Photo Credit: Nemes Laszlo

Adding genetic testing to clinical familial hypercholesterolemia screening improves risk assessment, prognosis and helps to guide targeted therapy.

The Centers for Disease Control and Prevention estimated that about 1 in 10 American adults have hypercholesterolemia, also known as high cholesterol. These individuals have total cholesterol counts exceeding 240 mg/dL, which increases their risk of heart disease. Familial hypercholesterolemia is one subset of hypercholesterolemia.

“Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipid metabolism that is characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and a high risk of atherosclerotic cardiovascular disease,” researchers wrote in the Journal of Clinical Medicine. “Familial hypercholesterolemia is typically caused by mutations in the LDL receptor gene (LDLR), although other alterations may be found.”

Luis Rodríguez-Padial, MD, PhD, and colleagues assessed patients found via a population-based diagnostic screening for FH that included a genetic analysis to improve “our understanding of the phenotype/genotype relationships associated with FH that can help optimize treatments and thereby improve prognoses.”

The researchers published their findings before the National Lipid Association’s 2025 meeting, though not as part of it. The NLA 2025 meeting included several sessions on hyperlipidemia, including one that focused on FH.

Study Methods

The researchers selected 469 patients for inclusion in this study. Each patient was at least 18 years old, had a total cholesterol level of 290 mg/dL or greater, LDL-C exceeding 220 mg/dL, and triglycerides lower than 200 mg/dL.

They evaluated the patients using the Dutch Lipid Clinics Network (DLCN) criteria. Patients with 3-5 DLCN points were categorized as possibly having FH, 6-7 points indicated probable FH, and those with eight or more points were classified as definite FH. Records also included other information related to cardiovascular risk and history.

The researchers selected patients with probable or definite FH for genetic testing, using next-generation sequencing (NGS), as were 10 randomly selected patients with possible FH.

Relevant Findings & Clinical Impact

 Dr. Rodríguez-Padial and colleagues found that patients with DLCN scores of 6 or higher were younger, experienced less hypertension, and had higher rates of smoking. They also had a family history of heart disease, and their relatives had more severe cases of severe high cholesterol.

Through testing that screened for 11 genetic markers, 67.9% of patients with a DLCN score of 6 or lower received a positive result for FH, as well as 58.9% of those with a score of 6-7 and 85.7% of those with a score of 8 or higher. Just 2 of the 10 patients with a score of 3-5 tested positive for FH.

The researchers separated patients into three classes based on their pathology. The researchers found that only patients with class I pathology had genetic variants that could distinguish specific phenotypes of FH.

The findings indicate that molecular characterization of patients with FH can determine a more precise prognosis, according to the researchers.

“These results highlight the benefits of using genetic studies to complement the clinical diagnosis of FH, as molecular tools better characterize patients and provide an individualized cardiovascular risk assessment, potentially leading to improved treatment and prognosis,” Dr. Rodrigeuz-Padial and colleagues wrote.