Estudo de Anomalias plaquetares hereditárias por sequenciação massiva (NGS)

Detalhes bibliográficos
Autor(a) principal: Dinis, Maria José Pereira
Data de Publicação: 2022
Tipo de documento: Dissertação
Idioma: por
Título da fonte: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Texto Completo: http://hdl.handle.net/10451/59215
Resumo: Tese de mestrado, Biologia Molecular e Genética, 2022, Universidade de Lisboa, Faculdade de Ciências
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spelling Estudo de Anomalias plaquetares hereditárias por sequenciação massiva (NGS)Doenças rarasPlaquetaAnomalias plaquetares hereditáriasNGSTeses de mestrado - 2023Departamento de Biologia VegetalTese de mestrado, Biologia Molecular e Genética, 2022, Universidade de Lisboa, Faculdade de CiênciasHereditary platelet dysfunctions (HPD) constitute a heterogeneous group of rare, underdiagnosed disorders affecting platelet number (thrombocytopenia) and/or function (platelet dysfunction) that course with a tendency for bleeding of variable intensity depending on the type of deficit, exposure to bleeding events such as surgery or trauma. The diagnosis of HPDs has been relatively limited by their considerable clinical heterogeneity, and by the scarcity of reproducible and specific tests. For this reason, molecular studies using NGS, using preselected gene panels or exome, have been implemented. The present study aimed to identify variants in several genes associated with platelet abnormalities in a group of 67 individuals, from different regions of Portugal, belonging to 39 unrelated families, with a history of (macro)thrombocytopenia, platelet dysfunction in order to allow an improvement in the genotype-phenotype correlation. There were 44 different variants detected in 13 genes: 11 ITGB3 (25%); 8 in ITGA2B (19%), 5 in GP1BA (12%), 4 in GP9 (9%) and 3 in ANKRD26, NBEAL2, TUBB1 (7%), 2 in TBXA2R (2%) and 1 in GP6, NBEA, PLAU, MYH9 and PR2Y12 (2%). Six of the 44 variants were in homozygosity and the rest were in heterozygosity with the majority being missense: 32 missense (73%), 4 small deletions (9%), 3 regulatory (7%), 2 splicing (5%), 2 nonsense (5%) and 1 small insertion (2%) (table 3). The predictive value of pathogenicity according to ACMG criteria was obtained: 12 (27%) pathogenic; 9 (20%) probable pathogenic; 20 (45%) of uncertain significance and 3 (7%) probable benign. Of the variants identified, 26 (59%) were not previously described in the databases, reinforcing the importance of these molecular studies for constantly updating the genetic heterogeneity of platelet abnormalities. There was a good genotype/phenotype correlation in all patients, especially in the most severe cases of thrombocytopenia and/or hemorrhage that presented variants in homozygosity (15%), compound heterozygosity (7.5%) and diagnosis of Bernard-Soulier Syndrome, Glanzmann Thrombastenia or Grey Platelet Syndrome. By identifying the variants in the various genes it was possible in each purpose to clarify the type of platelet abnormality. Thus, the purposes presented i) megakaryopoiesis and THC2 (n=4); in granular contents/storage (n=3); ii) in platelet membrane receptors - GPIb/IX/V and GPIIb/IIIa (n=26); iii) in platelet formation and cytoskeleton regulation (n=5) and, iv) in platelet function signaling (n=3). Thus, the genotype-phenotype correlation was effective and highlighted the crucial importance of molecular studies to clarify the etiology of platelet dysfunction. In the present study it was possible to elucidate the segregation of the identified variants in 10 families (28 relatives). The genotype/phenotype propensities were clarified, the familial variants identified and, when necessary, genetic counseling and prenatal diagnosis were made available. It is essential to validate a clinical-laboratorial approach with the optimization of these methodologies that allows a better genotype-phenotype analysis. In this way, we contribute to the clarification of the pathophysiology of platelet dysfunctions and to a more accurate diagnosis that allows for the most appropriate therapeutic options for each patient.Fidalgo, Teresa de Jesus SemedoMoreira, Rita Maria Pulido Garcia Zilhão AranhaRepositório da Universidade de LisboaDinis, Maria José Pereira2023-09-12T08:42:03Z202320222023-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/59215TID:203492390porinfo:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-03-17T15:01:06Zoai:repositorio.ulisboa.pt:10451/59215Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-29T03:31:43.444396Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Estudo de Anomalias plaquetares hereditárias por sequenciação massiva (NGS)
title Estudo de Anomalias plaquetares hereditárias por sequenciação massiva (NGS)
spellingShingle Estudo de Anomalias plaquetares hereditárias por sequenciação massiva (NGS)
Dinis, Maria José Pereira
Doenças raras
Plaqueta
Anomalias plaquetares hereditárias
NGS
Teses de mestrado - 2023
Departamento de Biologia Vegetal
title_short Estudo de Anomalias plaquetares hereditárias por sequenciação massiva (NGS)
title_full Estudo de Anomalias plaquetares hereditárias por sequenciação massiva (NGS)
title_fullStr Estudo de Anomalias plaquetares hereditárias por sequenciação massiva (NGS)
title_full_unstemmed Estudo de Anomalias plaquetares hereditárias por sequenciação massiva (NGS)
title_sort Estudo de Anomalias plaquetares hereditárias por sequenciação massiva (NGS)
author Dinis, Maria José Pereira
author_facet Dinis, Maria José Pereira
author_role author
dc.contributor.none.fl_str_mv Fidalgo, Teresa de Jesus Semedo
Moreira, Rita Maria Pulido Garcia Zilhão Aranha
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Dinis, Maria José Pereira
dc.subject.por.fl_str_mv Doenças raras
Plaqueta
Anomalias plaquetares hereditárias
NGS
Teses de mestrado - 2023
Departamento de Biologia Vegetal
topic Doenças raras
Plaqueta
Anomalias plaquetares hereditárias
NGS
Teses de mestrado - 2023
Departamento de Biologia Vegetal
description Tese de mestrado, Biologia Molecular e Genética, 2022, Universidade de Lisboa, Faculdade de Ciências
publishDate 2022
dc.date.none.fl_str_mv 2022
2023-09-12T08:42:03Z
2023
2023-01-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/59215
TID:203492390
url http://hdl.handle.net/10451/59215
identifier_str_mv TID:203492390
dc.language.iso.fl_str_mv por
language por
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.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron:RCAAP
instname_str FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron_str RCAAP
institution RCAAP
reponame_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
collection Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository.name.fl_str_mv Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
repository.mail.fl_str_mv info@rcaap.pt
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