Functional Confirmation of DNA Repair Defect in Ataxia Telangiectasia (AT) Infants Identified by Newborn Screening for Severe Combined Immunodeficiency (NBS SCID)

Abstract

Background: The introduction of newborn screening for severe combined immunodeficiencies (NBS SCID) in 2010 was a significant public health milestone. Although SCID was the primary target, several other conditions associated with severe T-cell lymphopenia have subsequently been identified as secondary targets. The differential diagnosis in infants with an abnormal T-cell receptor excision circle result on NBS SCID who do not meet criteria for typical SCID is often broad, and often the evaluation of these conditions requires immunological and functional testing, in conjunction with genetic analysis, to obtain an accurate diagnosis and develop an appropriate management and treatment plan.

Objective: We describe here 3 infants identified by NBS SCID, who required additional workup as they did not have a typical SCID phenotype and meet the relevant diagnostic criteria. Genetic testing identified pathogenic variants in ATM in all 3 patients, and the pathogenicity of the variants was confirmed by a functional flow cytometry assay.

Methods: The patients underwent immunological and genetic workup to identify an underlying cause of their abnormal NBS SCID. Ataxia telangiectasia (AT) was suspected based on clinical and family history, and immunological analyses. The diagnosis was confirmed in all patients with a rapid functional flow cytometric assay and genetic testing.

Results: A rapid functional flow cytometry assay was used as a diagnostic and confirmatory tool, in conjunction with genetic testing, to make a diagnosis of AT. Experimental validation of the causal relationship between genotype and phenotype allowed for expeditious diagnosis, which facilitated early discussions with families regarding prognosis, treatment, and management.

Conclusions: Even with increased rapidity and access to genetic results, functional testing is 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. Consideration should be given to the use of functional assays as an essential component of an integrated evaluation to characterize the genetics and mechanisms of inborn errors of immunity.

Keywords: ATM; Alpha-fetoprotein; Ataxia telangiectasia; DNA double-strand breaks; DNA repair defect; Functional testing; Immune deficiency; NBS; Newborn screening; Nonhomologous end-joining (NHEJ).