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

2023; Elsevier BV; Volume: 65; Issue: 2 Linguagem: Inglês

10.1016/j.jlr.2023.100490

1539-7262

Ana Margarida Medeiros, Ana Catarina Alves, Beatriz Miranda, Joana Rita Chora, Mafalda Bourbon, Mafalda Bourbon, Quitéria Rato, Ana Catarina Alves, Ana Margarida Medeiros, Ana Catarina Gomes, Ana Cristina Ferreira, Ana Maria Minarelli Gaspar, Ana Marques, Ana Garabal, Ana Paula Bogalho, Ana Rita Pereira, Anabela Raimundo, André Travessa, Andreia Lopes, António Afonso, António Furtado, António Guerra, António M. Monteiro, António Trindade, Armindo Ribeiro, Bernardo Dias Pereira, Bernardo Marques, Carla Laranjeira, Catarina Moniz, Cecília Frutuoso, C Reis, Cláudia Rodrigues, Clementina Fernandes, Conceição Ferreira, Daniel Correia Freire Ferreira, Diogo Torres, Elisabete Martins, Elsa Gaspar, Fabiana Pimentel, Fernando Dias Simões, Francisco Araújo, F.J.G. Silva, Goreti Lobarinhas, Graça Morais, Guida Gama, Guilherme Lourenço, Helena Ferreira Mansilha, Héléna Pereira, Heloísa G. dos Santos, Henedina Antunes, Inês Batista Gomes, Inês Colaço, Isabel Azevedo, Isabel Palma, João Anselmo, J Porto, João Pedro Ramos, João Sequeira Duarte, Jorge Pintado Alves, José Miguel Salgado, José Pereira de Moura, Leonor Sassetti, Lina Cardoso Ramos, Luísa Diogo, Luísa Mota‐Vieira, Luísa Pires, Márcio de Moura, Margarida Bruges, Margarida Venâncio, Maria do Rosário Barroso, Maria João Virtuoso, Maria Luísa Gonçalves, Mário Oliveira, Mendes Nunes, J.M. Costa, Miguel Mendes, Miguel Toscano Rico, Mónica Tavares, Natalina Miguel, Oana Moldovan, Olga Azevedo, Patrícia Lipari Pinto, Patrícia Pais, Patrícia Freire de Vasconcelos, Paula Garcia, Paula Martins, Pedro Silva Cunha, P. S. Lemos, Quitéria Rato, Raquel Coelho, Raquel Gouveia Silva, Raquel Ribeiro, Rita Jotta de Oliveira, Roberto Magalhães Pinto, Sandra de Souza Pereira, Sérgio Ferreira Cristina, Sílvia Sequeira, Susana Correia, Tânia Vassalo, Tiago Pack, Vânia Martins, Vera Frazão Vieira,

Cancer, Lipids, and Metabolism

Abstract 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 , ABCG8 ), polygenic hypercholesterolemia and hyper-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 1005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A NGS panel, covering 8 genes and 8-SNPs to determine LDL-c polygenic risk score (PRS) 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 1000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype-positive, genotype-negative) have Lp(a)>50mg/dL (30%), high PRS (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 NGS panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person's treatment according to the affected pathway.