Genetic Testing May Not Identify Familial Hypercholesterolemia in At-Risk Patients


Positive detection rate for FH through next-generation sequencing was 27.0%, compared to 8.4% using 24-variant array based test.

Amy C. Sturm, MS

Amy C. Sturm, MS

While familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease, data show some genetic testing may only screen a small subset of pathogenic variants.

Investigators, led by Amy C. Sturm, MS, Genomic Medicine Institute, Geisinger, Weis Center for Research found that the limited-variant screens may lead to false reassurance in individuals at risk for FH that they do not carry a disease-causing variant.

The team used a cross-sectional study to identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen.


Investigators performed retrospective analyses of next-generation sequencing (NGS) results for clinically significant variants associated with FH, with results for 24 variants screened in a limited-variant array.

The data was collected for 2 cohorts, including individuals referred by ordering clinician for FH genetic testing from November 2015 – June 2020 and individual samples for proactive genetic testing were received from February 2016 – June 2020.

Panels were ordered by a clinician on behalf of an individual or a request for test was initiated by an individual with third-party physician approval.

Data included up to 147 genes addressing inherited health conditions such as FH. Investigators collected information on age and ancestry through self-report, either preset options or free text answers.

The team tested each cohort for more than 2000 possible variants in 4 FH-associated genes: LDLR, APOB, PCSK9, and LDLRAPI.

Main outcomes included the number of pathogenic or likely pathogenic (P/LP) variants.


Sturm and colleagues found 4563 individuals referred by clinician for FH testing based on clinical suspicion.

Median age at testing was 49 years, with 2528 female individuals.

Through self-report, investigators identified 2902 (63.6%) White/Caucasian, 315 (6.9%) were Hispanic, 280 were Black/African American, and 214 (4.7%) were Asian.

Data show positive detection rate by NGS was 27.0% (1230 of 4563), while testing using the 24-variant array-based test, only 8.4% would have been identified and thus, informed they were carrying a disease-associated variant.

Further, 69% of individuals (843 of 1230) with P/LP identified by the NGS-based test would have been missed by the array-based test.

The team noted that ancestry had an impact on the potential for missed findings in the indication cohort among individuals with a P/LP finding.

Data show 93.7% (59 of 63) of self-reported Black/African American individuals and 84.7% (122 of 144) of Hispanic individuals would have been missed through the limited variant screen, in comparison to 33.3% (4 of 12) Ashkenazi Jewish individuals.

The team found the prevalence of clinically significant FH variants was approximately 1:191 per the comprehensive test.

The study shows 61.8% (21 of 34) individuals with an FH-associated P/LP finding would have been missed by limited-variant screen.


Investigators concluded that limited-variant, array-based testing may significantly reduce clinical sensitivity and create false reassurance among patients with disease-causing FH variants.

“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,” investigators wrote.

The study, “Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis,” was published online in JAMA Cardiology.

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