Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function

Autores
Lacbawan, F.; Solomon, B. D.; Roessler, E.; El-Jaick, K.; Domene, Sabina; Vélez, J. I.; Zhou, N.; Hadley, D.; Balog, J. Z.; Long, R.; Fryer, A.; Smith, W.; Omar, S.; McLean, S. D.; Clarkson, K.; Lichty, A.; Clegg, N. J.; Delgado, M. R.; Levey, E.; Stashinko, E.; Potocki, L.; VanAllen, M. I.; Clayton Smith, J.; Donnai, D.; Bianchi, D. W.; Juliusson, P. B.; Njølstad, P. R.; Brunner, H. G.; Carey, J. C.; Hehr, U.; Müsebeck, J.; Wieacker, P. F.; Postra, A.; Hennekam, R. C. M.; Van Den Boogaard, M. J. H.; Van Haeringen, A.; Paulussen, A.; Herbergs, J.; Schrander Stumpel, C. T. R. M.; Janecke, A. R.; Chitayat, D.; Hahn, J.; McDonald McGinn, D. M.; Zackai, E.H.; Dobyns, W. B.; Muenke, Maximilian
Año de publicación
2009
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. Objective: To characterise genetic and clinical findings in patients with SIX3 mutations. Methods: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. Results: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of nonchromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. Conclusions: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models.
Fil: Lacbawan, F.. Suny Downstate Medical Center; Estados Unidos. National Human Genome Research Institute; Estados Unidos
Fil: Solomon, B. D.. National Human Genome Research Institute; Estados Unidos
Fil: Roessler, E.. National Human Genome Research Institute; Estados Unidos
Fil: El-Jaick, K.. National Human Genome Research Institute; Estados Unidos
Fil: Domene, Sabina. National Human Genome Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Vélez, J. I.. National Human Genome Research Institute; Estados Unidos
Fil: Zhou, N.. National Human Genome Research Institute; Estados Unidos
Fil: Hadley, D.. National Human Genome Research Institute; Estados Unidos
Fil: Balog, J. Z.. National Human Genome Research Institute; Estados Unidos
Fil: Long, R.. National Human Genome Research Institute; Estados Unidos
Fil: Fryer, A.. Royal Liverpool Children's Hospital; Estados Unidos
Fil: Smith, W.. Maine Medical Center; Estados Unidos
Fil: Omar, S.. Michigan State University; Estados Unidos
Fil: McLean, S. D.. San Antonio Military Medical Center; Estados Unidos
Fil: Clarkson, K.. Greenwood Genetics Center; Estados Unidos
Fil: Lichty, A.. Greenwood Genetics Center; Estados Unidos
Fil: Clegg, N. J.. Ut Southwestern Medical School; Estados Unidos
Fil: Delgado, M. R.. Ut Southwestern Medical School; Estados Unidos
Fil: Levey, E.. University Johns Hopkins; Estados Unidos
Fil: Stashinko, E.. University Johns Hopkins; Estados Unidos
Fil: Potocki, L.. Texas Children's Hospital Houston; Estados Unidos
Fil: VanAllen, M. I.. University of British Columbia; Canadá
Fil: Clayton Smith, J.. University of Manchester; Reino Unido
Fil: Donnai, D.. University of Manchester; Reino Unido
Fil: Bianchi, D. W.. Tufts University School Of Medicine; Estados Unidos
Fil: Juliusson, P. B.. Helse Bergen Haukeland University Hospital; Noruega
Fil: Njølstad, P. R.. University Of Bergen; Noruega. Helse Bergen Haukeland University Hospital; Noruega
Fil: Brunner, H. G.. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Carey, J. C.. University Of Utah Health Sciences; Estados Unidos
Fil: Hehr, U.. Universitat Regensburg; Alemania
Fil: Müsebeck, J.. Universitat Bremen; Alemania
Fil: Wieacker, P. F.. Westfalische Wilhelms Universitat; Alemania
Fil: Postra, A.. University of Amsterdam; Países Bajos
Fil: Hennekam, R. C. M.. Institute Of Child Health; Reino Unido
