A 52-year-old man with a family history of premature coronary artery disease presents with xanthomas on his Achilles tendons and eyelids. Serum total cholesterol is 580 mg/dL and LDL cholesterol is 420 mg/dL despite dietary modification. Which investigation is most appropriate to confirm the suspected diagnosis of familial hypercholesterolaemia?

Explanation

## Diagnosis of Familial Hypercholesterolaemia (FH) **Key Point:** Genetic testing for mutations in the LDLR (LDL receptor), APOB (apolipoprotein B), or PCSK9 (proprotein convertase subtilisin/kexin type 9) genes is the gold standard confirmatory investigation for familial hypercholesterolaemia. ### Pathophysiology of FH Familial hypercholesterolaemia is an autosomal dominant disorder caused by loss-of-function mutations affecting LDL receptor-mediated clearance of cholesterol from the bloodstream. Approximately 90% of cases result from LDLR mutations, 5–10% from APOB mutations (affecting LDL binding), and <1% from PCSK9 mutations (affecting LDL receptor degradation). ### Why Genetic Sequencing is the Gold Standard | Feature | Genetic Sequencing | Other Investigations | |---------|-------------------|----------------------| | **Diagnostic certainty** | Definitive; identifies causative mutation | Supportive; not diagnostic | | **Clinical utility** | Enables cascade screening in family members | Cannot guide family management | | **Specificity** | 100% for FH diagnosis | Cannot distinguish FH from polygenic hypercholesterolaemia | | **Regulatory approval** | Required for genetic counselling and therapy eligibility | Insufficient alone | **High-Yield:** The Dutch Lipid Clinic Network Criteria use clinical features (xanthomas, family history, LDL >190 mg/dL in adults) to assign a pretest probability; genetic testing confirms the diagnosis and is essential for cascade screening in relatives. ### Clinical Pearl In this patient, the combination of **tendon xanthomas** (pathognomonic for FH), **severely elevated LDL** (>350 mg/dL), and **family history of premature CAD** places him in the "definite FH" category, making genetic confirmation both diagnostic and prognostically important for risk stratification and family screening. **Mnemonic: FH-GENES** — **F**amilial **H**ypercholesterolaemia diagnosis requires **G**enetic **E**xamination for **N**ucleotide **E**rrors in **S**pecific genes (LDLR, APOB, PCSK9).