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The familial hypercholesterolaemia phenotype: Monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causes
Author(s) -
Mariano Cibelle,
Alves Ana Catarina,
Medeiros Ana Margarida,
Chora Joana Rita,
Antunes Marília,
Futema Marta,
Humphries Steve E.,
Bourbon Mafalda
Publication year - 2020
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13697
Subject(s) - pcsk9 , apolipoprotein b , sanger sequencing , medicine , genetics , phenotype , familial hypercholesterolemia , ldl receptor , biology , mutation , cholesterol , lipoprotein , gene
Familial hypercholesterolaemia (FH) is a monogenic disorder characterised by high low‐density lipoprotein cholesterol (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. 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 polymerase chain reaction 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.