Fil: Van Den Boogaard, M. J. H.. University Medical Center Utrecht; Países Bajos
Fil: Van Haeringen, A.. Leiden University Medical Center; Países Bajos
Fil: Paulussen, A.. Academic Hospital Maastricht; Países Bajos
Fil: Herbergs, J.. Academic Hospital Maastricht; Países Bajos
Fil: Schrander Stumpel, C. T. R. M.. Academic Hospital Maastricht; Países Bajos
Fil: Janecke, A. R.. Medizinische Universitat Innsbruck; Austria
Fil: Chitayat, D.. Mount Sinai Hospital Of University Of Toronto; Canadá
Fil: Hahn, J.. Stanford University School Of Medicine; Estados Unidos
Fil: McDonald McGinn, D. M.. The Children's Hospital Of Philadelphia; Estados Unidos
Fil: Zackai, E.H.. The Children's Hospital Of Philadelphia; Estados Unidos
Fil: Dobyns, W. B.. University of Chicago; Estados Unidos
Fil: Muenke, Maximilian. National Human Genome Research Institute; Estados Unidos
Materia
Holoprosencephaly
Hpe
Six3
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/80616
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/80616
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and functionLacbawan, F.Solomon, B. D.Roessler, E.El-Jaick, K.Domene, SabinaVélez, J. I.Zhou, N.Hadley, D.Balog, J. Z.Long, R.Fryer, A.Smith, W.Omar, S.McLean, S. D.Clarkson, K.Lichty, A.Clegg, N. J.Delgado, M. R.Levey, E.Stashinko, E.Potocki, L.VanAllen, M. I.Clayton Smith, J.Donnai, D.Bianchi, D. W.Juliusson, P. B.Njølstad, P. R.Brunner, H. G.Carey, J. C.Hehr, U.Müsebeck, J.Wieacker, P. F.Postra, A.Hennekam, R. C. M.Van Den Boogaard, M. J. H.Van Haeringen, A.Paulussen, A.Herbergs, J.Schrander Stumpel, C. T. R. M.Janecke, A. R.Chitayat, D.Hahn, J.McDonald McGinn, D. M.Zackai, E.H.Dobyns, W. B.Muenke, MaximilianHoloprosencephalyHpeSix3https://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Background: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. Objective: To characterise genetic and clinical findings in patients with SIX3 mutations. Methods: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. Results: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of nonchromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. Conclusions: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models.Fil: Lacbawan, F.. Suny Downstate Medical Center; Estados Unidos. National Human Genome Research Institute; Estados UnidosFil: Solomon, B. D.. National Human Genome Research Institute; Estados UnidosFil: Roessler, E.. National Human Genome Research Institute; Estados UnidosFil: El-Jaick, K.. National Human Genome Research Institute; Estados UnidosFil: Domene, Sabina. National Human Genome Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Vélez, J. I.. National Human Genome Research Institute; Estados UnidosFil: Zhou, N.. National Human Genome Research Institute; Estados UnidosFil: Hadley, D.. National Human Genome Research Institute; Estados UnidosFil: Balog, J. Z.. National Human Genome Research Institute; Estados UnidosFil: Long, R.. National Human Genome Research Institute; Estados UnidosFil: Fryer, A.. Royal Liverpool Children's Hospital; Estados UnidosFil: Smith, W.. Maine Medical Center; Estados UnidosFil: Omar, S.. Michigan State University; Estados UnidosFil: McLean, S. D.. San Antonio Military Medical Center; Estados UnidosFil: Clarkson, K.. Greenwood Genetics Center; Estados UnidosFil: Lichty, A.. Greenwood Genetics Center; Estados UnidosFil: Clegg, N. J.. Ut Southwestern Medical School; Estados UnidosFil: Delgado, M. R.. Ut Southwestern Medical School; Estados UnidosFil: Levey, E.. University Johns Hopkins; Estados UnidosFil: Stashinko, E.. University Johns Hopkins; Estados UnidosFil: