What are the recommended testing and treatment approaches for Familial Hypercholesterolemia (FH)?

Familial Hypercholesterolemia Testing

All individuals with strong clinical suspicion of FH—including those with phenotypic homozygous FH, definite or highly probable heterozygous FH in adults or children—should be offered genetic testing using targeted next-generation sequencing of LDLR, APOB, PCSK9, and LDLRAP1 genes in a certified laboratory. 1

Who Should Undergo Genetic Testing

Strong Indications (Class 1 Recommendation)

• Phenotypic homozygous FH with physical stigmata or both parents affected 1
• Definite or highly probable heterozygous FH based on clinical criteria in adults, children, or adolescents 1
• LDL-cholesterol ≥190 mg/dL (≥4.9 mmol/L) in adults after excluding secondary causes 2, 3
• Children with LDL-cholesterol >190 mg/dL on two occasions with parental history of high LDL-cholesterol or premature cardiovascular disease 1

Moderate Indications (Class 2 Recommendation)

• Probable phenotypic heterozygous FH based on clinical scoring systems 1
• Adults meeting Dutch Lipid Clinic Network or Simon Broome criteria for probable FH 2, 3

Weaker Indications (Class 3 Recommendation)

• Possible phenotypic FH when incomplete information exists and genetic results would affect clinical management 1

Technical Requirements for Genetic Testing

The testing must be comprehensive and performed correctly to avoid false negatives:

• Use targeted next-generation sequencing of all exons and exon-intron boundaries of LDLR, APOB, PCSK9, and LDLRAP1 1
• Include specific APOB exons encoding the LDL receptor ligand-binding region 1
• Perform deletion/duplication analysis in LDLR gene 1
• Testing must occur in a certified laboratory using accredited methods 1
• Variants must be classified according to ACMG, AMP, or ClinGen FH Variant Curation Expert Panel guidelines 1

Critical Caveat About Negative Results

A negative genetic test does not exclude FH if the clinical phenotype is strongly suggestive, as the condition may result from undetected genetic variants or polygenic hypercholesterolemia. 1, 3 This is a common pitfall—approximately 20-40% of clinically diagnosed FH patients will not have an identifiable pathogenic variant with current testing methods. 3

Genetic Counseling Requirements

Genetic counseling is mandatory, not optional:

• Pre-test and post-test genetic counseling must be offered to all individuals suspected of having FH 1
• Minimum counseling components include three-generation family medical history, risk and psychological assessment, family-based care planning, enabling cascade testing, and anticipatory guidance 1
• Pre-conception counseling should be offered to all couples where both partners are known or suspected to have FH 1
• Prenatal or pre-implantation genetic testing should be offered if both partners have FH, particularly if they previously had a child with homozygous FH 1

Cascade Testing After Index Case Identification

Once a pathogenic variant is identified in the proband, systematic family screening becomes essential:

• Cascade genetic testing is highly cost-effective and should be implemented immediately 1
• Test all first-degree relatives first for the specific familial variant 1
• If first-degree relatives are unavailable or decline, sequentially extend to second-degree and third-degree relatives 1
• Continue until all at-risk family members have been offered testing 1
• Children at risk should be tested at the earliest opportunity if a parent carries a pathogenic variant 1

When Genetic Testing Is Not Available

If genetic testing is not feasible, use phenotypic cascade testing:

• Measure fasting lipid profile including LDL-cholesterol in all first-degree relatives 1
• Use age-specific, sex-specific, and country-specific LDL-cholesterol thresholds above the 95th percentile 1, 2
• Do not use clinical diagnostic tools like Dutch Lipid Clinic Network or Simon Broome criteria for relatives—these are only valid for index cases 1

Polygenic Risk Scores

Polygenic scores for hypercholesterolemia are not yet fully standardized and should be used with caution when assessing the differential diagnosis of FH in clinical practice. 1, 3 They may help distinguish monogenic FH from polygenic hypercholesterolemia but should not replace comprehensive genetic testing. 1

Common Pitfalls to Avoid

• Do not rely solely on clinical criteria when genetic testing is available—genetic confirmation enables cascade testing and improves treatment adherence 1, 4
• Do not use direct-to-consumer genetic tests for clinical diagnosis of FH 1
• Do not forget to adjust LDL-cholesterol values for concurrent lipid-lowering medications when interpreting phenotypic criteria 1, 3
• Do not measure LDL-cholesterol during acute illness as it can be temporarily altered 5
• Do not assume negative genetic testing excludes FH in patients with strong clinical phenotype 1

Treatment Implications of Genetic Testing

Genetic confirmation of FH has direct treatment implications:

• All genetically confirmed FH patients require aggressive lipid-lowering therapy regardless of current LDL-cholesterol levels 3, 6
• Start with high-intensity statins (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) 3, 6
• Target LDL-cholesterol <100 mg/dL (<2.6 mmol/L), or <70 mg/dL (<1.8 mmol/L) if atherosclerotic cardiovascular disease is present 3, 7
• Add ezetimibe if <50% LDL-cholesterol reduction or target not achieved on maximally tolerated statin 3
• Consider PCSK9 inhibitors if LDL-cholesterol remains ≥70 mg/dL despite statin plus ezetimibe 3, 7