Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype

Detalhes bibliográficos
Autor(a) principal: Medeiros, Ana Margarida
Data de Publicação: 2023
Outros Autores: Alves, Ana Catarina, Miranda, Beatriz, Chora, Joana Rita, Bourbon, Mafalda, investigators of the Portuguese FH Study
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.18/9045
Resumo: investigators of the Portuguese FH Study: Mafalda Bourbon, Quitéria Rato, Ana Catarina Alves, Ana Margarida Medeiros, Ana Catarina Gomes, Ana Cristina Ferreira, Ana Gaspar, Ana Margarida Marques, Ana Maria Garabal, Ana Paula Bogalho, Ana Rita Pereira, Anabela Raimundo, André Travessa, Andreia Lopes, António Afonso, António Furtado, António Guerra, António Monteiro, António Trindade, Armindo Ribeiro, Bernardo Dias Pereira, Bernardo Marques, Carla Laranjeira, Catarina Senra Moniz, Cecília Frutuoso, Cláudia Falcão Reis, Cláudia Rodrigues, Clementina Fernandes, Conceição Ferreira, Daniel Ferreira, Diogo Torres, Elisabete Martins, Elsa Gaspar, Fabiana Pimentel, Fernando Simões, Francisco Araújo, Francisco Silva, Goreti Lobarinhas, Graça Morais, Guida Gama, Guilherme Lourenço, Helena Mansilha, Helena Pereira, Heloísa Santos, Henedina Antunes, Inês Batista Gomes, Inês Colaço, Isabel Azevedo, Isabel Palma, João Anselmo, João Porto, João Ramos, João Sequeira Duarte, Jorge Pintado Alves, José Miguel Salgado, José Pereira de Moura, Leonor Sassetti, Lina Cardoso Ramos, Luísa Diogo Matos, Luísa Mota Vieira, Luísa Pires, Márcio de Moura, Margarida Bruges, Margarida Venâncio, Maria do Rosário Barroso, Maria João Virtuoso, Maria Luísa Gonçalves, Mário Martins Oliveira, Mendes Nunes, Miguel Costa, Miguel Mendes, Miguel Toscano Rico, Mónica Tavares, Natalina Miguel, Oana Moldovan, Olga Azevedo, Patrícia Lipari Pinto, Patrícia Pais, Patrícia Vasconcelos, Paula Garcia, Paula Martins, Pedro Marques da Silva, Piedade Lemos, Quitéria Rato, Raquel Coelho, Raquel Gouveia da Silva, Raquel Ribeiro, Rita Jotta de Oliveira, Roberto Pinto, Sandra Pereira, Sérgio Ferreira Cristina, Sílvia Sequeira, Susana Correia, Tânia Vassalo, Tiago Pack, Vânia Martins, Vera Frazão Vieira.
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spelling Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotypeFamilial HypercholesterolemiaFH-phenocopy GenesPolygenic HypercholesterolemiaHyper-Lp(a)Doenças Cardio e Cérebro-vascularesinvestigators of the Portuguese FH Study: Mafalda Bourbon, Quitéria Rato, Ana Catarina Alves, Ana Margarida Medeiros, Ana Catarina Gomes, Ana Cristina Ferreira, Ana Gaspar, Ana Margarida Marques, Ana Maria Garabal, Ana Paula Bogalho, Ana Rita Pereira, Anabela Raimundo, André Travessa, Andreia Lopes, António Afonso, António Furtado, António Guerra, António Monteiro, António Trindade, Armindo Ribeiro, Bernardo Dias Pereira, Bernardo Marques, Carla Laranjeira, Catarina Senra Moniz, Cecília Frutuoso, Cláudia Falcão Reis, Cláudia Rodrigues, Clementina Fernandes, Conceição Ferreira, Daniel Ferreira, Diogo Torres, Elisabete Martins, Elsa Gaspar, Fabiana Pimentel, Fernando Simões, Francisco Araújo, Francisco Silva, Goreti Lobarinhas, Graça Morais, Guida Gama, Guilherme Lourenço, Helena Mansilha, Helena Pereira, Heloísa Santos, Henedina Antunes, Inês Batista Gomes, Inês Colaço, Isabel Azevedo, Isabel Palma, João Anselmo, João Porto, João Ramos, João Sequeira Duarte, Jorge Pintado Alves, José Miguel Salgado, José Pereira de Moura, Leonor Sassetti, Lina Cardoso Ramos, Luísa Diogo Matos, Luísa Mota Vieira, Luísa Pires, Márcio de Moura, Margarida Bruges, Margarida Venâncio, Maria do Rosário Barroso, Maria João Virtuoso, Maria Luísa Gonçalves, Mário Martins Oliveira, Mendes Nunes, Miguel Costa, Miguel Mendes, Miguel Toscano Rico, Mónica Tavares, Natalina Miguel, Oana Moldovan, Olga Azevedo, Patrícia Lipari Pinto, Patrícia Pais, Patrícia Vasconcelos, Paula Garcia, Paula Martins, Pedro Marques da Silva, Piedade Lemos, Quitéria Rato, Raquel Coelho, Raquel Gouveia da Silva, Raquel Ribeiro, Rita Jotta de Oliveira, Roberto Pinto, Sandra Pereira, Sérgio Ferreira Cristina, Sílvia Sequeira, Susana Correia, Tânia Vassalo, Tiago Pack, Vânia Martins, Vera Frazão Vieira.Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person's treatment according to the affected pathway.Was supported by the Portuguese Cardiology Society (grant number: D13123) and FCT (grant numbers: PTDC/SAU-GMG/101874/2008 and PTDC/SAUSER/29180/2017). This work was also supported by UIDB/04046/2020 (DOI: 10.54499/UIDB/04046/2020) and UIDP/04046/2020 (DOI: 10.54499/UIDP/04046/2020) center grants from FCT, Portugal (to BioISI).Elsevier/ American Society for Biochemistry and Molecular BiologyRepositório Científico do Instituto Nacional de SaúdeMedeiros, Ana MargaridaAlves, Ana CatarinaMiranda, BeatrizChora, Joana RitaBourbon, Mafaldainvestigators of the Portuguese FH Study2024-02-06T13:13:54Z2023-12-182023-12-18T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/9045engJ Lipid Res. 2023 Dec 18;65(2):100490. doi: 10.1016/j.jlr.2023.100490. Online ahead of print0022-227510.1016/j.jlr.2023.100490info: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:RCAAP2024-02-10T01:30:55Zoai:repositorio.insa.pt:10400.18/9045Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T02:37:22.997405Repositório 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 Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype
title Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype
spellingShingle Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype
Medeiros, Ana Margarida
Familial Hypercholesterolemia
FH-phenocopy Genes
Polygenic Hypercholesterolemia
Hyper-Lp(a)
Doenças Cardio e Cérebro-vasculares
title_short Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype
title_full Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype
title_fullStr Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype
title_full_unstemmed Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype
title_sort Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype
author Medeiros, Ana Margarida
author_facet Medeiros, Ana Margarida
Alves, Ana Catarina
Miranda, Beatriz
Chora, Joana Rita
Bourbon, Mafalda
investigators of the Portuguese FH Study
author_role author
author2 Alves, Ana Catarina
Miranda, Beatriz
Chora, Joana Rita
Bourbon, Mafalda
investigators of the Portuguese FH Study
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório Científico do Instituto Nacional de Saúde
dc.contributor.author.fl_str_mv Medeiros, Ana Margarida
Alves, Ana Catarina
Miranda, Beatriz
Chora, Joana Rita
Bourbon, Mafalda
investigators of the Portuguese FH Study
dc.subject.por.fl_str_mv Familial Hypercholesterolemia
FH-phenocopy Genes
Polygenic Hypercholesterolemia
Hyper-Lp(a)
Doenças Cardio e Cérebro-vasculares
topic Familial Hypercholesterolemia
FH-phenocopy Genes
Polygenic Hypercholesterolemia
Hyper-Lp(a)
Doenças Cardio e Cérebro-vasculares
description investigators of the Portuguese FH Study: Mafalda Bourbon, Quitéria Rato, Ana Catarina Alves, Ana Margarida Medeiros, Ana Catarina Gomes, Ana Cristina Ferreira, Ana Gaspar, Ana Margarida Marques, Ana Maria Garabal, Ana Paula Bogalho, Ana Rita Pereira, Anabela Raimundo, André Travessa, Andreia Lopes, António Afonso, António Furtado, António Guerra, António Monteiro, António Trindade, Armindo Ribeiro, Bernardo Dias Pereira, Bernardo Marques, Carla Laranjeira, Catarina Senra Moniz, Cecília Frutuoso, Cláudia Falcão Reis, Cláudia Rodrigues, Clementina Fernandes, Conceição Ferreira, Daniel Ferreira, Diogo Torres, Elisabete Martins, Elsa Gaspar, Fabiana Pimentel, Fernando Simões, Francisco Araújo, Francisco Silva, Goreti Lobarinhas, Graça Morais, Guida Gama, Guilherme Lourenço, Helena Mansilha, Helena Pereira, Heloísa Santos, Henedina Antunes, Inês Batista Gomes, Inês Colaço, Isabel Azevedo, Isabel Palma, João Anselmo, João Porto, João Ramos, João Sequeira Duarte, Jorge Pintado Alves, José Miguel Salgado, José Pereira de Moura, Leonor Sassetti, Lina Cardoso Ramos, Luísa Diogo Matos, Luísa Mota Vieira, Luísa Pires, Márcio de Moura, Margarida Bruges, Margarida Venâncio, Maria do Rosário Barroso, Maria João Virtuoso, Maria Luísa Gonçalves, Mário Martins Oliveira, Mendes Nunes, Miguel Costa, Miguel Mendes, Miguel Toscano Rico, Mónica Tavares, Natalina Miguel, Oana Moldovan, Olga Azevedo, Patrícia Lipari Pinto, Patrícia Pais, Patrícia Vasconcelos, Paula Garcia, Paula Martins, Pedro Marques da Silva, Piedade Lemos, Quitéria Rato, Raquel Coelho, Raquel Gouveia da Silva, Raquel Ribeiro, Rita Jotta de Oliveira, Roberto Pinto, Sandra Pereira, Sérgio Ferreira Cristina, Sílvia Sequeira, Susana Correia, Tânia Vassalo, Tiago Pack, Vânia Martins, Vera Frazão Vieira.
publishDate 2023
dc.date.none.fl_str_mv 2023-12-18
2023-12-18T00:00:00Z
2024-02-06T13:13:54Z
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/10400.18/9045
url http://hdl.handle.net/10400.18/9045
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv J Lipid Res. 2023 Dec 18;65(2):100490. doi: 10.1016/j.jlr.2023.100490. Online ahead of print
0022-2275
10.1016/j.jlr.2023.100490
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 Elsevier/ American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv Elsevier/ American Society for Biochemistry and Molecular Biology
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
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
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reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection 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
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