Potocki, L.. Texas Children's Hospital Houston; Estados UnidosFil: VanAllen, M. I.. University of British Columbia; CanadáFil: Clayton Smith, J.. University of Manchester; Reino UnidoFil: Donnai, D.. University of Manchester; Reino UnidoFil: Bianchi, D. W.. Tufts University School Of Medicine; Estados UnidosFil: Juliusson, P. B.. Helse Bergen Haukeland University Hospital; NoruegaFil: Njølstad, P. R.. University Of Bergen; Noruega. Helse Bergen Haukeland University Hospital; NoruegaFil: Brunner, H. G.. Radboud University Nijmegen Medical Centre; Países BajosFil: Carey, J. C.. University Of Utah Health Sciences; Estados UnidosFil: Hehr, U.. Universitat Regensburg; AlemaniaFil: Müsebeck, J.. Universitat Bremen; AlemaniaFil: Wieacker, P. F.. Westfalische Wilhelms Universitat; AlemaniaFil: Postra, A.. University of Amsterdam; Países BajosFil: Hennekam, R. C. M.. Institute Of Child Health; Reino UnidoFil: Van Den Boogaard, M. J. H.. University Medical Center Utrecht; Países BajosFil: Van Haeringen, A.. Leiden University Medical Center; Países BajosFil: Paulussen, A.. Academic Hospital Maastricht; Países BajosFil: Herbergs, J.. Academic Hospital Maastricht; Países BajosFil: Schrander Stumpel, C. T. R. M.. Academic Hospital Maastricht; Países BajosFil: Janecke, A. R.. Medizinische Universitat Innsbruck; AustriaFil: Chitayat, D.. Mount Sinai Hospital Of University Of Toronto; CanadáFil: Hahn, J.. Stanford University School Of Medicine; Estados UnidosFil: McDonald McGinn, D. M.. The Children's Hospital Of Philadelphia; Estados UnidosFil: Zackai, E.H.. The Children's Hospital Of Philadelphia; Estados UnidosFil: Dobyns, W. B.. University of Chicago; Estados UnidosFil: Muenke, Maximilian. National Human Genome Research Institute; Estados UnidosB M J Publishing Group2009-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/80616Lacbawan, F.; Solomon, B. D.; Roessler, E.; El-Jaick, K.; Domene, Sabina; et al.; Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function; B M J Publishing Group; Journal Of Medical Genetics; 46; 6; 6-2009; 389-3980022-2593CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1136/jmg.2008.063818info:eu-repo/semantics/altIdentifier/url/https://jmg.bmj.com/content/46/6/389info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:31:31Zoai:ri.conicet.gov.ar:11336/80616instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:31:31.6CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function
title Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function
spellingShingle Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function
Lacbawan, F.
Holoprosencephaly
Hpe
Six3
title_short Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function
title_full Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function
title_fullStr Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function
title_full_unstemmed Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function
title_sort Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function
dc.creator.none.fl_str_mv Lacbawan, F.
Solomon, B. D.
Roessler, E.
El-Jaick, K.
Domene, Sabina
Vélez, J. I.
Zhou, N.
Hadley, D.
Balog, J. Z.
Long, R.
Fryer, A.
Smith, W.
Omar, S.
McLean, S. D.
Clarkson, K.
Lichty, A.
Clegg, N. J.
Delgado, M. R.
Levey, E.
Stashinko, E.
Potocki, L.
VanAllen, M. I.
Clayton Smith, J.
Donnai, D.
Bianchi, D. W.
Juliusson, P. B.
Njølstad, P. R.
Brunner, H. G.
Carey, J. C.
Hehr, U.
Müsebeck, J.
Wieacker, P. F.
Postra, A.
Hennekam, R. C. M.
Van Den Boogaard, M. J. H.
Van Haeringen, A.
Paulussen, A.
Herbergs, J.
Schrander Stumpel, C. T. R. M.
