Peer-reviewed article
Genetic screening of children for familial hypercholesterolaemia: the VRONI study.
Schmieder RS, Schlieben LD, Amosov A, Krefting J, Santer R et al. ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This study screened over 25,000 children aged 5-15 years in Germany for familial hypercholesterolaemia (FH), a genetic condition that raises cholesterol levels and increases heart disease risk. Using blood tests and genetic analysis, researchers identified children carrying FH-causing genetic variants. The study found FH is more common than previously thought, occurring in about 1 in 163 children, and showed that a two-step screening approach (first checking cholesterol levels, then genetic testing for high cholesterol cases) is an effective way to identify affected children early.
Key points
- Out of 25,431 children screened, 1,689 had elevated LDL cholesterol (≥3.36 mmol/L), representing the 93rd percentile
- Genetic variants were identified in 440 children through focused panel testing and sequencing
- The prevalence of FH-causing variants was 1 in 163 children (0.61%), significantly higher than the previously reported 1 in 250
- A founder variant in the LDLR gene was found 40 times more frequently than the European average, explaining some of the high prevalence
- Two-step screening (biochemical followed by genetic testing) was shown to be feasible and effective, with gene sequencing superior to variant panel screening
Limitations
The study identified significant ascertainment bias in recruitment across paediatrician practices, which required statistical adjustment to estimate true population prevalence. The findings may be specific to the Southern German population where a founder variant was unusually common, and results may not generalise to all populations.
Abstract
Background and aims The role of genetic testing as part of universal screening programmes for familial hypercholesterolaemia (FH) in children is not well defined. Here, a two-step approach to identify children carrying FH-causing variants was investigated. Methods In this study from Southern Germany, paediatricians were invited to offer FH screening to all children aged 4.8-14.9 years at routine paediatric examinations. The FH screening programme began in September 2020 in Bavaria and has involved up to 480 paediatricians. It included biochemical and genetic testing using 0.2 mL of blood taken from a fingertip. In case of low-density lipoprotein cholesterol (LDL-C) serum concentration ≥3.36 mmol/L (≥130 mg/dL), FH-causing variants were determined in the same sample with a focused panel covering most frequent variants (n = 48) and sequencing of relevant genes. Results Out of 25 431 children screened so far, 1689 children had an LDL-C ≥ 3.36 mmol/L (>130 mg/dL), which defined this concentration as the 93rd percentile. Pathogenic variants were identified by the focused panel in 157 and by next-generation sequencing in 283 children, respectively. While 17% (283/1670) of all genetically analysed children tested positive, the fraction of individuals with FH-causing variants increased across the spectrum of LDL-C serum concentrations from 4.7% (23/492) at 3.36-3.49 mmol/L (130-135 mg/dL) to 78.6% (81/103) above 5.17 mmol/L (200 mg/dL). Overall, the prevalence of FH-causing variants was high (1:90). One reason was a founder variant (n = 63) within the LDLR gene, found 40 times more frequent than European average. The analysis of recruitment data revealed significant ascertainment bias, with lower recruitment rate practices exhibiting higher prevalence. After adjustment for the bias using a generalized linear mixed model, the predicted prevalence was 1 in 163 (0.61%), which is highly consistent with large-scale genomic benchmarks as gnomAD (1:165, n = 622 057) and the UK Biobank (1:176, n = 48 741). Conclusions The prevalence of FH determined in this study is significantly higher than previously published estimates (∼1:250), highlighting the importance of this condition for public health and supporting calls for a national paediatric screening programme, given the availability of effective treatment options. For children between 5 and 15 years, biochemical screening is an effective way to select patients for genetic testing, with sequencing of candidate genes being superior to variant screening. In summary, the VRONI study demonstrates the feasibility and efficacy of a combined biochemical and genetic screening for FH in children.
Findings the Hub has extracted
Each claim below is labelled by its type of design and links back to this report.
- Intervention
- Two-step universal screening programme combining biochemical testing (LDL cholesterol measurement from fingertip blood) followed by genetic testing (focused variant panel and gene sequencing) for children with elevated cholesterol
- Population
- Children aged 4.8-14.9 years attending routine paediatric examinations in Bavaria, Germany (25,431 children screened)
Key finding
1,689 children (6.6%) had elevated LDL cholesterol ≥3.36 mmol/L