What is the importance of clarifying familial hypercholesterolemia (FH) and what genetic test is needed for diagnosis?

Importance of Clarifying Familial Hypercholesterolemia and Required Genetic Testing

Genetic testing is the most accurate way to diagnose Familial Hypercholesterolemia (FH) and should be performed in all suspected cases to confirm diagnosis, enable cascade testing of family members, and guide appropriate treatment decisions. 1, 2

Importance of Clarifying FH Diagnosis

• FH is a co-dominant, highly penetrant monogenic disorder characterized by markedly elevated LDL-cholesterol concentrations from birth, which if untreated, inevitably leads to premature atherosclerotic cardiovascular disease (ASCVD) 2
• Early diagnosis is critical as FH affects approximately 1 in 311 people, potentially impacting up to 35 million people worldwide, with only about 10% of cases currently diagnosed 2
• Accurate diagnosis allows for early intervention with aggressive lipid-lowering therapy, significantly altering the natural history of FH and preventing premature cardiovascular events 2
• Clarifying FH enables identification of affected family members through cascade testing, which is highly cost-effective 1, 3

Diagnostic Approach

• Initial diagnosis relies on elevated LDL-cholesterol concentrations, family history of premature coronary artery disease, and physical stigmata such as tendon xanthomas 1, 4
• LDL-cholesterol measurement is the cornerstone test for FH diagnosis, with age-specific, sex-specific and country-specific LDL-cholesterol concentrations above the 95th percentile used to screen for index cases 4
• In adults, the most widely used clinical diagnostic methods are the Dutch Lipid Clinic Network and the Simon Broome criteria 1
• Physical signs including tendon xanthomas, xanthelasmata, and corneal arcus (in individuals under 45 years) can raise suspicion of FH 5

Genetic Testing Requirements

• Genetic testing identifies pathogenic variants in genes that impair LDL receptor function, providing the most accurate diagnosis of FH 1, 4
• Testing should focus on the three most common causative genes: 3
  • LDLR (LDL receptor gene) - most common cause
  • APOB (apolipoprotein B gene)
  • PCSK9 (proprotein convertase subtilisin/kexin type 9 gene)
• Comprehensive genetic testing should be performed in index cases with suspected FH to identify the specific pathogenic variant 1
• Genetic testing results should be reported only for clear pathogenic or likely pathogenic variants; benign variants or common polymorphisms should not be reported 1
• Variants of uncertain significance may be reported only if communication is undertaken by a genetic counselor or clinician with expertise in genetics 1

Implementation of Genetic Testing

• Pre-test and post-test genetic counseling should be offered to all patients and at-risk relatives as an integral component of testing 1
• Genetic counseling should include risk assessment, anticipatory guidance, family-based care, and psychological assessment 1
• After identifying a pathogenic variant in the proband, cascade genetic testing for the specific variant should be offered to all first-degree relatives, then second-degree and third-degree relatives if needed 1
• At-risk children should be offered cascade genetic testing at the earliest opportunity if an FH-causing variant has been identified in a parent or other first-degree relative 1
• "Reverse" cascade testing (from child to parents) should be offered after a child is identified as a proband with FH 1

When Genetic Testing Is Not Available

• If genetic testing is not available, phenotypic cascade testing using age-specific, sex-specific and country-specific LDL-cholesterol concentrations should be used 1
• Clinical tools for diagnosing FH probands (such as Dutch Lipid Clinic Network criteria) are not valid for cascade testing of family members 1
• Phenotypic cascade testing should initially be offered to all first-degree relatives, then second-degree and third-degree relatives 1

Common Pitfalls and Caveats

• Genetic testing is currently underutilized due to costs, inadequate clinical skills in genomic medicine, genetic privacy concerns, and limited availability of genetic counseling services 1
• Hypertriglyceridemia can interfere with LDL-cholesterol calculation; direct LDL-cholesterol measurement is recommended when triglycerides exceed 4.5 mmol/L (400 mg/dL) 4
• Adjustment for concurrent lipid-lowering medications is required to make an accurate phenotypic diagnosis 1, 4
• Polygenic scores for hypercholesterolemia are not yet fully standardized and should be used with caution when assessing the differential diagnosis of FH 1
• A pathogenic variant may not be found in all clinically diagnosed FH cases due to polygenic hypercholesterolemia or unidentified pathogenic variants 1