👤 Tomas Freiberger

Familial hypercholesterolemia is a monogenic Mendelian disorder characterized by elevated LDL cholesterol and premature atherosclerotic cardiovascular disease. It is caused by pathogenic variants in LDLR , APOB , and PCSK9 , with rarer involvement of LDLRAP1 and APOE . Despite advances in molecular diagnostics, no causative variant is identified in approximately 25-75% of clinically diagnosed cases. Familial hypercholesterolemia is currently defined as an autosomal semi-dominant disorder with a gene-dosage effect, whereby biallelic pathogenic variants result in markedly more severe phenotypes than heterozygous variants. Terminology for homozygous familial hypercholesterolemia has been refined. Former terms such as 'true homozygote', 'compound heterozygote', and 'double heterozygotes' have been replaced by monogenic biallelic forms, with identical or different variants, and digenic biallelic forms involving two familial hypercholesterolemia-associated genes. Polygenic risk score (PRS) and lipoprotein(a) measurement help explain familial hypercholesterolemia-like phenotypes in patients without a monogenic cause and enable determination of polygenic severe hypercholesterolemia and/or hyperlipoproteinemia(a). Although advances in molecular genetics have improved variant detection, interpretation remains challenging. Integration of case-level data and functional studies, including high-throughput LDLR assays and APOB structural analyses, has enhanced variant pathogenicity classification. Combining monogenic variant detection, PRS determination and lipoprotein(a) assessment enables comprehensive diagnosis, tailored risk stratification, and personalized familial hypercholesterolemia management. Show less

Familial dysbetalipoproteinemia (FD) is an autosomal recessive (rarely dominant) inherited disorder that is almost exclusively associated with the apolipoprotein E gene (APOE) variability. Nonetheless, only a small proportion of APOE2/E2 subjects develop the phenotype for mixed dyslipidemia; the context of other trigger metabolic or genetic factors remains unknown. One hundred and one patients with FD and eighty controls (all APOE2/E2 homozygotes; rs429358) were screened for 18 single-nucleotide polymorphisms (SNPs) within the genes involved in triglyceride metabolism. Two SNPs were significantly associated with the FD phenotype (rs439401 within APOE; P < 0.0005 and rs964184 within ZPR1/APOA5/A4/C3/A1 gene cluster; P < 0.0001). Unweighted genetic risk scores - from these two SNPs (GRS2), and, also, additional 13 SNPs with P-value below 0.9 (GRS15) - were created as an additional tool to improve the risk estimation of FD development in subjects with the APOE2/E2 genotype. Both GRS2 and GRS15 were significantly (P < 0.0001) increased in patients and both GRSs discriminated almost identically between the groups (P = 0.86). Subjects with an unweighted GRS2 of three or more had an almost four-fold higher risk of FD development than other individuals (odds ratio (OR) 3.58, 95% confidence interva (CI): 1.78-7.18, P < 0.0005). We identified several SNPs that are individual additive factors influencing FD development. The use of unweighted GRS2 is a simple and clinically relevant tool that further improves the prediction of FD in APOE2/E2 homozygotes with corresponding biochemical characteristics. Show less