Janecke, A. R.
Chitayat, D.
Hahn, J.
McDonald McGinn, D. M.
Zackai, E.H.
Dobyns, W. B.
Muenke, Maximilian
author Lacbawan, F.
author_facet Lacbawan, F.
Solomon, B. D.
Roessler, E.
El-Jaick, K.
Domene, Sabina
Vélez, J. I.
Zhou, N.
Hadley, D.
Balog, J. Z.
Long, R.
Fryer, A.
Smith, W.
Omar, S.
McLean, S. D.
Clarkson, K.
Lichty, A.
Clegg, N. J.
Delgado, M. R.
Levey, E.
Stashinko, E.
Potocki, L.
VanAllen, M. I.
Clayton Smith, J.
Donnai, D.
Bianchi, D. W.
Juliusson, P. B.
Njølstad, P. R.
Brunner, H. G.
Carey, J. C.
Hehr, U.
Müsebeck, J.
Wieacker, P. F.
Postra, A.
Hennekam, R. C. M.
Van Den Boogaard, M. J. H.
Van Haeringen, A.
Paulussen, A.
Herbergs, J.
Schrander Stumpel, C. T. R. M.
Janecke, A. R.
Chitayat, D.
Hahn, J.
McDonald McGinn, D. M.
Zackai, E.H.
Dobyns, W. B.
Muenke, Maximilian
author_role author
author2 Solomon, B. D.
Roessler, E.
El-Jaick, K.
Domene, Sabina
Vélez, J. I.
Zhou, N.
Hadley, D.
Balog, J. Z.
Long, R.
Fryer, A.
Smith, W.
Omar, S.
McLean, S. D.
Clarkson, K.
Lichty, A.
Clegg, N. J.
Delgado, M. R.
Levey, E.
Stashinko, E.
Potocki, L.
VanAllen, M. I.
Clayton Smith, J.
Donnai, D.
Bianchi, D. W.
Juliusson, P. B.
Njølstad, P. R.
Brunner, H. G.
Carey, J. C.
Hehr, U.
Müsebeck, J.
Wieacker, P. F.
Postra, A.
Hennekam, R. C. M.
Van Den Boogaard, M. J. H.
Van Haeringen, A.
Paulussen, A.
Herbergs, J.
Schrander Stumpel, C. T. R. M.
Janecke, A. R.
Chitayat, D.
Hahn, J.
McDonald McGinn, D. M.
Zackai, E.H.
Dobyns, W. B.
Muenke, Maximilian
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
dc.subject.none.fl_str_mv Holoprosencephaly
Hpe
Six3
topic Holoprosencephaly
Hpe
Six3
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. Objective: To characterise genetic and clinical findings in patients with SIX3 mutations. Methods: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. Results: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of nonchromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. Conclusions: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models.
