Leeuw, Nicole Kloosterman, Wigard P. Thorland, Erik C. Gripp, Karen W. Morton, Cynthia C. Gusella, James F. Talkowski, Michael E. An, Yu Anderson, Mary-Anne Antolik, Caroline Anyane-Yeboa, Kwame Atkin, Joan F. Bartell, Tina Bernstein, Jonathan A. Gropman, Andrea L. Beyer, Elizabeth Blumenthal, Ian Bongers, Ernie M.H.F. Brilstra, Eva H. Brown, Chester W. Brüggenwirth, Hennie T. Callewaert, Bert Chiang, Colby Corning, Ken Cox, Helen Hanson-Kahn, Andrea Cuppen, Edwin Currall, Benjamin B. Cushing, Tom David, Dezső Deardorff, Matthew A. Dheedene, Annelies D'Hooghe, Marc |
dc.subject.por.fl_str_mv |
Cytogenetics Structural Variation Balanced Chromosomal Abnormality Congenital Anomaly Intellectual Disability Autism Translocation Inversion Chromothripsis Topologically Associated Domain (TAD) MEF2C Cytogenetic Abnormalities Human Congenital Anomalies Doenças Genómicas Doenças Genéticas |
topic |
Cytogenetics Structural Variation Balanced Chromosomal Abnormality Congenital Anomaly Intellectual Disability Autism Translocation Inversion Chromothripsis Topologically Associated Domain (TAD) MEF2C Cytogenetic Abnormalities Human Congenital Anomalies Doenças Genómicas Doenças Genéticas |
description |
Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-11-14 2016-11-14T00:00:00Z 2017-03-03T17:09:28Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.18/4461 |
url |
http://hdl.handle.net/10400.18/4461 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Nat Genet. 2017 Jan;49(1):36-45. doi: 10.1038/ng.3720. Epub 2016 Nov 14. 1061-4036 10.1038/ng.3720 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/embargoedAccess |
eu_rights_str_mv |
embargoedAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Nature Publishing Group |
publisher.none.fl_str_mv |
Nature Publishing Group |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799132131954262016 |