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Familial Hypercholesterolemia (FH): 25 Years Of Findings In The Portuguese FH Study
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Resumo(s)
Familial Hypercholesterolemia (FH) is a hereditary condition characterized by elevated LDL-C levels, which leads to increased risk of atherosclerosis and cardiovascular events. FH presents an estimated frequency of 1/300 and is expected to affect almost 33,000 Portuguese individuals. Therefore, this work summarizes the advances achieved in 25 years of diagnosis and investigation within the Portuguese FH Study (EPHF).
A lipid profile and genetic diagnosis were performed for 1291 referred index cases fulfilling FH clinical criteria (523 children, 768 adults) and 2288 relatives. In 2017, a Next Generation Sequencing panel including FH genes (LDLR, APOB, PCSK9) and FH phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, ABCG8) was implemented.
In approximately 40% (n=464) of the EPHF cohort, a genetic cause of FH was identified: 451 index cases with heterozygous FH (HeFH) and 13 with homozygous FH (HoFH). The majority of pathogenic variants were found in the LDLR gene (93%), compared with APOB (5%) and PCSK9 (2%) genes. Cascade screening allowed the identification of FH in 624 relatives (622 HeFH and 2 HoFH). Among adults with FH, 20% present cardiovascular disease (CVD) and 17% have premature CVD. Variants of uncertain significance in FH genes were identified in 63 index cases. Within 60% of the EPHF cohort (group of index cases where the genetic cause of hypercholesterolemia was not identified), 35% present hyper-Lp(a). Other monogenic causes of dyslipidemia were discovered during genetic analysis: 4 cases with lysosomal lipase deficiency (LIPA gene) and 4 cases with sitosterolemia (ABCG5 and/or ABCG8 genes).
The genetic identification of FH corresponds to 3% of the expected number of individuals affected in Portugal. Nevertheless, other rare lipid metabolism disorders were identified. To overcome FH underdiagnosis in Portugal and to promote early diagnosis and treatment to prevent CDV complications, a cost-effective screening chip array is under development.
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Familial Hypercholesterolemia (FH) Portuguese FH Study (EPHF) Doenças Cardio e Cérebro-vasculares Portugal