What is the approach to diagnose familial hypercholesterolemia (FH)?

How to Test for Familial Hypercholesterolemia

Initial Screening Approach

Begin with LDL-cholesterol measurement using age-specific, sex-specific, and country-specific thresholds above the 95th percentile for the population to identify potential index cases. 1

Lipid Testing Strategy

• Non-fasting samples are acceptable for initial screening, though the Friedewald equation should be used cautiously due to hypertriglyceridemia interference. 1, 2
• If triglycerides exceed 4.5 mmol/L (>400 mg/dL), obtain a 12-hour fasting sample and measure LDL-cholesterol using a direct assay to avoid calculation errors. 1, 2
• Use LDL-cholesterol >4.9 mmol/L (≥190 mg/dL) as a trigger for FH evaluation in community settings. 1, 3
• Adjust LDL-cholesterol values for concurrent lipid-lowering medications (statins, ezetimibe, PCSK9 inhibitors) if pretreatment values are unavailable; if diagnosis remains uncertain, repeat testing after medication washout or full recovery from acute illness. 1, 2

Clinical Diagnostic Criteria

After identifying elevated LDL-cholesterol, apply the Dutch Lipid Clinic Network or Simon Broome criteria in adults as the most widely validated phenotypic diagnostic tools. 3, 4

Key Clinical Features to Assess

• Family history of premature cardiovascular disease (coronary artery disease before age 55 in men, 60 in women). 1, 3
• Physical stigmata: tendon xanthomas (especially Achilles tendon), xanthelasmas, or premature corneal arcus (before age 45). 3, 4, 5
• Personal history of premature atherosclerotic cardiovascular disease. 1, 3

Genetic Testing Protocol

Genetic testing should be offered to all individuals with definite or highly probable phenotypic FH based on clinical and/or family history. 1, 3

Testing Specifications

• Use targeted next-generation sequencing of all exons and exon-intron boundaries of LDLR, APOB, PCSK9, and LDLRAP1 genes. 1, 3
• Include analysis of exons in APOB encoding the LDLR ligand-binding region. 1, 3
• Perform analysis for deletions and duplications in LDLR. 1, 3
• Testing must be conducted in a certified laboratory using accredited methods. 1, 3
• Genetic testing should be considered in individuals with probable phenotypic HeFH, and may be considered in those with possible HeFH when incomplete information exists and the result affects clinical management. 1

Genetic Counseling Requirements

• Pre-test and post-test genetic counseling should be offered to all individuals suspected of having FH, including obtaining a three-generation family medical history, risk and psychological assessment, and enabling cascade testing. 1
• Genetic testing should be requested by a specialist clinician skilled in counseling, genomic medicine, and FH care; in rural or remote regions, general practitioners may request testing under close specialist guidance. 1

Cascade Testing of Family Members

After identifying a pathogenic variant in the proband, offer cascade genetic testing for that specific variant to all first-degree relatives. 1, 3

Cascade Testing Algorithm

• If first-degree relatives are unavailable or decline testing, sequentially extend to second-degree and then third-degree relatives until all at-risk individuals have been offered testing. 1
• When genetic testing is not feasible, use phenotypic cascade testing with age-specific, sex-specific, and country-specific LDL-cholesterol thresholds; note that Dutch Lipid Clinic Network and Simon Broome criteria are NOT valid for diagnosing relatives. 1
• "Reverse" cascade testing from child to parents should be offered after a child is identified as a proband with FH. 1
• Cascade testing should ideally be centrally coordinated by a well-resourced, dedicated center. 1

Age-Specific Testing Protocols

Children with Suspected Homozygous FH

Test children with suspected homozygous FH (physical stigmata or both parents with FH) as early as possible—at newborn stage or by age 2 years—with LDL-cholesterol measurement followed by genetic confirmation. 1, 3, 2

Children at Risk of Heterozygous FH

Screen children at risk of heterozygous FH at or after age 5 years using LDL-cholesterol concentrations, or as early as age 2 in those with strong family history of premature cardiovascular disease. 1, 3, 2

• 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 first-degree relative. 1

Multiple Screening Strategies

Use multiple screening strategies simultaneously: selective, opportunistic, and universal screening to maximize case detection. 1, 3

Selective Screening

• Target adults with premature cardiovascular disease (especially coronary artery disease) and family history of premature cardiovascular disease and/or hypercholesterolemia. 1, 3

Opportunistic Screening

• Screen patients presenting to dermatologists (before isotretinoin), rheumatologists/orthopedic surgeons (Achilles xanthomas), ophthalmologists (corneal arcus, xanthelasma), and pharmacists (point-of-care testing). 3
• Implement alerts and interpretive comments on laboratory lipid profile reports to enable case detection. 3

Universal Screening

• Universal screening using age-specific and sex-specific LDL-cholesterol criteria should be considered for children and adolescents, after which diagnosis should be formally confirmed and reverse cascade testing offered to parents. 1, 3

Common Pitfalls and Caveats

• If a pathogenic or likely pathogenic variant is not detected, FH should not be excluded, particularly if the clinical phenotype is strongly suggestive, because the condition may result from undetected genetic variants. 1
• Variants detected by genetic testing should be classified and reported according to contemporary standardized guidelines (ACMG, AMP, or ClinGen FH Variant Curation Expert Panel). 1
• Restrict reporting of variants to those with clear pathogenic or likely pathogenic impact; variants of uncertain significance may be reported only when communicated by a genetic counselor or clinician with genetics expertise. 1
• Polygenic scores for hypercholesterolemia may be useful but are not yet fully standardized and should be used with caution in clinical practice. 1