Newborn screening for severe combined immunodeficiency: breaking the bubble

Severe combined immunodeficiency (SCID) is one of the most severe form of inborn errors of immunity characterized by the absence or dysfunction of T-lymphocytes affecting both cellular and humoral immunity. Infants with SCID are asymptomatic at birth, but develop severe infections in the first months of life. Without curative treatment, in the form of allogeneic hematopoietic stem cell transplantation (HSCT) or gene therapy (GT), affected infants die within the first year of life. Early treatment, before the onset of infections, results in the best outcomes making SCID a suitable candidate for early detection via newborn screening (NBS). NBS for SCID is based on the detection of T-cell receptor excision circles (TRECs), a marker for thymic production of naïve T-cells. Since the introduction of the TREC assay 15 years ago, many countries have adopted SCID in their NBS programs leading to improved outcomes for SCID patients worldwide. There are several hurdles and challenges associated with the introduction of SCID into these complex, multifaceted NBS programs. This thesis highlights the many aspects that are associated with NBS for SCID addressing innovative societal and ethical implications, as well as technical aspects and cost-effectiveness within a prospective implementation pilot study. In the end, results presented in this thesis have led to the implementation of SCID in the Dutch NBS program on 1 January 2021.