What is the recommended management for individuals with a family history of familial hyperlipidemia?

Genetic Testing for Familial Hyperlipidemia

Direct Recommendation

Genetic testing should be offered to all individuals with a strong clinical suspicion of familial hypercholesterolemia (FH) based on elevated LDL-cholesterol and family history, and must be performed in accredited laboratories using next-generation sequencing of LDLR, APOB, PCSK9, and LDLRAP1 genes. 1

Who Should Receive Genetic Testing

Strong Indications (Class 1 Recommendations)

• Definite or highly probable phenotypic FH in adults, children, or adolescents based on clinical criteria 1
• Phenotypic homozygous FH (HoFH) with physical stigmata such as tendon xanthomas or premature arcus cornealis 1
• Children with both parents known to have FH - test as early as newborn stage or by age 2 years 1
• LDL-C ≥190 mg/dL (≥4.9 mmol/L) in adults without secondary causes 2

Moderate Indications (Class 2 Recommendations)

• Probable phenotypic diagnosis of heterozygous FH (HeFH) based on Dutch Lipid Clinic Network or Simon Broome criteria 1, 2
• Children at risk of HeFH - screen at or after age 5 years, or as early as age 2 with strong family history of premature cardiovascular disease 1

Consider Testing (Class 3 Recommendations)

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

Technical Requirements for Genetic Testing

Testing must be performed in a fully accredited laboratory using targeted next-generation sequencing that includes: 1

• All exons and exon-intron boundaries of LDLR, APOB, PCSK9, and LDLRAP1
• Exons in APOB encoding the LDL receptor ligand-binding region
• Analysis for deletions and duplications in LDLR

Variants must be classified according to standardized guidelines from the American College of Medical Genetics and Genomics (ACMG), Association for Molecular Pathology (AMP), or ClinGen FH Variant Curation Expert Panel 1

Critical Pitfall: Negative Genetic Test Does Not Exclude FH

If a pathogenic or likely pathogenic variant is not detected, FH should not be excluded if the clinical phenotype is strongly suggestive, as the condition may result from undetected genetic variants or polygenic hypercholesterolemia 1, 2. This occurs because current genetic testing does not capture all pathogenic variants 1, 2.

Genetic Counseling Requirements

Pre-test and post-test genetic counseling must be offered to all individuals suspected of having FH and their at-risk relatives 1. This counseling should include: 1

• Three-generation family medical history
• Risk and psychological assessment
• Family-based care planning
• Enabling cascade testing
• Anticipatory guidance

Pre-conception counseling should be offered to all couples, especially if 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 in parents with HeFH who previously had a child with HoFH 1.

Cascade Testing After Positive Genetic Result

Once a disease-causing variant is identified in the proband, cascade genetic testing is highly cost-effective and should be used 1, 2. The algorithm proceeds as follows: 1

1. First-degree relatives - offer known familial variant testing initially
2. Second-degree relatives - if first-degree relatives are unavailable or decline testing
3. Third-degree relatives - continue sequential extension until all at-risk individuals have been offered testing
4. Reverse cascade testing from child to parents should be offered after a child is identified as having FH 1

If genetic testing is not available, phenotypic cascade testing using age-specific, sex-specific, and country-specific LDL-cholesterol concentrations should be used 1. Note that clinical diagnostic tools for probands (Dutch Lipid Clinic Network criteria, Simon Broome criteria) are not valid for cascade testing of relatives 1.

Phenotypic Diagnosis When Genetic Testing Unavailable

The diagnosis should be made using country-specific phenotypic criteria with LDL-cholesterol concentrations measured after fasting on two occasions 1. Key considerations: 1

• Non-fasting samples may be considered for screening
• Use Friedewald equation with caution due to confounding effect of hypertriglyceridemia
• If triglycerides >400 mg/dL (>4.5 mmol/L), re-screen with 12-hour fasting sample using direct LDL-C assay
• Adjust LDL-C values for cholesterol-lowering medications (statins, ezetimibe, PCSK9 inhibitors)

Common Barriers to Implementation

Genetic testing remains underutilized due to: 1, 2

• High costs of genetic tests
• Inadequate clinical skills in genomic medicine among healthcare providers
• Genetic privacy concerns and restrictions on life insurance
• Limited availability of genetic counseling services

Direct-to-consumer genetic tests are not recommended or appropriate for clinical diagnosis of FH 1

Clinical Impact of Genetic Confirmation

Genetic confirmation enables: 2

• Identification of affected family members through cascade testing
• Appropriate treatment decisions and intensity
• Differentiation from polygenic hypercholesterolemia
• Risk stratification for cardiovascular disease

Polygenic scores for hypercholesterolemia are not yet fully standardized and should be used with caution when assessing differential diagnosis of FH in clinical practice 1

Management Implications

All FH patients require aggressive cholesterol-lowering therapy regardless of genetic test results 3. Treatment should begin with high-intensity statins (atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily), adding ezetimibe if LDL-C remains >100 mg/dL, and escalating to PCSK9 inhibitors if goals are not met 3, 4.

For pediatric patients age ≥10 years with HeFH confirmed genetically or phenotypically, statin therapy should be initiated targeting LDL-C <135 mg/dL or approximately 50% reduction 3, 4.