Barmettler S, Coffey K, Smith MJ, et al. - In this study, 3 infants identified by newborn screening for severe combined immunodeficiencies (NBS SCID) are described; these infants did not exhibit a typical SCID (Severe combined immunodeficiencies) phenotype and meet the relevant diagnostic criteria and hence required additional workup. All 3 patients showed pathogenic variants in ATM in genetic testing, and a functional flow cytometry assay confirmed the pathogenicity of the variants. Based on clinical and family history, and immunological analyses, they suspected ataxia telangiectasia (AT). They used a rapid functional flow cytometry assay as a diagnostic and confirmatory tool, in combination with genetic testing, to make a diagnosis of AT. Experimental validation of the causal association between genotype and phenotype allowed for expeditious diagnosis, which allowed early discussions with families concerning prognosis, treatment, and management. Based on these observations, they suggest that functional testing may be required for clinical diagnosis in infants identified by NBS SCID who do not fit into the classic categories or have novel genetic variants to confirm the diagnosis. They recommend giving consideration to the use of functional assays as an essential component of an integrated evaluation to determine the genetics and mechanisms of inborn errors of immunity.