Genes Responsible for Familial Hypercholesterolemia
Familial hypercholesterolemia is primarily caused by pathogenic variants in three major genes: LDLR (most common), APOB, and PCSK9, with LDLR mutations accounting for the vast majority of genetically confirmed cases. 1
Primary Causative Genes
The genetic architecture of FH follows a clear hierarchy based on frequency and clinical impact:
LDLR Gene (LDL Receptor)
- Accounts for the majority of pathogenic variants identified in clinical FH, representing the most common genetic cause 1, 2
- Over 700 different mutations have been identified worldwide in this gene 2
- Carriers of pathogenic LDLR variants have a 10-fold higher risk of premature atherosclerotic cardiovascular disease compared to the general population 1
- Up to 5% of FH patients may have deletions or rearrangements in the LDLR gene that require specialized testing techniques 2
APOB Gene (Apolipoprotein B)
- Represents 1%-5% of genetically confirmed FH cases 1
- Approximately 3% of FH patients in the UK, North Europe, and USA carry specific mutations in this gene 2
- The disorder caused by APOB mutations is sometimes designated as familial defective apolipoprotein B 100 (FDB), which tends to be milder than LDLR-FH but still causes childhood hypercholesterolemia and premature coronary heart disease in some individuals 2
PCSK9 Gene (Proprotein Convertase Subtilisin/Kexin Type 9)
- Accounts for up to 3% of FH cases 1
- Gain-of-function mutations in PCSK9 cause increased degradation of LDL receptors, reducing receptor numbers on cell surfaces and leading to monogenic hypercholesterolemia 2
Rare Causative Genes
When the three major genes are negative, consider these rarer genetic causes 1:
- LDLRAP1 (LDL receptor adaptor protein 1) - causes autosomal recessive FH
- STAP1 (signal transducing adaptor family member 1)
- APOE (apolipoprotein E)
- LIPA (lipase A, lysosomal acid type)
Polygenic Hypercholesterolemia
Some cases of clinical FH result from the combined effects of multiple common cholesterol-raising alleles rather than a single major gene mutation 1. This polygenic form can be identified using a "polygenic risk score" and represents a significant proportion of patients who present with the FH phenotype but lack a monogenic cause. These individuals have elevated cardiovascular risk (6-fold increased risk with LDL-C >5 mmol/L) but substantially lower than those with monogenic FH (22-fold increased risk) 1.
Clinical Implications for Genetic Testing
Genetic testing can identify pathogenic variants in 30%-80% of individuals with clinical FH 1. The most recent guidelines recommend:
- Genetic testing should be offered when available to complement diagnosis and enable cascade screening of family members 1
- Testing panels should include LDLR, APOB, PCSK9, and LDLRAP1 as a minimum 3, 4
- More than 95% of detected causal variants are found in LDLR and APOB genes 5
Important Caveats
The inability to detect an FH-causing variant should never be used as a basis to withhold treatment 1. Reasons for negative genetic testing include:
- Variants of uncertain significance
- Polygenic causation
- Complex rearrangements not detected by standard sequencing
- Variants in rare or as-yet-unidentified genes
- Technical limitations of current testing methods
Individuals with LDL-C >5 mmol/L and a confirmed FH-causing variant have a 22-fold excess cardiovascular risk, while those with similar LDL-C but no identified variant still have a 6-fold increased risk - both groups warrant aggressive lipid-lowering therapy 1.