Purpose: Genomic newborn screening programs are emerging worldwide. With the support of the local pediatric team of Liege, Belgium, we developed a panel of 405 genes that are associated with 165 early-onset, treatable diseases with the goal of creating a newborn screening test using targeted next-generation sequencing for all early-onset, treatable, and serious conditions. Methods: A process was developed that informed the future parents about the project and collected their consent during a face-to-face discussion with a trained investigator. The first baby was screened on 1 September 2022. The main objective of the study was to test the feasibility and the acceptability of targeted sequencing at birth as a first-tier newborn screening approach to detect treatable genetic conditions or genetic conditions for which a pre-symptomatic or early symptomatic clinical trial is available. Results: As of 20 June 2024, the parents of 4425 children had been offered the test; 4005 accepted (90.5%) and 420 refused (9.5%). The main reasons for refusal were the research nature of the project and the misunderstanding of what constitutes genetic conditions. Conclusions: These data demonstrate the high acceptability of genomic newborn screening in a properly informed population.