Limited-Variant Screening Tests Often Miss Familial Hypercholesterolemia

By Reuters Staff

May 31, 2021

NEW YORK (Reuters Health) - Two-thirds of cases of familial hypercholesterolemia (FH) would be missed by relying on array-based genetic tests that screen for only a limited number of variants, according to a new study.

"Negative findings on a limited-variant screen in an individual who actually carries a disease-causing variant may lead to false reassurance that a disease-associated variant is not present, resulting in missed opportunities to initiate or intensify treatment and identify at-risk relatives," report Amy Sturm, of the Geisinger Genomic Medicine Institute in Danville, Pennsylvania, and colleagues in JAMA Cardiology.

Array-based genotyping tests looks for a limited set of FH-linked variants. In contrast, tests that use next-generation sequencing (NGS) can detect more than 2,000 FH-associated variants as well as novel clinically actionable pathogenic or likely pathogenic variants. Both types of tests for FH are available in clinical settings and direct-to-consumers.

For their study, Sturm and colleagues compared comprehensive NGS genetic test results for clinically significant FH variants with results for a subset of 24 variants screened by a limited-variant array. The analysis included deidentified NGS test results for 4,563 individuals who had an indication for FH diagnostic testing and 6,482 individuals tested as part of proactive screening.

In the indication cohort, the positive detection rate was 8.4% for a limited-variant screen compared to 27.0% with NGS-based comprehensive test. As a result, 68.9% of individuals with a pathogenic or likely pathogenic variant in an FH-associated gene would have been missed by the limited screen.

"The inferior detection rate of the limited-variant screening was most pronounced among Hispanic and Black/African American individuals," the authors note.

In the proactive cohort, the prevalence of clinically significant FH variants was roughly one in 191 per the comprehensive test, and 61.8% of individuals with an FH-associated pathogenic or likely pathogenic variant would have been missed by a limited-variant screen.

"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 and colleagues say.

In an accompanying note, JAMA Cardiology editors Dr. Pradeep Natarajan and Dr. Elizabeth McNally note that 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)," note Dr. Natarajan, of Massachusetts General Hospital and Harvard Medical School, in Boston, and Dr. McNally of Northwestern University Feinberg School of Medicine, in Chicago.

They conclude: "When FH is strongly clinical suspected, even if array-based FH reporting has negative results, a clinical genetic test should still be considered."

The study had no specific funding.

SOURCE: https://bit.ly/3uogp3r and https://bit.ly/3i18Jl8 JAMA Cardiology, online May 26, 2021.

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