Familial hypercholesterolemia (FH) is a hereditary form of high cholesterol that increases the risk for heart disease and stroke, the first and fifth leading causes of death in the United States, respectively. According to the FH Foundation, approximately 1 in 6 adults have high cholesterol, and high cholesterol is caused by FH in about one in every 500 people in the US. Although over 30 million individuals may have FH, many are unaware of their risk.
Genetic testing is available to identify individuals with FH. However, the value of genetic testing has not always been clear, and therefore payer coverage of testing has been inconsistent.
Expert Guidance on Genetic Testing for FH
In a statement published in the Journal of the American College of Cardiology, an international expert panel convened by The Familial Hypercholesterolemia Foundation discussed the rationale of genetic screening for FH. The FH Foundations’ Consensus Statement on Genetic Testing for FH recommends genetic testing for FH as the standard of care for definite or probable cases and their at-risk relatives. “Diagnosis offers the opportunity to prevent FH-related cardiovascular disease,” the statement reads. “Genetic testing is especially important for those with consistently high cholesterol, have had a heart attack at an early age, or have a family history of high cholesterol or early onset heart disease.”
Testing should include the genes encoding the LDL receptor (LDLR), apolipoprotein B (APOB), and PCSK9, with other genes considered for certain patient phenotypes.
The group recommended offering genetic testing for FH to any child or adult with strong clinical index of suspicion for it due to clinical or family history or both. This could include LDL persistently ≥160 mg/dL for children or 190 mg/dL for adults without apparent secondary cause when there is a first-degree relative similarly affected, or with premature coronary artery disease, or where family history is not available.
Even in the absence of a positive family history, testing should be offered for persistent LDLs of at least 190 mg/dL for children or 250 mg/dL for adults without an apparent secondary cause of hypercholesterolemia, the expert panel said.
Additionally, genetic testing for FH may aid in greater risk stratification for heart disease. According to the investigators, individuals with no FH pathogenic variant and LDL-C levels ≥190 mg/dL have a 6-fold higher risk for coronary artery disease vs a 22-fold increased risk in patients with an FH pathogenic variant and LDL-C levels ≥190 mg/dL.
Genetic testing can also help clinicians guide therapy for patients with FH. For instance, FH caused by PCSK9 mutations is particularly responsive to PCSK9 inhibitors.
Existing Barriers to Routine Testing
Currently, FH genetic testing is underutilized in the US, according to the panel, which cited a testing rate of just 3.9% in the CASCADE FH Registry among people with a clinical diagnosis.
How to best detect FH is still being investigated. While a simple and affordable universal cholesterol blood test identifies FH in children, older family members—who also may have the condition—typically need a more expensive genetic test.
Genomic sequencing, which is required to detect FH mutations, is expensive, precluding the possibility of universal screening. Because FH has several different mutations on at least three genes that need to be screened, all three genes need to sequenced. Insurers therefore must determine the patients for whom screening is most beneficial.
Cascade screening, which involves screening first-degree family members after an index case is identified, is one option being explored. Since most causative mutations for FH are inherited in autosomal dominant fashion, approximately half of first-degree relatives also inherit the mutations. Screening at-risk family members of patients with FH may be helpful in identifying other people who might require treatment for the disorder. Using this principle, cascade FH screening employs screening first- and second-degree relatives (in that order) of affected FH patients with lipid profile, which is guided by family history of premature coronary heart disease. According to the American College of Cardiology, this strategy of targeted genetic testing in affected family members has been shown to be cost-effective.
Cascade testing has a Tier 1 indication by the CDC.
Weighing the Pros and Cons
According to the FH Foundation, some benefits of genetic testing for FH include:
- Confirmation of a clinical diagnosis of FH, especially in cases where it is not clear whether the person has FH or not;
- Supplemental information about a patient’s risk or diagnosis, since not all individuals with FH present the same;
- Potential initiation and intensification of therapy by a healthcare provider, as well as willingness on the part of the patient to start, intensify, or continue taking prescribed medications;
- Information regarding why a healthy lifestyle and diet have not been able to control cholesterol levels on their own;
- Leading to other family members being screened;
- Determining whether or not FH has been passed down to a child.
However, genetic testing is not right for everyone. Additionally, the FH Foundations notes that the genetic test itself has limitations. The results are not always a simple negative or positive; for example, a negative test result does not mean someone does not have FH but rather that their genetic cause(s) were not identified with current knowledge and genetic testing technologies. They may also have polygenic hypercholesterolemia.
Presence of causative mutations also can affect an individual’s eligibility for long-term care, life, and disability insurance as well as employment, so it is recommended that genetic testing be done in conjunction with a trained genetic counselor.
For genetic testing for FH to be more widely implemented in clinical practice, randomized trials and cost-effectiveness studies are needed to assess the incremental benefit of genetic testing over clinical criteria for screening and diagnosis of FH.