280 - Unravelling the genetic background in individuals with Familial Hypercholesterolemia phenotype (ID 1033)
Abstract
Background and Aims
Genetic diagnosis is the only method to correctly identify patients with Familial hypercholesterolemia (FH) but 40%–50% of these individuals do not have a causative variant in LDLR, APOB and PCSK9 genes. In this work, we aim to characterize the genetic background of individuals with FH phenotype.
Methods
The Portuguese FH Study is using an NGS panel as a new method for the genetic diagnosis of FH, including 8 genes (LDLR, APOB, PCSK9, LDLRAP1, ABCG5, ABCG8, APOE, LIPA) and a 6-SNP LDL-C genetic risk score (GRS). A set of 104 individuals (60 adults and 44 children) with clinical diagnosis of FH was analysed.
Results
FH was confirmed in 30 individuals: 1 homozygous and 29 heterozygous (28 pathogenic/likely pathogenic LDLR variants and 1 pathogenic PCSK9 variant). Additionally, 27 individuals presented at least one putative pathogenic variant in APOB, APOE, ABCG5 or ABCG8. No variants were identified in 47 subjects, but in 41 it was observed a high likelihood of polygenic hypercholesterolaemia (25 with GRS>P75th and 16 with GRS P25th-P75th). Overall, we’ve identified 22 LDLR, 1 PCSK9, 12 APOB, 1 LDLRAP1, 3 APOE, 9 ABCG5 and 9 ABCG8 different variants.
Conclusions
A causative FH variant was identified in 29% of the individuals and 26% have putative pathogenic variants in other genes related to the FH phenotype. It was observed a high proportion of patients (13%) carriers of ABCG5/8 putative pathogenic variants. In 45% of the individuals, the cause of the dyslipidaemia is not related to these genes and in 39% is due to a polygenic inheritance.
