ABOUT FAMILIAL HYPERCHOLESTEROLEMIA

Your cholesterol has been high since childhood — not because of diet, but because your cells can't clear LDL from your bloodstream. Knowing the genetic cause changes the treatment.

Whole genome sequencing identifies LDLR, APOB, and PCSK9 variants driving familial hypercholesterolemia — enabling early, targeted therapy and cascade screening for your family.

LDLR
APOB
PCSK9

About this condition

Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is the most common monogenic cause of premature coronary artery disease, affecting approximately 1 in 250 individuals worldwide. It results from inherited variants in genes encoding proteins that regulate LDL cholesterol clearance from the bloodstream. The LDLR gene encodes the LDL receptor, which removes LDL cholesterol from circulation; the APOB gene encodes apolipoprotein B-100, the ligand that binds to the LDL receptor; and PCSK9 encodes a protease that degrades LDL receptors. Variants in any of these genes impair the cell's ability to clear LDL, leading to lifelong markedly elevated circulating LDL cholesterol.

LDLR variants account for 85–90% of genetically confirmed FH cases. Over 1,600 distinct pathogenic LDLR variants have been catalogued. APOB and PCSK9 variants account for the remaining cases. Heterozygous FH affects approximately 1 in 250 to 500 people; homozygous FH is rarer (1 in 160,000 to 300,000) but causes severe cardiovascular disease in childhood. Untreated heterozygous FH carriers have greater than 50% cumulative risk of coronary events by age 50 in men and age 60 in women. Despite its prevalence and the availability of genetic testing, fewer than 10% of affected individuals are identified worldwide.

Confirming an FH diagnosis unlocks aggressive treatment strategies that dramatically reduce cardiovascular risk. High-intensity statin therapy is first-line; those with inadequate LDL reduction become candidates for PCSK9 inhibitors, which can lower LDL by 50% beyond statins. Newer agents such as bempedoic acid and inclisiran provide additional options. Identifying a pathogenic variant in a proband triggers cascade testing of all first-degree relatives — finding other carriers before a first cardiac event enables early treatment and prevention. For children identified as carriers, early lipid management can prevent or delay coronary disease by decades.

LDLR, APOB, and PCSK9 variants operate through different mechanisms — receptor synthesis, LDL binding, or receptor degradation — but all result in the same phenotype of elevated LDL and premature atherosclerosis.

Gene locus: LDLR (19p13.2), APOB (2p24.1), PCSK9 (1p32.3)

Standard FH panels test a fixed list of known variants. They miss novel mutations and fail to detect mutations in ~60% of clinically diagnosed patients.

Novel variants are the rule, not the exception

Targeted FH panels typically test only known, previously characterized pathogenic variants in LDLR, APOB, and PCSK9. However, with over 1,600 LDLR variants catalogued and new mutations continually being discovered, panels miss rare and novel variants. In clinical cohorts, identifiable mutations in these three genes account for only approximately 40% of patients with a clinical FH diagnosis. The remaining 60% may harbor novel rare variants, variants in less-tested genes (LDLRAP1, APOE), or have a polygenic basis with multiple small-effect loci contributing. Whole genome sequencing captures the entire coding and regulatory sequence of all FH-related genes simultaneously.

A finding enables aggressive treatment before plaque forms

When a pathogenic FH variant is confirmed, it transforms treatment strategy. High-intensity statins become justified in children as young as 8–10 years old (typically contraindicated in the general pediatric population), dramatically reducing lifetime atherosclerotic burden. Adult carriers become candidates for combination therapy with PCSK9 inhibitors or newer agents if statins alone prove insufficient. Cascade testing of family members identifies at-risk relatives before the first cardiac event — often the first indication of FH is a fatal heart attack, which genetic testing can prevent in relatives.

Your cholesterol has been high since childhood — not because of diet, but because your cells can't clear LDL from your bloodstream. Knowing the genetic cause changes the treatment.

Familial Hypercholesterolemia

Standard FH panels test a fixed list of known variants. They miss novel mutations and fail to detect mutations in ~60% of clinically diagnosed patients.

Novel variants are the rule, not the exception

A finding enables aggressive treatment before plaque forms

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