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Experts Recommend Genetic Testing for Familial Hypercholesterolemia to Improve Diagnosis

NEW YORK (GenomeWeb) – An expert panel convened by the Familial Hypercholesterolemia Foundation has recommended that genetic testing should be the standard of care for patients who have a definite or probable diagnosis for FH based on clinical factors and family history.

The panel, comprising 30 cardiovascular, lipid, genetics, and advocacy experts led by the FH Foundation, recommended in a paper published in the Journal of the American College of Cardiology today that those with very high LDL cholesterol and a positive family history of high cholesterol or early heart attack should be evaluated for pathogenic variants in at least three genes — LDLR, APOB, and PCSK9 — though doctors may assess other genes based on a patient's specific phenotype.

According to the authors, led by Amy Sturm, director of cardiovascular genomic counseling at the Geisinger Genomic Medicine Institute, such testing would result in more patients being definitely diagnosed with FH, facilitate cascade testing of family members, allow treatments to be initiated earlier, and enable better risk stratification. The authors based their recommendations on expert opinions and reviews of the published literature on the topic.

"Diagnosing and treating FH in childhood reduces the risk of early heart disease by about 80 percent, which is why it’s so important to find families with FH and especially children who have this invisible, life-threatening genetic disorder," Sturm said in a statement. "In addition, understanding the exact genetic mutation can better inform the initiation and treatment of FH with more intense lipid-lowering therapies and ultimately improve outcomes."

FH is caused by a genetic defect that hinders the body's ability to remove low density lipoprotein (LDL) cholesterol from the blood. High LDL levels in the blood are more likely to result in narrowing of the arteries, which puts patients at substantially higher lifetime risk for heart disease and stroke at an early age. If gone undiagnosed and poorly managed from an early age, men with FH are at 50 percent risk of having a fatal or nonfatal coronary event by age 50 and women have a 30 percent risk of such an event by age 60.

The condition occurs in around 1 out of 220 people and the foundation estimates that there are 30 million people with FH worldwide. However, FH is significantly underdiagnosed, largely due to the wide spectrum of phenotypes caused by a range of pathogenic variants. According to the FH Foundation, more than 90 percent of patients worldwide and more than 1 million in the US remain undiagnosed.

A number of expert guidelines include genetic testing as a key diagnostic method for FH, alongside clinical information, such as high LDL-C levels, a personal or family history of cardiovascular disease, and physical examination findings. However, data from the CASCADE FH Registry suggests that in the US, only 3.9 percent of patients in the repository with a clinical diagnosis for FH have had genetic testing. 

Wider use of genetic testing to identify FH patients is necessary, according to the expert panel, since cardiovascular conditions and other disease phenotypes might show up in a minority of patients, and there might be incomplete information on the prevalence of such conditions among relatives. Moreover, while patients with pathogenic FH variants generally have higher LDL-C levels, studies have shown a wide range of levels among patients.

"Because individuals with FH-associated variants may not have LDL-C levels above certain thresholds, yet have an elevated risk for CAD, genetic testing has utility in identifying those with FH who are at increased risk and who likely would not otherwise be diagnosed," Sturm and colleagues wrote in the JACC paper.  

More than 2,000 unique genetic variants associated with FH have been identified to date, with around half being classified as pathogenic or likely pathogenic. More than 90 percent of pathogenic variants are in LDLR, between 5 percent and 10 percent are in APOB, and less than 1 percent are in PCSK9. Genetic testing doesn't always detect a pathogenic variant in one of these genes, and the authors noted that FH should be diagnosed clinically in the event of a negative test result.

A number of genetic testing labs now offer next-generation sequencing panels that include assessment of LDLR, APOB, and PCSK9 and cost less than $500 for patient testing. Once a pathogenic variant in known, testing at-risk family members for the same variant is less expensive. "Larger, more inclusive lipid disorder NGS panels are also available that provide evaluation of not only the main FH genes but also the genes causing conditions with phenotypic overlap," Sturm and colleagues wrote.

"In this era of precision medicine, genetic testing is an important tool to identify people at high risk for FH and guide the management of their LDL cholesterol to reduce long-term morbidity and mortality from early and aggressive CAD," Daniel Rader, chair of the department of genetics at the University of Pennsylvania and a co-author of the paper, said in a statement. "Physicians should entertain the diagnosis of FH in their patients who have a family history of early heart disease and/or high LDL cholesterol, and consider offering a genetic test in those who may have FH."