Severe combined immunodeficiency (SCID) is a congenital clinical disorder that is not evident at birth. Without treatment, most babies with SCID will die in infancy from virulent infection. This guideline addresses the detection of SCID by population-based newborn screening (NBS) using dried blood spot (DBS) specimens to measure T-cell receptor excision circles (TREC). Responding to recent US recommendations, the document is intended to facilitate the incorporation of SCID NBS into the routine operation of NBS programs worldwide. Based on extensive input from NBS laboratories, it describes the laboratory tests currently used to measure TREC in DBS by real-time quantitative PCR. The document also describes biological and clinical features of SCID and of other conditions potentially identified by SCID NBS. It provides an overview of laboratory operations including physical layout, instrumentation, TREC assay protocols, automated methodologies, and alternative platforms. The document includes a summary of diagnostic tests used for follow-up of abnormal TREC results as well as other short-term and long-term follow-up activities, including case tracking. It describes variants of SCID that may not be detected by TREC assays in newborn DBS. The guideline delineates the steps for implementing SCID NBS: validating the laboratory test, conducting pilot studies, and transitioning to routine screening. It is directed toward NBS laboratory personnel, public health program personnel, producers of laboratory products related to NBS, and those involved with oversight of NBS testing.

This guideline addresses the detection of severe combined immunodeficiency (SCID) by population-based newborn screening (NBS) using dried blood spot (DBS) specimens. The guideline is intended to facilitate the incorporation of SCID NBS into the routine operation of existing NBS programs. Methodologically, it focuses on measuring T-cell receptor excision circles (TREC) in DBS by real-time quantitative PCRa (qPCR), the method in use by all NBS laboratories at the time of guideline publication. It also describes other qPCR methods for measuring TREC in DBS that may come into future use. 

This guideline includes detailed information for laboratory practice including calibration, QC, and proficiency testing (PT). It also addresses program issues such as short-term follow-up (notification and tracking to establish or rule out a diagnosis). The guideline includes clinical and immunological background on SCID and other immunodeficiency disorders that may present with low or no TREC content in newborns. It draws heavily on the experience of the NBS programs that have already operationalized the TREC assay for population-based NBS. The document includes several appendixes that provide additional information important to the guideline. In particular, Appendix C includes the operational algorithms in use by four of the NBS programs conducting SCID NBS at the time this document development committee was convened. The guideline is primarily intended for use by NBS laboratory personnel, producers of laboratory products related to NBS, and those involved with oversight of NBS programs. 

The guideline is limited to NBS applications. It discusses, but does not detail, the methods used in diagnostic laboratory tests for immune deficiencies on whole blood, including immunophenotyping by flow cytometry (addressed in CLSI document H42) and lymphocyte function assays (some of which are addressed in CLSI document I/LA26). It does not discuss blood spot collection for NBS, which is the subject of a separate guideline (see CLSI document LA04). While the document includes general guidelines for short- and long-term follow-up, the knowledge base for assessing sensitivity, specificity, and predictive value is not yet sufficient to express accurate quantitative values for these parameters. These parameters will be revisited in future editions of this guideline.