What is the role of genetic testing in Familial Hypercholesterolemia (FH)?

From the Guidelines

Genetic testing plays a crucial role in the diagnosis and management of Familial Hypercholesterolemia (FH).

Key Points

• Genetic testing should be offered to all individuals with a strong suspicion of FH based on clinical and/or family history 1.
• The testing should be carried out using an accredited method in a certified laboratory, using targeted next-generation sequencing of all exons and exon–intron boundaries of LDLR, APOB, PCSK9, and LDLRAP1 1.
• Genetic counselling should be offered before and after genetic testing to all individuals suspected of having FH, including risk and psychological assessment, family-based care, and enabling of cascade testing 1.
• Cascade genetic testing is highly cost-effective and should be used after a disease-causing variant has been identified in the proband or index case, initially offered to all first-degree relatives and then extended to at-risk second-degree and third-degree relatives 1.
• If genetic testing is not feasible, the diagnosis of FH in at-risk relatives should be made phenotypically using age-specific, sex-specific, and country-specific LDL-cholesterol concentrations 1.

Clinical Recommendations

• Genetic testing for FH should be considered in individuals with a probable phenotypic diagnosis of HeFH, and may be considered in individuals with a phenotypic diagnosis of possible HeFH 1.
• Variants detected by genetic testing should be classified and reported according to contemporary standardized guidelines, such as those of the ACMG, AMP, or ClinGen FH Variant Curation Expert Panel 1.
• If a pathogenic or likely pathogenic variant is not detected, FH should not be excluded, particularly if the clinical phenotype is strongly suggestive of FH 1.

Benefits of Genetic Testing

• Genetic testing can provide a definitive diagnosis of FH, allowing for early initiation of treatment and prevention of cardiovascular disease 1.
• Cascade genetic testing can identify at-risk family members, enabling early intervention and prevention of cardiovascular disease 1.
• Genetic testing can also inform reproductive decisions and provide an opportunity for prenatal or pre-implantation genetic testing if both partners are known to have FH 1.

From the Research

Role of Genetic Testing in Familial Hypercholesterolemia (FH)

• Genetic testing plays a crucial role in the diagnosis and management of Familial Hypercholesterolemia (FH) 2, 3, 4, 5, 6
• The testing can facilitate definitive diagnosis, identify pathogenic variants that indicate higher cardiovascular risk, and guide treatment decisions 2, 3
• Genetic testing can also improve risk stratification beyond LDL-C and family history, and enhance the effectiveness of cascade screening 3, 5

Benefits of Genetic Testing in FH

• Early detection and treatment of FH through genetic testing can significantly reduce the burden of the condition 3, 6
• Genetic testing can identify individuals with FH who may be missed by clinical diagnostic criteria, and improve treatment initiation and adherence 3, 4
• The testing can also provide information on the genetic basis of the disease, which can be useful for family members and guide reproductive decisions 2, 5

Recommendations for Genetic Testing in FH

• The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives 2
• Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) 2
• Alternative approaches to genetic testing, such as expanding screening programs and testing in primary care or cardiology clinics, are being explored 5