PO77 Familial Hypercholesterolemia (FH) genetic testing in Portugal

Familial Hypercholesterolemia (FH) is a hereditary condition characterized by markedly elevated LDL-C levels, which leads to increased risk of atherosclerosis and premature cardiovascular disease (pCVD). FH estimated worldwide frequency is 1/300 and in Portugal it is expected to affect almost 33,000 individuals. To investigate the genetic cause of individuals with a clinical diagnosis of FH, individuals can be referred by their clinicians to the Portuguese FH Study (PFHS), which was established in 1999 and is free of charge under a research protocol. The purpose of this work is to summarize the outcomes of FH genetic testing in the PFHS. From 1999 to 2024, a total of 1386 index cases (555 children, 831 adults) fulfilling FH clinical criteria were referred to the PFHS, as well as 2389 relatives. All cases underwent lipid profiling (total cholesterol, LDL-c, HDL-c, triglycerides, Lp(a), and other relevant apolipoproteins) and genetic diagnosis. In 2017, a Next Generation Sequencing panel including FH primary genes (LDLR, APOB, PCSK9) and FH phenocopy genes was implemented. (1). A total of 491 individuals were confirmed genetically with FH. Among 831 adults (18-78 years old), the positive diagnostic rate reached 31% (n=260). These individuals presented likely pathogenic (LP) and pathogenic (P) variants in the three FH-causative genes: 91% in LDLR, 7% in APOB, and 2% in PCSK9. Eleven cases of homozygous FH were identified in this group. Variants of unknown significance (VUS) in genes causing FH were identified in 6% (n=53) of the adults. In FH-confirmed patients, pCVD was present in 21% of the cases, the majority suffering myocardial infarction as a manifestation of the disease. In contrast with adult cases, in the paediatric group (n=555, 1-17 years old) the positive diagnostic rate achieved was higher: 46% (n=231). In this group, 92% were diagnosed with FH due to LP/P variants in the LDLR gene, 6% in APOB, and 2% in PCSK9. A total of 4 children were identified as having homozygous FH. Detection of VUS variants occurred only in 17 children (3%). CVD was not observed in this paediatric sub-cohort, not even in homozygous FH children. Moreover, by recruiting family members of index cases, cascade screening resulted in the identification of 652 new cases of FH, leading to a total of 1143 FH individuals genetically identified, thus showing the relevance of this approach. Despite the efforts to enhance the awareness of FH in Portugal, the genetic identification of FH cases only corresponds to 3.5% of the expected number of affected individuals in Portugal. Functional assessment of VUS variants remains essential for an accurate diagnosis, and it is being performed in the scope of PerMedFH and FH EARLY projects. Currently, a cost-effective screening chip array is under development (in FH EARLY) to overcome FH underdiagnosis in Portugal and worldwide, to promote early and affordable diagnosis and timely treatment to prevent CVD complications.