Public health applications of whole-exome (WES) and whole-genome sequencing (WGS) for newborns screening (NBS) programs could potentially improve outcomes of treatable pediatric diseases with the ability to re-evaluate the data over time if needed. However, the genomic NBS application opens up a series of questions that have to be addressed: informed consent, the public healthcare context, the vulnerability of the population studied, and the complexity of interpretation of the data in the absence of phenotype. Moreover, to limit variants of unknown significance and incidental findings, previous research programs focused the analyses on a set of genes that cause treatable pediatric conditions. Still, no unique criteria are available for their selection. The first aim of our study deals with the technical and feasibility evaluation of WGS approaches, the definition of a selected panel of actionable genes, and the ethical instances deriving from proposing a genetic NBS. The pilot study will be conducted across three possible scenarios: in the first one, a batch of singleton WGS will be analyzed using an automatic pipeline of a virtual gene panel related to treatable pediatric diseases without any clinical data; the second one will reproduce a comprehensive NBS by wide, no phenotype-driven, WGS analysis on trios. In the third one, trio-WGS will be performed with the patient's clinical data to evaluate the information needed for its correct execution and the number of additional diagnoses compared to WES. The second aim deals with a technical and sustainability comparison of WES and WGS approaches on fifty healthy newborns and their parents. After genetic counseling, only families giving their informed consent will be included in the study. After pseudoanonymization, WES analysis will be performed on trios, WGS will be performed on newborns, and the segregation of selected variants will subsequently be evaluated in the parents. The overall study will produce a complete set of data related to technical issues, interpretative challenges, socioeconomics, and ethical implications of using WES or WGS in newborn screening and diagnostic contexts. Moreover, it will pave the way for a critical evaluation of the sustainability of genomic NBS introduction in our public healthcare reality.