The familial hypercholesterolaemia phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes

Detalhes bibliográficos
Autor(a) principal: Mariano, C.
Data de Publicação: 2019
Outros Autores: Alves, A.C., Medeiros, A., Chora, J.R., Antunes, M., Futema, M., Humphries, S.E., Bourbon, M.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.18/6563
Resumo: Familial Hypercholesterolaemia (FH) is a monogenic disorder characterised by high LDL-C concentrations and increased cardiovascular risk. However, in clinically defined FH cohorts worldwide, an FH-causing variant is only found in 40-50% of the cases. The aim of this work was to characterise the genetic cause of the FH phenotype in Portuguese clinical FH patients. Methods and Results Between 1999 and 2017, 731 index patients (311 children and 420 adults) who met the Simon Broome diagnostic criteria had been referred to our laboratory. LDLR, APOB, PCSK9, APOE, LIPA, LDLRAP1, ABCG5/8 genes were analysed by PCR amplification and Sanger sequencing. The 6-SNP LDL-C genetic risk score (GRS) for polygenic hypercholesterolaemia was validated in the Portuguese population and cases with a GRS over the 25th percentile were considered to have a high likelihood of polygenic hypercholesterolaemia. An FH-causing mutation was found in 39% of patients (94% in LDLR, 5% APOB and 1% PCSK9), while at least 29% have polygenic hypercholesterolaemia and 1% have other lipid disorders. A genetic cause for the FH phenotype was found in 503 patients (69%). All known causes of the FH phenotype should be investigated in FH cohorts to ensure accurate diagnosis and appropriate management.
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spelling The familial hypercholesterolaemia phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causesThe FH phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causesFH phenotype: monogenic, polygenic and other causesFamilial HypercholesterolaemiaGenetic Risk ScoreMonogenic DyslipidaemiaPhenocopiesPolygenic HypercholesterolaemiaHipercolesterolemia FamiliarDoenças Cardio e Cérebro-vascularesFamilial Hypercholesterolaemia (FH) is a monogenic disorder characterised by high LDL-C concentrations and increased cardiovascular risk. However, in clinically defined FH cohorts worldwide, an FH-causing variant is only found in 40-50% of the cases. The aim of this work was to characterise the genetic cause of the FH phenotype in Portuguese clinical FH patients. Methods and Results Between 1999 and 2017, 731 index patients (311 children and 420 adults) who met the Simon Broome diagnostic criteria had been referred to our laboratory. LDLR, APOB, PCSK9, APOE, LIPA, LDLRAP1, ABCG5/8 genes were analysed by PCR amplification and Sanger sequencing. The 6-SNP LDL-C genetic risk score (GRS) for polygenic hypercholesterolaemia was validated in the Portuguese population and cases with a GRS over the 25th percentile were considered to have a high likelihood of polygenic hypercholesterolaemia. An FH-causing mutation was found in 39% of patients (94% in LDLR, 5% APOB and 1% PCSK9), while at least 29% have polygenic hypercholesterolaemia and 1% have other lipid disorders. A genetic cause for the FH phenotype was found in 503 patients (69%). All known causes of the FH phenotype should be investigated in FH cohorts to ensure accurate diagnosis and appropriate management.Cibelle Mariano was supported by a PhD student grant [SFRH/BD/52494/2014]. Marta Futema is supported by the Fondation Leducq Transatlantic Networks of Excellence Program grant (no 14 CVD03). The work of Marilia Antunes is partially funded by UID/MAT/000016/2019. SEH acknowledges funding from the British Heart Foundation grant (BHF PG08/008) and from the NIHR UCLH BRC. MB acknowledges funding from Science and Technology Foundation (PIC/IC/83020/2007) (PIC/IC/83333/2007) for the e_COR and Portuguese FH Study and from Portuguese Cardiology Society for the Portuguese FH Study.John Wiley and SonsRepositório Científico do Instituto Nacional de SaúdeMariano, C.Alves, A.C.Medeiros, A.Chora, J.R.Antunes, M.Futema, M.Humphries, S.E.Bourbon, M.2020-04-30T20:55:10Z2019-12-192019-12-19T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfapplication/pdfhttp://hdl.handle.net/10400.18/6563engClin Genet. 2020 Mar;97(3):457-466. doi: 10.1111/cge.13697. Epub 2019 Dec 310009-916310.1111/cge.13697info: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:RCAAP2023-07-20T15:41:36Zoai:repositorio.insa.pt:10400.18/6563Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:41:24.520434Repositório 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 The familial hypercholesterolaemia phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes
The FH phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes
FH phenotype: monogenic, polygenic and other causes
title The familial hypercholesterolaemia phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes
spellingShingle The familial hypercholesterolaemia phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes
Mariano, C.
