Mariano, C.Alves, A.C.Medeiros, A.Chora, J.R.Antunes, M.Futema, M.Humphries, S.E.Bourbon, M.2020-04-302020-04-302019-12-19Clin Genet. 2020 Mar;97(3):457-466. doi: 10.1111/cge.13697. Epub 2019 Dec 310009-9163http://hdl.handle.net/10400.18/6563Familial 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.engFamilial HypercholesterolaemiaGenetic Risk ScoreMonogenic DyslipidaemiaPhenocopiesPolygenic HypercholesterolaemiaHipercolesterolemia FamiliarDoenças Cardio e Cérebro-vascularesjournal article10.1111/cge.13697