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Expert panel endorses genetic screening for FH
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A Journal of the American College of Cardiology Scientific Panel convened by the Familial Hypercholesterolemia Foundation recommended that genetic testing be the standard of care for patients with definite or probable FH.
“Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages and more accurate risk stratification,” the panel wrote.
According to the panel, the testing should include the LDLR, APOB and PCSK9 genes, as well as any others that make sense to test based on phenotype.
Early diagnosis needed
“Because [FH] is a genetic condition that causes cholesterol to be very high over the lifetime, the treatment for it should begin much earlier in life,” Samuel S. Gidding, MD, chief medical officer of the FH Foundation and a member of the panel, told Cardiology Today. “If a 50-year-old patient shows up in a doctor’s office for the first time with very high cholesterol, the doctor has no knowledge of whether that cholesterol has risen over time or has been high their whole life. If it has been high for your whole life, your risk for a heart attack is three times as high. So genetic testing becomes important.”
While genetic testing for FH has become common in several European countries, it is not widely used in the United States, and that needs to change, Gidding said.
“Genetic testing has shown tremendous benefits in identifying untreated individuals who would benefit from initiation of lipid-lowering therapy,” he said. “This has been sadly neglected in the United States. This scientific panel presented the opportunity to leverage the advocacy and research arms of the FH Foundation for an authoritative statement. There is no prior scientific statement that specifically identifies index cases for genetic testing.”
The panel wrote that “at a minimum, genetic testing for patients with suspected FH should include analysis of LDLR, the region of APOB encoding the LDLR ligand, and PCSK9. Importantly, an FH diagnosis is not excluded if genetic testing does not detect a pathogenic variant in one of these genes, as the FH phenotype may be due to undetected pathogenic variants, variants in other genes, and/or variants in as-yet-undiscovered genes. Pathogenic variants in other genes can cause an FH phenotype.”
Who should be tested
According to the panel, genetic testing should be offered to patients for whom there is strong suspicion of FH based on clinical or family history, including:
- Children with persistent LDL ≥ 160 mg/dL and adults with persistent LDL ≥ 190 mg/dL if there is no apparent secondary cause of hypercholesterolemia and there is at least one family member with a history of early CAD or there is no family history available.
- Children with persistent LDL ≥ 190 mg/dL and adults with persistent LDL ≥ 250 mg/dL if there is no apparent secondary cause of hypercholesterolemia, regardless of family history.
The panel wrote that genetic testing may be considered for the following patients:
- Children with persistent LDL ≥ 160 mg/dL with no apparent secondary cause of hypercholesterolemia and at least one parent with persistent LDL ≥ 190 mg/dL or a family history of hypercholesterolemia and premature CAD.
- Adults with no pretreatment LDL levels who had premature CAD and a family history of hypercholesterolemia and premature CAD.
- Adults with persistent LDL ≥ 160 mg/dL with no apparent secondary cause of hypercholesterolemia who have a family history of hypercholesterolemia and a personal or family history of premature CAD.
Cascade genetic screening should be performed in at-risk relatives of those diagnosed with FH, the panel wrote. It should first be offered to first-degree relatives, or to second-degree relatives if first-degree relatives are unavailable or do not want to be tested. “Cascade genetic testing should commence throughout the entire extended family until all at-risk
individuals have been tested and all known relatives with FH have been identified,” the panel wrote.
“This statement uniquely provides a definition of those index cases where a physician, particularly a cardiologist, should start the screening process,” Gidding, who was division head of pediatric cardiology at Nemours Cardiac Center and A. I. DuPont Hospital for Children, and professor of pediatrics at Thomas Jefferson University when the statement was written, told Cardiology Today. “This could be a patient who had a heart attack at age 35, it could be someone who was referred to them because their cholesterol is way out of bounds, any of these scenarios could prompt genetic testing in addition to the doctor starting statins or counseling patients about their own risks and diet management.” – by Erik Swain
Disclosure: Gidding reports he has served as a consultant for Regenexbio. Please see the statement for a list of the other authors’ relevant financial disclosures.
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