Journal of Lipid Research (Feb 2024)

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

  • 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 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

Journal volume & issue
Vol. 65, no. 2
p. 100490

Abstract

Read online

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.

Keywords