Universal Screening Bests Family Hx to ID of Familial Hypercholesterolemia in Children

Family history alone is inadequate for identifying children with familial hypercholesterolemia (FH), according to a study published Sept. 15 in the Journal of the American College of Cardiology. A universal cholesterol screening program may be effective for earlier identification of these children with FH, who are at 100-fold elevated risk for cardiovascular complications in early adulthood without timely intervention.

Current recommendations call for screening children in the United States between nine and 11 years of age, although the exact form of screening (universal or based on family history) is not unanimously agreed upon. Prospective, epidemiological studies are lacking in children, so Slovenia's experience with universal screening (US) for hypercholesterolemia in 5-year-old children is "useful," experts say.

In the current study, 272 Slovenian children (mean referral age 7.3 years) were identified through US to have elevated total cholesterol (TC; higher than 6 mmol/l or higher than 5 mmol/l plus a family history positive for premature cardiovascular complications). These children subsequently were genotyped for variants in four genes associated with FH (LDLR, PCSK9, APOB [exon 26], and APOE).

The researchers found that more than half of the referred children (57 percent) carried disease-causing FH variants (38.6 percent in LDLR, 18.4 percent in APOB, and none in PCSK9). Among the participants without disease-causing variants, 18.7 percent were carriers of the hypercholesterolemia-associated APOE E4 isoform and 24.3 percent had conditions that remained genetically undiagnosed (a figure in line with other studies estimating polygenic or multifactorial hypercholesterolemia). Interestingly, in patients with no family history, variants in LDLR, APOB, or the APOE E4 isoform were seen in 48.6 percent, 60.0 percent, and 76.5 percent of children, respectively.

"A disease-causing genetic variant for FH was identified in 57 percent of participants referred from the US, with an additional one-fifth identified with the most common multifactorial form of hypercholesterolemia, amounting to [more than] 75.0 percent of referred participants carrying a disease-causing or disease-associated genetic variant," write the authors led by Gasper Klancar, from University Children's Hospital in Slovenia. "Comparable diagnostic yield in the adult population with clinical presentation of hypercholesterolemia and our pediatric population without any clinical signs indicates that universal screening may be an efficacious strategy for early detection of FH and prevention of cardiovascular complications."

"The primary focus of lipid screening in children should be on how to identify young individuals with genetic causes of dyslipidemia, such as FH ," writes Stephen Daniels, M.D., Ph.D., from the University of Colorado, in an accompanying editorial. "Even if one accepts that screening has merit, many questions remain, such as ... what is the best age for screening, which lipid measure is most useful, and what cut point would be used to indicate abnormality?"

The authors acknowledge future research will be necessary to determine the optimum timing and size of FH-associated gene panels, but they note that universal testing using next-generation sequencing (NGS) has some advantages including a "significant" cost reduction (approximately 3-fold decrease for the central European region) and faster identification of causative genetic variants (approximately 7-fold reduction in turnaround time based on their lab's experience with NGS versus more "widely used genetic screening methods" (denaturing high-pressure liquid chromatography or high resolution DNA melting analysis and Sanger sequencing).

Takeaway: Universal cholesterol screening in children may be a more effective means of identifying FH in a timely manner, than screening based on family history alone.