Fil: Lacbawan, F.. Suny Downstate Medical Center; Estados Unidos. National Human Genome Research Institute; Estados Unidos
Fil: Solomon, B. D.. National Human Genome Research Institute; Estados Unidos
Fil: Roessler, E.. National Human Genome Research Institute; Estados Unidos
Fil: El-Jaick, K.. National Human Genome Research Institute; Estados Unidos
Fil: Domene, Sabina. National Human Genome Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Vélez, J. I.. National Human Genome Research Institute; Estados Unidos
Fil: Zhou, N.. National Human Genome Research Institute; Estados Unidos
Fil: Hadley, D.. National Human Genome Research Institute; Estados Unidos
Fil: Balog, J. Z.. National Human Genome Research Institute; Estados Unidos
Fil: Long, R.. National Human Genome Research Institute; Estados Unidos
Fil: Fryer, A.. Royal Liverpool Children's Hospital; Estados Unidos
Fil: Smith, W.. Maine Medical Center; Estados Unidos
Fil: Omar, S.. Michigan State University; Estados Unidos
Fil: McLean, S. D.. San Antonio Military Medical Center; Estados Unidos
Fil: Clarkson, K.. Greenwood Genetics Center; Estados Unidos
Fil: Lichty, A.. Greenwood Genetics Center; Estados Unidos
Fil: Clegg, N. J.. Ut Southwestern Medical School; Estados Unidos
Fil: Delgado, M. R.. Ut Southwestern Medical School; Estados Unidos
Fil: Levey, E.. University Johns Hopkins; Estados Unidos
Fil: Stashinko, E.. University Johns Hopkins; Estados Unidos
Fil: Potocki, L.. Texas Children's Hospital Houston; Estados Unidos
Fil: VanAllen, M. I.. University of British Columbia; Canadá
Fil: Clayton Smith, J.. University of Manchester; Reino Unido
Fil: Donnai, D.. University of Manchester; Reino Unido
Fil: Bianchi, D. W.. Tufts University School Of Medicine; Estados Unidos
Fil: Juliusson, P. B.. Helse Bergen Haukeland University Hospital; Noruega
Fil: Njølstad, P. R.. University Of Bergen; Noruega. Helse Bergen Haukeland University Hospital; Noruega
Fil: Brunner, H. G.. Radboud University Nijmegen Medical Centre; Países Bajos
Fil: Carey, J. C.. University Of Utah Health Sciences; Estados Unidos
Fil: Hehr, U.. Universitat Regensburg; Alemania
Fil: Müsebeck, J.. Universitat Bremen; Alemania
Fil: Wieacker, P. F.. Westfalische Wilhelms Universitat; Alemania
Fil: Postra, A.. University of Amsterdam; Países Bajos
Fil: Hennekam, R. C. M.. Institute Of Child Health; Reino Unido
Fil: Van Den Boogaard, M. J. H.. University Medical Center Utrecht; Países Bajos
Fil: Van Haeringen, A.. Leiden University Medical Center; Países Bajos
Fil: Paulussen, A.. Academic Hospital Maastricht; Países Bajos
Fil: Herbergs, J.. Academic Hospital Maastricht; Países Bajos
Fil: Schrander Stumpel, C. T. R. M.. Academic Hospital Maastricht; Países Bajos
Fil: Janecke, A. R.. Medizinische Universitat Innsbruck; Austria
Fil: Chitayat, D.. Mount Sinai Hospital Of University Of Toronto; Canadá
Fil: Hahn, J.. Stanford University School Of Medicine; Estados Unidos
Fil: McDonald McGinn, D. M.. The Children's Hospital Of Philadelphia; Estados Unidos
Fil: Zackai, E.H.. The Children's Hospital Of Philadelphia; Estados Unidos
Fil: Dobyns, W. B.. University of Chicago; Estados Unidos
Fil: Muenke, Maximilian. National Human Genome Research Institute; Estados Unidos
description Background: Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. Objective: To characterise genetic and clinical findings in patients with SIX3 mutations. Methods: Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. Results: In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of nonchromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. Conclusions: Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype-phenotype correlation, as shown by functional studies using animal models.
publishDate 2009
dc.date.none.fl_str_mv 2009-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/80616
Lacbawan, F.; Solomon, B. D.; Roessler, E.; El-Jaick, K.; Domene, Sabina; et al.; Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function; B M J Publishing Group; Journal Of Medical Genetics; 46; 6; 6-2009; 389-398
0022-2593
CONICET Digital
CONICET
url http://hdl.handle.net/11336/80616
identifier_str_mv Lacbawan, F.; Solomon, B. D.; Roessler, E.; El-Jaick, K.; Domene, Sabina; et al.; Clinical spectrum of SIX3-associated mutations in holoprosencephaly: Correlation between genotype, phenotype and function; B M J Publishing Group; Journal Of Medical Genetics; 46; 6; 6-2009; 389-398
0022-2593
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1136/jmg.2008.063818
info:eu-repo/semantics/altIdentifier/url/https://jmg.bmj.com/content/46/6/389
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv B M J Publishing Group
publisher.none.fl_str_mv B M J Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.069144

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