VRONI Study: Advancing Pediatric Genetic Screening for Familial Hypercholesterolaemia to Improve Early Cardiovascular Health

Highlight

The VRONI study evaluated a large cohort of children aged 4.8 to 14.9 years in Bavaria, using a two-step screening approach involving biochemical LDL-C measurement followed by targeted genetic testing for FH-causing variants. The study found a higher prevalence of FH variants (adjusted prevalence 1:163) than prior estimates, underscoring the significance of early detection. Sequencing-based genetic testing outperformed focused variant panels, particularly at higher LDL-C levels. Importantly, the study demonstrated feasibility of integrating combined biochemical and genetic screening into routine pediatric care.

Study Background and Disease Burden

Familial hypercholesterolaemia (FH) is an inherited disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels from birth, substantially increasing lifelong risk of premature atherosclerotic cardiovascular disease. Worldwide, FH prevalence is traditionally estimated at about 1 in 250 individuals. Early identification and treatment in childhood can markedly reduce long-term morbidity and mortality. However, diagnosing FH early remains challenging due to variable clinical presentation and modest awareness among practitioners and families. Biochemical screening alone often fails to conclusively diagnose FH, and the role of universal genetic screening in children is under debate. This leaves a critical unmet medical need to establish efficient, accurate, and practical strategies to identify children with FH within routine healthcare settings.

Study Design

The VRONI (“Vorsorgeuntersuchung auf familiäre Hypercholesterinämie bei Kindern”) study was initiated in Southern Germany in September 2020, inviting pediatricians to screen all children aged 4.8 to 14.9 years during routine examinations. Up to 480 pediatric practices participated in Bavaria. Screening included biochemical LDL-C determination from a small fingertip blood sample (0.2 mL). Children with LDL-C ≥3.36 mmol/L (130 mg/dL), representing the 93rd percentile, were reflexively tested for FH-causing genetic variants using a two-step approach: an initial focused panel covering 48 common variants, and next-generation sequencing (NGS) of FH-relevant genes (LDLR, APOB, PCSK9).

Key Findings and Results

As of the study report, 25,431 children had undergone screening, with 1,689 (6.6%) exhibiting LDL-C levels ≥3.36 mmol/L. Among these, 1,670 children underwent genetic testing. FH-causing pathogenic variants were identified by the focused panel in 157 children, while NGS detected an additional 126 variant carriers beyond the panel, totaling 283 confirmed FH cases (17% of genetically tested children). The prevalence of FH variant carriers progressively increased with higher LDL-C levels, being only 4.7% in the 130-135 mg/dL range but rising to 78.6% in children with LDL-C >200 mg/dL.

Initial unadjusted prevalence was approximately 1 in 90, likely influenced by a founder LDLR gene variant present 40 times more frequently than European averages. Recruitment bias was identified, as practices recruiting fewer children had higher FH prevalence, implying selective sampling. After adjustment using a generalized linear mixed model, the corrected prevalence estimate was 1 in 163 (0.61%), aligning closely with large genomic databases such as gnomAD and the UK Biobank.

The study also substantiated that biochemical screening serves as a practical initial filter for genetic testing in pediatric populations. Moreover, comprehensive gene sequencing outperformed limited focused panels by detecting broader variant spectra, supporting recommendations for gene-based diagnostics.

Expert Commentary

The VRONI study compellingly illustrates that universal LDL-C screening at pediatric visits, combined with reflex genetic testing, can efficiently identify children with FH, paving the way for early intervention. Identifying a higher-than-previously-estimated prevalence emphasizes FH as a major public health issue warranting national pediatric screening policies. The study also addresses the challenges of ascertainment bias and founder effects by employing robust statistical adjustment and genomic benchmarking, increasing confidence in its prevalence estimates.

Nonetheless, limitations exist: the study population was localized to Southern Germany, potentially limiting generalizability. The recruitment variability among pediatric practices highlights challenges in implementing uniform screening. Also, the long-term clinical impact of screening and subsequent management on cardiovascular outcomes remains to be elucidated.

Current guidelines increasingly endorse early detection and treatment of FH in children. VRONI’s findings support and refine these recommendations by demonstrating a feasible, scalable approach that integrates biochemical and genetic tools within routine pediatric care. This approach aligns with precision medicine principles enabling targeted prevention of lifelong cholesterol burden.

Conclusion and Summary

The VRONI study establishes the efficacy and feasibility of a two-step universal pediatric screening program to detect FH-causing variants, highlighting a higher population prevalence than previously recognized. Children with LDL-C ≥3.36 mmol/L should be prioritized for genetic testing through sequencing of candidate FH genes to maximize diagnostic yield. This strategy enables early identification and treatment initiation, with the potential to substantially reduce premature cardiovascular disease burden associated with FH.

The study’s outcomes support calls for implementing national pediatric screening programs for FH where they are not yet established, leveraging the availability of effective lipid-lowering therapies. Future efforts should focus on longitudinal follow-up to assess the impact of early detection on clinical outcomes, optimize screening algorithms, and address disparities in access and uptake.

Funding and ClinicalTrials.gov

The VRONI study was supported by the DigiMed Bayern Consortium. Specific funding details and clinical trial registration information were not provided in the abstract.

References

• Schmieder RS, Schlieben LD, Amosov A, et al. Genetic screening of children for familial hypercholesterolaemia: the VRONI study. Eur Heart J. 2026;47(33):4641-4654. PMID: 42301736.
• Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Eur Heart J. 2013;34(45):3478-3490.
• Wiegman A, Gidding SS, Watts GF, et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015;36(36):2425-2437.