Familial Hypercholesterolaemia
Genetic Risk Score
Monogenic Dyslipidaemia
Phenocopies
Polygenic Hypercholesterolaemia
Hipercolesterolemia Familiar
Doenças Cardio e Cérebro-vasculares
title_short The familial hypercholesterolaemia phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes
title_full The familial hypercholesterolaemia phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes
title_fullStr The familial hypercholesterolaemia phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes
title_full_unstemmed The familial hypercholesterolaemia phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes
title_sort The familial hypercholesterolaemia phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes
author Mariano, C.
author_facet Mariano, C.
Alves, A.C.
Medeiros, A.
Chora, J.R.
Antunes, M.
Futema, M.
Humphries, S.E.
Bourbon, M.
author_role author
author2 Alves, A.C.
Medeiros, A.
Chora, J.R.
Antunes, M.
Futema, M.
Humphries, S.E.
Bourbon, M.
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório Científico do Instituto Nacional de Saúde
dc.contributor.author.fl_str_mv Mariano, C.
Alves, A.C.
Medeiros, A.
Chora, J.R.
Antunes, M.
Futema, M.
Humphries, S.E.
Bourbon, M.
dc.subject.por.fl_str_mv Familial Hypercholesterolaemia
Genetic Risk Score
Monogenic Dyslipidaemia
Phenocopies
Polygenic Hypercholesterolaemia
Hipercolesterolemia Familiar
Doenças Cardio e Cérebro-vasculares
topic Familial Hypercholesterolaemia
Genetic Risk Score
Monogenic Dyslipidaemia
Phenocopies
Polygenic Hypercholesterolaemia
Hipercolesterolemia Familiar
Doenças Cardio e Cérebro-vasculares
description Familial Hypercholesterolaemia (FH) is a monogenic disorder characterised by high LDL-C concentrations and increased cardiovascular risk. However, in clinically defined FH cohorts worldwide, an FH-causing variant is only found in 40-50% of the cases. The aim of this work was to characterise the genetic cause of the FH phenotype in Portuguese clinical FH patients. Methods and Results Between 1999 and 2017, 731 index patients (311 children and 420 adults) who met the Simon Broome diagnostic criteria had been referred to our laboratory. LDLR, APOB, PCSK9, APOE, LIPA, LDLRAP1, ABCG5/8 genes were analysed by PCR amplification and Sanger sequencing. The 6-SNP LDL-C genetic risk score (GRS) for polygenic hypercholesterolaemia was validated in the Portuguese population and cases with a GRS over the 25th percentile were considered to have a high likelihood of polygenic hypercholesterolaemia. An FH-causing mutation was found in 39% of patients (94% in LDLR, 5% APOB and 1% PCSK9), while at least 29% have polygenic hypercholesterolaemia and 1% have other lipid disorders. A genetic cause for the FH phenotype was found in 503 patients (69%). All known causes of the FH phenotype should be investigated in FH cohorts to ensure accurate diagnosis and appropriate management.
publishDate 2019
dc.date.none.fl_str_mv 2019-12-19
2019-12-19T00:00:00Z
2020-04-30T20:55:10Z
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/10400.18/6563
url http://hdl.handle.net/10400.18/6563
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Clin Genet. 2020 Mar;97(3):457-466. doi: 10.1111/cge.13697. Epub 2019 Dec 31
0009-9163
10.1111/cge.13697
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv John Wiley and Sons
publisher.none.fl_str_mv John Wiley and Sons
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
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collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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