Clinical and Genetic Analysis of Children with Kartagener Syndrome
Autor(a) principal: | |
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Data de Publicação: | 2019 |
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/10400.16/2363 |
Resumo: | Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by dysfunction of motile cilia causing ineffective mucus clearance and organ laterality defects. In this study, two unrelated Portuguese children with strong PCD suspicion underwent extensive clinical and genetic assessments by whole-exome sequencing (WES), as well as ultrastructural analysis of cilia by transmission electron microscopy (TEM) to identify their genetic etiology. These analyses confirmed the diagnostic of Kartagener syndrome (KS) (PCD with situs inversus). Patient-1 showed a predominance of the absence of the inner dynein arms with two disease-causing variants in the CCDC40 gene. Patient-2 showed the absence of both dynein arms and WES disclosed two novel high impact variants in the DNAH5 gene and two missense variants in the DNAH7 gene, all possibly deleterious. Moreover, in Patient-2, functional data revealed a reduction of gene expression and protein mislocalization in both genes' products. Our work calls the researcher's attention to the complexity of the PCD and to the possibility of gene interactions modelling the PCD phenotype. Further, it is demonstrated that even for well-known PCD genes, novel pathogenic variants could have importance for a PCD/KS diagnosis, reinforcing the difficulty of providing genetic counselling and prenatal diagnosis to families. |
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Clinical and Genetic Analysis of Children with Kartagener SyndromeCCDC40DNAH5DNAH7primary ciliary dyskinesiasitus inversuswhole-exome sequencingPrimary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by dysfunction of motile cilia causing ineffective mucus clearance and organ laterality defects. In this study, two unrelated Portuguese children with strong PCD suspicion underwent extensive clinical and genetic assessments by whole-exome sequencing (WES), as well as ultrastructural analysis of cilia by transmission electron microscopy (TEM) to identify their genetic etiology. These analyses confirmed the diagnostic of Kartagener syndrome (KS) (PCD with situs inversus). Patient-1 showed a predominance of the absence of the inner dynein arms with two disease-causing variants in the CCDC40 gene. Patient-2 showed the absence of both dynein arms and WES disclosed two novel high impact variants in the DNAH5 gene and two missense variants in the DNAH7 gene, all possibly deleterious. Moreover, in Patient-2, functional data revealed a reduction of gene expression and protein mislocalization in both genes' products. Our work calls the researcher's attention to the complexity of the PCD and to the possibility of gene interactions modelling the PCD phenotype. Further, it is demonstrated that even for well-known PCD genes, novel pathogenic variants could have importance for a PCD/KS diagnosis, reinforcing the difficulty of providing genetic counselling and prenatal diagnosis to families.RP was funded by a PhD grant from the National Foundation for Science and Technology (FCT) (Ref.: PD/BD/105767/2014). This work was also supported by the Institutions of the authors and in part by FCT/UMIB (Pest-OE/SAU/UI0215/2014).MDPIRepositório Científico do Centro Hospitalar Universitário de Santo AntónioPereira, R.Barbosa, T.Gales, L.Oliveira, E.Santos, R.Oliveira, J.Sousa, M.2020-05-05T14:01:00Z2019-08-152019-08-15T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.16/2363engPereira R, Barbosa T, Gales L, et al. Clinical and Genetic Analysis of Children with Kartagener Syndrome. Cells. 2019;8(8):900. Published 2019 Aug 15. doi:10.3390/cells80809002073-440910.3390/cells8080900info: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:RCAAP2023-10-20T11:00:29Zoai:repositorio.chporto.pt:10400.16/2363Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:38:34.339754Repositório 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 |
Clinical and Genetic Analysis of Children with Kartagener Syndrome |
title |
Clinical and Genetic Analysis of Children with Kartagener Syndrome |
spellingShingle |
Clinical and Genetic Analysis of Children with Kartagener Syndrome Pereira, R. CCDC40 DNAH5 DNAH7 primary ciliary dyskinesia situs inversus whole-exome sequencing |
title_short |
Clinical and Genetic Analysis of Children with Kartagener Syndrome |
title_full |
Clinical and Genetic Analysis of Children with Kartagener Syndrome |
title_fullStr |
Clinical and Genetic Analysis of Children with Kartagener Syndrome |
title_full_unstemmed |
Clinical and Genetic Analysis of Children with Kartagener Syndrome |
title_sort |
Clinical and Genetic Analysis of Children with Kartagener Syndrome |
author |
Pereira, R. |
author_facet |
Pereira, R. Barbosa, T. Gales, L. Oliveira, E. Santos, R. Oliveira, J. Sousa, M. |
author_role |
author |
author2 |
Barbosa, T. Gales, L. Oliveira, E. Santos, R. Oliveira, J. Sousa, M. |
author2_role |
author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Centro Hospitalar Universitário de Santo António |
dc.contributor.author.fl_str_mv |
Pereira, R. Barbosa, T. Gales, L. Oliveira, E. Santos, R. Oliveira, J. Sousa, M. |
dc.subject.por.fl_str_mv |
CCDC40 DNAH5 DNAH7 primary ciliary dyskinesia situs inversus whole-exome sequencing |
topic |
CCDC40 DNAH5 DNAH7 primary ciliary dyskinesia situs inversus whole-exome sequencing |
description |
Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by dysfunction of motile cilia causing ineffective mucus clearance and organ laterality defects. In this study, two unrelated Portuguese children with strong PCD suspicion underwent extensive clinical and genetic assessments by whole-exome sequencing (WES), as well as ultrastructural analysis of cilia by transmission electron microscopy (TEM) to identify their genetic etiology. These analyses confirmed the diagnostic of Kartagener syndrome (KS) (PCD with situs inversus). Patient-1 showed a predominance of the absence of the inner dynein arms with two disease-causing variants in the CCDC40 gene. Patient-2 showed the absence of both dynein arms and WES disclosed two novel high impact variants in the DNAH5 gene and two missense variants in the DNAH7 gene, all possibly deleterious. Moreover, in Patient-2, functional data revealed a reduction of gene expression and protein mislocalization in both genes' products. Our work calls the researcher's attention to the complexity of the PCD and to the possibility of gene interactions modelling the PCD phenotype. Further, it is demonstrated that even for well-known PCD genes, novel pathogenic variants could have importance for a PCD/KS diagnosis, reinforcing the difficulty of providing genetic counselling and prenatal diagnosis to families. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-08-15 2019-08-15T00:00:00Z 2020-05-05T14:01:00Z |
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/10400.16/2363 |
url |
http://hdl.handle.net/10400.16/2363 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Pereira R, Barbosa T, Gales L, et al. Clinical and Genetic Analysis of Children with Kartagener Syndrome. Cells. 2019;8(8):900. Published 2019 Aug 15. doi:10.3390/cells8080900 2073-4409 10.3390/cells8080900 |
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 |
MDPI |
publisher.none.fl_str_mv |
MDPI |
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 |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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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 |
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1799133646923235328 |