A 52-year-old man with a family history of premature coronary artery disease presents with xanthomas on his Achilles tendons and eyelids. Fasting lipid panel shows total cholesterol 480 mg/dL, LDL-C 420 mg/dL, and triglycerides 150 mg/dL. Clinical suspicion for familial hypercholesterolaemia is high. Which investigation would be most appropriate to confirm the diagnosis and assess the underlying genetic defect?

Explanation

## Diagnostic Approach to Familial Hypercholesterolaemia ### Clinical Presentation Recognition **Key Point:** The patient presents with classic features of familial hypercholesterolaemia (FH): tendon xanthomas, eyelid xanthomas, markedly elevated LDL-C (>400 mg/dL), and positive family history of premature CAD. ### Genetic Basis of FH Familial hypercholesterolaemia is primarily caused by mutations in three genes: | Gene | Frequency | Protein Function | Inheritance | |------|-----------|------------------|-------------| | LDLR | ~85% | LDL receptor (removes LDL from circulation) | Autosomal dominant | | APOB | ~10% | Apolipoprotein B-100 (ligand for LDLR) | Autosomal dominant | | PCSK9 | ~3–5% | Proprotein convertase (degrades LDLR) | Autosomal dominant | ### Why LDL Receptor Gene Sequencing is Correct **High-Yield:** LDL receptor (LDLR) gene mutations account for ~85% of heterozygous FH cases. Sequencing this gene is the **gold standard confirmatory test** because: 1. **Highest diagnostic yield** — detects the defect in the majority of FH patients 2. **Defines the genetic basis** — allows classification as heterozygous vs. homozygous 3. **Enables cascade screening** — identifies affected family members 4. **Guides therapy** — homozygotes may require apheresis or PCSK9 inhibitors; heterozygotes respond to statins 5. **Prognostic value** — certain mutations correlate with earlier CAD onset **Clinical Pearl:** In a patient with clinical FH (tendon xanthomas + LDL-C >400 mg/dL + family history), LDLR gene sequencing is the most appropriate next step to confirm the diagnosis and identify the specific mutation. ### Investigation Algorithm ```mermaid flowchart TD A[Clinical suspicion of FH]:::outcome --> B[Lipid panel + clinical features]:::action B --> C{Meets FH criteria?}:::decision C -->|Yes| D[LDLR gene sequencing]:::action D --> E{Mutation found?}:::decision E -->|Yes, heterozygous| F[Statin therapy + lifestyle]:::action E -->|Yes, homozygous| G[Apheresis + PCSK9i + statin]:::action E -->|No LDLR mutation| H[Sequence APOB or PCSK9]:::action ``` **Mnemonic:** **FH-LDLR** = **F**amilial **H**ypercholesterolaemia → **L**DL **D**efect → **L**DL **R**eceptor sequencing