Identification of novel genetic causes of Rett syndrome-like phenotypes
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/1822/45131 |
Resumo: | Background The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. Methods and results We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. Conclusions Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes. |
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Identification of novel genetic causes of Rett syndrome-like phenotypesRett syndromeEpilepsyWhole exome sequencingIntellectual disabilityScience & TechnologyBackground The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. Methods and results We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. Conclusions Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes.This work was supported by the Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 262055. This work was also supported by the FEDER through the Programa Operacional Factores de Competitividade-COMPETE and by Portuguese national funds through the FCT-Fundacao para a Ciencia e Tecnologia, grants number PIC/IC/83026/2007 and PIC/IC/83013/2007, PhD scholarship grant to MB number SFRH/BDINT/ 51549/2011 and PhD scholarship grant to FL number SFRH/BD/84650/2010.info:eu-repo/semantics/publishedVersionBMJ Publishing Group[et. al.]Universidade do MinhoLopes, Fátima Daniela TeixeiraBarbosa, Mafalda Fernanda Cabral SantosSoares, GabrielaSá, Joaquim deDias, Ana IsabelOliveira, GuiomarCabral, PedroTemudo, TeresaMaciel, P.2016-02-092016-02-09T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/45131engLopes, F., Barbosa, M., Ameur, A., Soares, G., De Sá, J., Dias, A. I., . . . Maciel, P. (2016). Identification of novel genetic causes of Rett syndrome-like phenotypes. Journal of Medical Genetics, 53(3), 190-199. doi: 10.1136/jmedgenet-2015-1035680022-259310.1136/jmedgenet-2015-10356826740508http://bmj.com/info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-21T12:40:19Zoai:repositorium.sdum.uminho.pt:1822/45131Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:37:04.970983Repositório 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 |
Identification of novel genetic causes of Rett syndrome-like phenotypes |
title |
Identification of novel genetic causes of Rett syndrome-like phenotypes |
spellingShingle |
Identification of novel genetic causes of Rett syndrome-like phenotypes Lopes, Fátima Daniela Teixeira Rett syndrome Epilepsy Whole exome sequencing Intellectual disability Science & Technology |
title_short |
Identification of novel genetic causes of Rett syndrome-like phenotypes |
title_full |
Identification of novel genetic causes of Rett syndrome-like phenotypes |
title_fullStr |
Identification of novel genetic causes of Rett syndrome-like phenotypes |
title_full_unstemmed |
Identification of novel genetic causes of Rett syndrome-like phenotypes |
title_sort |
Identification of novel genetic causes of Rett syndrome-like phenotypes |
author |
Lopes, Fátima Daniela Teixeira |
author_facet |
Lopes, Fátima Daniela Teixeira Barbosa, Mafalda Fernanda Cabral Santos Soares, Gabriela Sá, Joaquim de Dias, Ana Isabel Oliveira, Guiomar Cabral, Pedro Temudo, Teresa Maciel, P. |
author_role |
author |
author2 |
Barbosa, Mafalda Fernanda Cabral Santos Soares, Gabriela Sá, Joaquim de Dias, Ana Isabel Oliveira, Guiomar Cabral, Pedro Temudo, Teresa Maciel, P. |
author2_role |
author author author author author author author author |
dc.contributor.none.fl_str_mv |
[et. al.] Universidade do Minho |
dc.contributor.author.fl_str_mv |
Lopes, Fátima Daniela Teixeira Barbosa, Mafalda Fernanda Cabral Santos Soares, Gabriela Sá, Joaquim de Dias, Ana Isabel Oliveira, Guiomar Cabral, Pedro Temudo, Teresa Maciel, P. |
dc.subject.por.fl_str_mv |
Rett syndrome Epilepsy Whole exome sequencing Intellectual disability Science & Technology |
topic |
Rett syndrome Epilepsy Whole exome sequencing Intellectual disability Science & Technology |
description |
Background The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. Methods and results We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. Conclusions Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-02-09 2016-02-09T00:00:00Z |
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/1822/45131 |
url |
http://hdl.handle.net/1822/45131 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Lopes, F., Barbosa, M., Ameur, A., Soares, G., De Sá, J., Dias, A. I., . . . Maciel, P. (2016). Identification of novel genetic causes of Rett syndrome-like phenotypes. Journal of Medical Genetics, 53(3), 190-199. doi: 10.1136/jmedgenet-2015-103568 0022-2593 10.1136/jmedgenet-2015-103568 26740508 http://bmj.com/ |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
BMJ Publishing Group |
publisher.none.fl_str_mv |
BMJ 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 |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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