In familial hypercholesterolemia (FH), which gene mutation is most commonly responsible for the autosomal dominant form?

Explanation

## Familial Hypercholesterolemia (FH) ### Genetic Basis **Key Point:** Autosomal dominant familial hypercholesterolemia is **most commonly caused by mutations in the LDLR gene** (chromosome 19), which encodes the LDL receptor. ### Pathophysiology The LDL receptor is responsible for: 1. Binding and internalization of LDL particles from circulation 2. Removal of cholesterol-rich lipoproteins from blood 3. Regulation of hepatic cholesterol homeostasis When LDLR is mutated or absent: - LDL particles cannot be cleared efficiently from blood - Severe elevation of plasma LDL cholesterol (2–10× normal) - Premature atherosclerosis and coronary artery disease ### Genetic Forms of FH | Gene | Frequency | Phenotype | Inheritance | |------|-----------|-----------|-------------| | **LDLR** | ~85% of FH cases | Heterozygous: LDL 2–3× normal; Homozygous: LDL 6–10× normal | Autosomal dominant | | **APOB** | ~10% of FH cases | Defective LDL binding; similar to LDLR mutations | Autosomal dominant | | **PCSK9** | ~5% of FH cases | Increased LDLR degradation; gain-of-function | Autosomal dominant | | **LCAT** | Rare; causes LCAT deficiency | Different lipid profile; not classic FH | Autosomal recessive | **High-Yield:** Heterozygous FH affects ~1 in 500 people; homozygous FH is rare (~1 in 160,000) and presents with severe hypercholesterolemia, tendon xanthomas, and premature CAD in childhood. ### Clinical Features - **Tendon xanthomas** (especially Achilles tendon) - **Corneal arcus** (lipid deposition in cornea) - **Premature coronary artery disease** (men <55 years, women <65 years) - **Xanthelasmas** (yellowish deposits around eyelids) **Clinical Pearl:** Diagnosis is based on LDL cholesterol levels, family history, and presence of xanthomas. Genetic testing confirms LDLR, APOB, or PCSK9 mutations.