A 52-year-old Indian male with familial hypercholesterolaemia presents with xanthomas and premature coronary artery disease. Which is the most common genetic defect responsible for familial hypercholesterolaemia?

Explanation

## Genetic Defects in Familial Hypercholesterolaemia (FH) **Key Point:** Loss-of-function mutations in the LDL receptor (LDLR) gene account for ~85% of familial hypercholesterolaemia cases, making it the most common genetic cause. ### Classification of FH by Genetic Defect | Genetic Defect | Frequency | Mechanism | Phenotype | LDL Level | |---|---|---|---|---| | **LDLR mutation (loss-of-function)** | **~85%** | ↓ LDL receptor expression/function | Heterozygous: 2–3× normal; Homozygous: 6–10× normal | Very high | | APOB mutation (gain-of-function) | ~10% | Defective APOB-100 (familial defective APOB-100) | Heterozygous: 2× normal | High | | PCSK9 mutation (gain-of-function) | ~3–5% | ↑ LDLR degradation | Heterozygous: 2–3× normal | Very high | | LDLRAP1 mutation (loss-of-function) | <1% | ↓ Adaptor protein for LDLR endocytosis | Autosomal recessive; severe | Extremely high | **High-Yield:** LDLR mutations are by far the most common cause of FH. Heterozygous LDLR mutations affect ~1 in 250–500 people in most populations, making FH one of the most common monogenic disorders. ### Pathophysiology of LDLR Mutations **Clinical Pearl:** Loss-of-function LDLR mutations impair hepatic uptake of LDL particles, leading to: - Accumulation of LDL in plasma - Increased peripheral tissue uptake of LDL via non-specific pathways - Enhanced oxidation of LDL and foam cell formation - Premature atherosclerosis (often by 3rd–4th decade in heterozygotes; infancy in homozygotes) ### Diagnostic Features of LDLR-Mediated FH 1. **Heterozygous FH (1 mutant allele)** - LDL-C: 2–3× normal (~350–550 mg/dL) - Xanthomas by age 30–40 - CAD in males by age 40–50; females by age 50–60 - Prevalence: ~1 in 250–500 2. **Homozygous FH (2 mutant alleles)** - LDL-C: 6–10× normal (>600 mg/dL) - Xanthomas in childhood - CAD in childhood/adolescence - Prevalence: ~1 in 160,000–1,000,000 **Mnemonic:** **LDLR = 85%** — The LDL Receptor is the most common Defect in 85% of FH cases. ### Why LDLR Mutations Are Most Common - Large gene (~45 kb) with many exons → higher mutation rate - Haploinsufficiency: one functional copy insufficient for normal LDL clearance - No redundant pathway for LDLR-mediated uptake - Evolutionary pressure: heterozygotes may have had survival advantage in ancestral low-cholesterol environments ### Management Implications - **Statins:** First-line; block HMG-CoA reductase, upregulate residual LDLR - **PCSK9 inhibitors:** Prevent LDLR degradation; highly effective in LDLR-mutation FH - **Ezetimibe:** Inhibits intestinal cholesterol absorption - **LDL apheresis:** For homozygotes or severe heterozygotes unresponsive to medical therapy