A 52-year-old man with a family history of premature coronary artery disease presents with xanthomas over the Achilles tendons and eyelids. Serum total cholesterol is 520 mg/dL with LDL cholesterol of 380 mg/dL. Which investigation is most appropriate to confirm the diagnosis of familial hypercholesterolemia?

## Diagnostic Confirmation in Familial Hypercholesterolemia **Key Point:** Genetic testing is the gold standard for confirming familial hypercholesterolemia (FH) and identifying the underlying molecular defect. ### Why Genetic Testing Is Definitive Familial hypercholesterolemia is an autosomal dominant disorder caused by mutations in one of three genes: - **LDLR** (LDL receptor gene) — accounts for ~85% of FH cases - **APOB** (apolipoprotein B gene) — ~10% of cases - **PCSK9** (proprotein convertase subtilisin/kexin type 9) — ~5% of cases Genetic testing: 1. Confirms the diagnosis with certainty 2. Identifies the specific mutation 3. Enables cascade screening in family members 4. Guides intensity of lipid-lowering therapy 5. Determines eligibility for newer agents (e.g., PCSK9 inhibitors) ### Clinical Presentation Clues The patient has classic features of FH: - Tendon xanthomas (pathognomonic) - Corneal arcus - Premature CAD in family - Markedly elevated LDL cholesterol (>300 mg/dL in heterozygotes) **High-Yield:** The presence of xanthomas + severely elevated LDL + family history of premature CAD = FH until proven otherwise. Genetic confirmation is the next step. ### Role of Other Investigations | Investigation | Purpose | Limitation in FH Diagnosis | |---|---|---| | Lipoprotein(a) | Assess additional CV risk | Not diagnostic; present in general population | | Apolipoprotein B | Quantifies particle number | Elevated in FH but not specific | | Lipid panel | Baseline assessment | Supports clinical diagnosis but not confirmatory | **Clinical Pearl:** FH diagnosis is often made clinically using the Dutch Lipid Clinic Network criteria or Simon Broome criteria before genetic testing, but genetic confirmation is the gold standard and essential for family screening.