Population-based screening in children for early diagnosis and treatment of familial hypercholesterolemia: design of the VRONI study

Abstract

Background: Heterozygous familial hypercholesterolemia (FH) represents the most frequent monogenic disorder with an estimated prevalence of 1:250 in the general population. Diagnosis during childhood enables early initiation of preventive measures, reducing the risk of severe consecutive atherosclerotic manifestations. Nevertheless, population-based screening programs for FH are scarce.

Methods: In the VRONI study, children aged 5-14 years in Bavaria are invited to participate in an FH screening program during regular pediatric visits. The screening is based on low-density lipoprotein cholesterol measurements from capillary blood. If exceeding 130 mg/dl (3.34 mmol/l), i.e. the expected 95th percentile in this age group, subsequent molecular genetic analysis for FH is performed. Children with FH pathogenic variants enter a registry and are treated by specialized pediatricians. Furthermore, qualified training centers offer FH-focused training courses to affected families. For first-degree relatives, reverse cascade screening is recommended to identify and treat affected family members.

Results: Implementation of VRONI required intensive prearrangements for addressing ethical, educational, data safety, legal and organizational aspects, which will be outlined in this article. Recruitment started in early 2021, within the first months, more than 380 pediatricians screened over 5200 children. Approximately 50 000 children are expected to be enrolled in the VRONI study until 2024.

Conclusions: VRONI aims to test the feasibility of a population-based screening for FH in children in Bavaria, intending to set the stage for a nationwide FH screening infrastructure. Furthermore, we aim to validate genetic variants of unclear significance, detect novel causative mutations and contribute to polygenic risk indices (DRKS00022140; August 2020).

Figure 1

VRONI study—schematic overview. Flowchart of the study: all children aged 5–14 years living in Bavaria are offered a FH screening in the context of routine visits at their pediatrician. A blood sample will be taken and LDL-C centrally measured. In case of LDL-C levels above the 95th percentile, molecular genetic analysis for FH will be performed. Positive tested children and their parents will be informed comprehensively about FH and referred to a specialized training center. Children with elevated LDL-C levels but without known pathogenic FH mutations will undergo further diagnostics, including screening for secondary causes of hypercholesterolemia (e.g. obesity).

Figure 2

Follow-up in VRONI participants with elevated LDL-C levels. VRONI participants above the LDL-C threshold are subdivided into three distinct groups. Group A (known pathogenic mutations) receive quarterly follow-up visits by specialized pediatricians or pediatric cardiologists and are offered an FH-focused training course at a specialized training center. Group B (no known pathogenic mutation, but evidence for secondary causes of hypercholesterolemia) are recommended to be treated accordingly (e.g. referral to specialized obesity training centers in case of obesity). Group C (no known pathogenic mutation and negative screening for secondary causes) will be reviewed individually by a board of specialists.

Figure 3

Overview of the VRONI infrastructure in Bavaria. Distribution of contributing centers of the VRONI study in Bavaria. VRONI main office in pink, sequencing center in green, participating pediatricians in dark blue and pediatric cardiologists in light blue, preventive lifestyle centers in yellow and the VRONIplus training center in purple.

Figure 4

Distribution of LDL-cholesterol measurements in VRONI. Distribution of LDL-cholesterol levels of the first 5200 VRONI participants in Bavaria, Germany. The vertical line represents the predefined LDL-C threshold of 130 mg/dl (3.34 mmol/l).