Update on genetics of familial hypercholesterolemia - PubMed
3 days ago
- #genetics
- #familial hypercholesterolemia
- #cardiovascular disease
- Familial hypercholesterolemia (FH) is a monogenic Mendelian disorder causing elevated LDL cholesterol and premature cardiovascular disease.
- Pathogenic variants in LDLR, APOB, and PCSK9 are primary causes, with rarer involvement of LDLRAP1 and APOE.
- No causative variant is identified in 25-75% of clinically diagnosed cases despite advances in molecular diagnostics.
- FH is now defined as an autosomal semi-dominant disorder with a gene-dosage effect; biallelic variants lead to more severe phenotypes.
- Terminology for homozygous FH has been refined, replacing terms like 'true homozygote' with monogenic/digenic biallelic forms.
- Polygenic risk score (PRS) and lipoprotein(a) measurement help explain FH-like phenotypes in patients without monogenic causes.
- Advances in molecular genetics have improved variant detection, but interpretation remains challenging.
- Functional studies, including high-throughput LDLR assays and APOB structural analyses, enhance variant pathogenicity classification.
- Combining monogenic variant detection, PRS, and lipoprotein(a) assessment enables comprehensive diagnosis and personalized management.