Expanded newborn screening for inborn errors of immunity: the experience of tuscany

Background Inborn errors of immunity (IEIs) include 485 inherited disorders characterized by an increased susceptibility to life threatening infectious diseases, autoimmunity and malignant diseases with a high mortality rate in the first years of life. Severe Combined Immunodeficiency is the most severe of the IEIs and its detection should be a primary goal in a newborn screening (NBS) program. The term "actionable" has recently been used for all IEIs with outcomes that can be demonstrably improved through early specialized intervention.Objective: to evaluate the results of the expanded NBS strategy for IEIs in Tuscany Region (Italy), based on TREC (T-cell Receptor Excision Circles), KREC (Kappa Recombining Excision Circles) and Tandem Mass-based assays. Methods This is a retrospective study collecting data from all infants born in Tuscany from October 10, 2018, to October 10, 2022. Tandem mass assay to identify Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency, together with TREC and KREC molecular analysis were conducted on dried blood spot (DBS) from the newborns’ Guthrie Cards. A new DBS and evaluation by an immunologist were carried out when the results of the first test were outside the diagnostic cut-offs. Results 94,319 newborns were evaluated. Referral rates for TREC (0.031%) and KREC (0.074%) in this study are in line with the data available in literature. The results from the expanded NBS strategy revealed an incidence rate of 1/9,431 affected newborns. Conclusion This work represents the first description of a sustainable and real-life based expanded NBS program for IEIs with a high diagnostic incidence facilitating prompt management of identified patients.