Genetic Testing and Clinical Data Improve Screening for Familial Hypercholesterolemia

3D rendered Illustration, Erythrocyte cells and harmful Cholesterol or Triglyerides flowing through a Artery or Vein.
A study was conducted to develop a way to screen patient populations for familial hypercholesterolemia via clinical characteristics and genotype data.

Screening for familial hypercholesterolemia (FH) with the combination of clinical criteria and genetic testing may increase the identification and opportunity for early treatment in patients, according to a study in the Journal of the American Heart Association.

Researchers sought to estimate the probability of having any FH variant based on clinical characteristics and genotype data from participants in the UK Biobank. They then applied the predictive model to US adults from the National Health and Nutrition Examination Survey (NHANES) to estimate FH screening yields according to clinical criteria alone with use of the modified Dutch Lipid Clinic Network (DLCN), genetic testing alone, and a combination of clinical criteria with genetic testing.

A total of 49,738 participants in the UK Biobank were included. They had a mean baseline age of 57.1±8.0 years, 54.5% were women, and 93.4% were White. In addition, 39,790 NHANES participants were included in the primary analysis and 16,103 in the sensitivity analysis. The NHANES participants had a mean age of 46.4±16.7 years, 48.6% were women, and 68.5% were White.

The prevalence of any FH variants in participants from the UK Biobank was 0.27%. The final multivariable regression model included age, sex, use of lipid-lowering therapy, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, personal history of atherosclerotic cardiovascular disease, and family history of early coronary heart disease. The predicted probability of any FH variants was 0.26% with an area under the receiver operating characteristic curve of 0.88.

The predicted probability of any FH variants in NHANES was 0.38% (95% CI, 0.33%-0.42%) in the primary analysis and 0.37% (95% CI, 0.32%-0.43%) in the sensitivity analysis of complete cases.

Among US adults, FH screening was estimated to identify 652,100 (95% CI, 523,200-803,000) cases using DLCN clinical criteria alone and 659,000 (95% CI, 478,600-885,800) using genetic testing alone. FH screening would yield 3.7 (95% CI, 3.0-4.6) cases with use of clinical criteria alone, 3.8 (95% CI, 2.7-5.1) with use of genetic testing alone, and 6.6 (95% CI, 5.3-8.0) with use of clinical criteria with genetic testing, per 1000 people screened.

In young adults aged 20 to 39 years, use of DLCN clinical criteria only was estimated to yield 1.3 (95% CI, 0.6-2.5) FH cases per 1000 individuals screened, increasing to 4.2 (95% CI, 2.6-6.4) when genetic testing was added.

The researchers noted that their prediction model was based on adults from the United Kingdom aged 40 to 69 years and may not be generalizable to the more racially diverse US population and to younger adults. Also, the model has not been externally validated, and the analysis may underestimate the prevalence of FH based on clinical criteria alone. Furthermore, the study did not address the long-term costs and health consequences from FH screening and resulting treatment.

“Targeted FH screening strategies, such as genetic testing in young adults aged 20 to 39 years, may increase screening yield, and allow initiation of early preventive therapy,” the researchers noted.

Disclosure: One of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Bellows BK, Khera AV, Zhang Y, et al. Estimated yield of screening for heterozygous familial hypercholesterolemia with and without genetic testing in US adults. J Am Heart Assoc. Published online May 18, 2022. doi: 10.1161/JAHA.121.025192