De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes

© 2015 WILEY PERIODICALS, INC. Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulat...

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Detalles Bibliográficos
Autores: Gil-Rodríguez, María Concepción, Marcos-Alcalde, Íñigo, Gómez-Puertas, Paulino, Queralt, Ethel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/133475
Acceso en línea:http://hdl.handle.net/10261/133475
Access Level:acceso abierto
Palabra clave:CdLS
CdLSlike
CdLS-overlapping phenotypes
Cohesin complex
SMC3
Cornelia de Lange syndrome
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spelling De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypesGil-Rodríguez, María ConcepciónMarcos-Alcalde, ÍñigoGómez-Puertas, PaulinoQueralt, EthelCdLSCdLSlikeCdLS-overlapping phenotypesCohesin complexSMC3Cornelia de Lange syndrome© 2015 WILEY PERIODICALS, INC. Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ~1%-2% of CdLS-like phenotypes. Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder caused by mutation in five genes encoding subunits or regulators of the cohesin complex. To date, only the clinical features of the unique mildly affected CdLS male with SMC3 mutation have been published. Here, we report a series of 16 probands with 15 different intragenic mutations in SMC3 that provide a significant advance in our understanding of the clinical and molecular basis of Cornelia de Lange syndrome and overlapping phenotypes.CdLS Foundation of UK and Ireland for their long-term help and support. M.A.D. and I.D.K. are indebted to the USA Cornelia de Lange Syndrome FoundationPeer ReviewedJohn Wiley & SonsConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2016201620152016info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/133475reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1334752026-05-22T06:33:51Z
dc.title.none.fl_str_mv De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes
title De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes
spellingShingle De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes
Gil-Rodríguez, María Concepción
CdLS
CdLSlike
CdLS-overlapping phenotypes
Cohesin complex
SMC3
Cornelia de Lange syndrome
title_short De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes
title_full De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes
title_fullStr De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes
title_full_unstemmed De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes
title_sort De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes
dc.creator.none.fl_str_mv Gil-Rodríguez, María Concepción
Marcos-Alcalde, Íñigo
Gómez-Puertas, Paulino
Queralt, Ethel
author Gil-Rodríguez, María Concepción
author_facet Gil-Rodríguez, María Concepción
Marcos-Alcalde, Íñigo
Gómez-Puertas, Paulino
Queralt, Ethel
author_role author
author2 Marcos-Alcalde, Íñigo
Gómez-Puertas, Paulino
Queralt, Ethel
author2_role author
author
author
dc.contributor.none.fl_str_mv Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv CdLS
CdLSlike
CdLS-overlapping phenotypes
Cohesin complex
SMC3
Cornelia de Lange syndrome
topic CdLS
CdLSlike
CdLS-overlapping phenotypes
Cohesin complex
SMC3
Cornelia de Lange syndrome
description © 2015 WILEY PERIODICALS, INC. Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS-like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ~1%-2% of CdLS-like phenotypes. Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder caused by mutation in five genes encoding subunits or regulators of the cohesin complex. To date, only the clinical features of the unique mildly affected CdLS male with SMC3 mutation have been published. Here, we report a series of 16 probands with 15 different intragenic mutations in SMC3 that provide a significant advance in our understanding of the clinical and molecular basis of Cornelia de Lange syndrome and overlapping phenotypes.
publishDate 2015
dc.date.none.fl_str_mv 2015
2016
2016
2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/133475
url http://hdl.handle.net/10261/133475
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv John Wiley & Sons
publisher.none.fl_str_mv John Wiley & Sons
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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