A 52-year-old man with a family history of premature coronary artery disease presents with xanthomas and corneal arcus. Serum lipid profile shows total cholesterol 450 mg/dL, LDL-C 380 mg/dL, HDL-C 35 mg/dL, and triglycerides 150 mg/dL. What is the most common genetic defect responsible for this phenotype?

## Familial Hypercholesterolaemia (FH) — Most Common Genetic Dyslipoproteinaemia ### Clinical Presentation The patient presents with the classic triad of FH: - Xanthomas (tendon and eruptive) - Corneal arcus - Premature CAD with strong family history The lipid profile shows severe elevation of LDL-C (>300 mg/dL) with relatively normal triglycerides — pathognomonic for FH. ### Genetic Basis of FH Subtypes | Genetic Defect | Prevalence | Mechanism | LDL-C Level | Severity | |---|---|---|---|---| | **LDL receptor mutation** | **85–90%** | ↓ LDL-R expression/function → impaired clearance | 300–500 mg/dL | Heterozygous: moderate; Homozygous: severe | | APOB-100 mutation | 5–10% | Defective ligand → poor receptor binding | 250–400 mg/dL | Moderate | | PCSK9 mutation (gain-of-function) | 1–3% | ↑ LDL-R degradation | 250–400 mg/dL | Mild to moderate | | APOE mutation | <1% | Altered lipoprotein metabolism | Variable | Mild | **Key Point:** LDL receptor defects account for **85–90% of all FH cases** — this is the most common monogenic dyslipoproteinaemia worldwide and in India. ### Pathophysiology of LDL-R Deficiency 1. Reduced LDL receptor expression on hepatocytes 2. Impaired hepatic uptake of LDL particles 3. Prolonged LDL circulation time 4. Accumulation in extrahepatic tissues (skin, tendons, arteries) 5. Accelerated atherosclerosis **High-Yield:** Heterozygous FH (1 in 250–500 people) presents in adulthood with CAD by age 40–50. Homozygous FH (1 in 160,000–1,000,000) presents in childhood with CAD by age 10–20. ### Clinical Pearl The presence of **corneal arcus before age 40** and **tendon xanthomas** are highly specific for FH. LDL-R mutations cause the most severe phenotype because they completely abolish the primary clearance mechanism for LDL. **Mnemonic:** **FH-APOB** — the three main genetic causes: - **F**amilial hypercholesterolaemia → **LDL-R** (most common) - **H**yperlipoproteinaemia → **APOB** (defective B-100) - **P**PCSK9 (gain-of-function) ### Why LDL-R Mutation is the Answer The severity of hypercholesterolaemia (LDL-C 380 mg/dL), presence of xanthomas, corneal arcus, and early CAD family history all point to a defect in the **primary LDL clearance pathway**. LDL-R mutations are responsible for ~90% of FH cases and produce the most severe and clinically recognizable phenotype.