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.

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.