麻豆传媒

The majority of familial hypercholesterolemia (FH) cases would go undetected if people relied on array-based genetic tests alone, according to one study.

For example, the 23andMe test -- offering a limited screen for just 24 known FH variants -- would have missed over 60% of individuals with the autosomal dominant disorder, reported Amy Sturm, of the Geisinger Genomic Medicine Institute in Danville, Pennsylvania, and colleagues.

Array testing had a 68.9% miss rate for FH patients who had comprehensive genetic testing done for an FH indication; the miss rate was 61.8% for those who had undergone proactive health screening, they reported in .

"Limited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry," according to Sturm and colleagues.

In their study, nearly 94% and 85% of Black and Hispanic individuals with confirmed FH pathogenic variants would have been missed by limited-variant screening. The same would have been true for only a third of Ashkenazi Jewish people.

"The reduced yield of limited-variant screening could result in a major health care disparity for groups already affected by social and medical disenfranchisement that beget serious health disparities including a significantly higher rate of cardiovascular death among Black/African American individuals," the investigators said.

"When FH is strongly clinical suspected, even if array-based FH reporting has negative results, a clinical genetic test should still be considered," according to an by JAMA Cardiology editors Pradeep Natarajan, MD, MMSc, of Massachusetts General Hospital and Harvard Medical School in Boston, and Elizabeth McNally, MD, PhD, of Northwestern University Feinberg School of Medicine in Chicago.

"Genetic databases overrepresent European ancestry populations and therefore make interpretation of genetic variation more accurate in these cohorts. However, even 64% of the FH mutations in European American individuals would have been missed by the 24-variant [test]," observed Natarajan and McNally.

FH predisposes people to elevated levels of LDL cholesterol that can lead to premature coronary artery disease and early death.

"Unfortunately, genetic testing for FH is underused, with 90% of affected individuals worldwide remaining undiagnosed and only 3.9% of patients with FH in the U.S. having a record of genetic testing," Sturm and colleagues noted.

"Recent expert statements recommend that patients suspected of having FH be offered genetic testing and that first-degree relatives of genetically positive individuals be screened for FH by lipid profile or genetic testing," according to them.

Comprehensive genetic tests utilize next-generation sequencing (NGS) to detect more than 2,000 potentially pathogenic variants within full gene sequences.

In contrast, 23andMe and other assay-based screens only test for a small subset of known variants and do not report whether a person has one or two copies of a variant or whether copy number variants are present.

Both types of genetic tests for FH are available in clinical settings or direct-to-consumer.

"Whether testing is obtained directly by a consumer or through a clinical setting, those tested should consult with a genetic counselor or other qualified health care professional to fully understand the benefits and limitations of the different types of genetic testing for FH," Sturm's group urged.

For the study, the authors took deidentified NGS results, sourced from a single clinical laboratory, for gene panels of individuals receiving comprehensive genetic testing either for an FH indication (n=4,563) or as proactive health screening (n=6,482).

Both cohorts had been tested for more than 2,000 possible variants in four FH-associated genes: LDLR, APOB, PCSK9, and LDLRAP1.

People with an FH indication for testing had a positive detection rate of 27.0% with comprehensive NGS genotyping. The corresponding figure would have been 8.4% with the limited screening test.

In the proactive cohort of people without clinical suspicion of FH, the prevalence of clinically significant FH variants was approximately one in 191 according to the comprehensive test.

The authors acknowledged their inability to confirm genetic testing results with medical and family histories.

Comment