Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of lipid research, 2024-02, Vol.65 (2), p.100490-100490, Article 100490

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.