When detected by NBS, neonates with typical SCID present asymptomatically due to protection from maternal antibodies and lack of exposure to pathogens, but nevertheless require prompt preparation for allogeneic or autologous (gene therapy) hematopoietic stem cell transplantation (HSCT) to prevent fatal outcomes from infections. After 10 years of implementation process, as of December 2018, all the states in United States (US), District of Columbia and Puerto Rico have implemented newborn screening (NBS) for SCID, thus covering all children born in the United States ( 1, 2). Due to the severity of the disease, early diagnosis is essential. Severe T cell dysfunction will impede effective humoral immunity as B cell responses to most antigens are T cell dependent. SCID is caused by a defect in cellular and humoral immunity, primarily stemming from abnormal T cell development and/or function. ![]() Early identification of pathogenic IL2RG variants is especially important to ensure eligibility for gene therapy. We propose that such tests can facilitate confirmation of suspected cases of X-linked SCID in newborns when initial genetic testing is inconclusive. Pathogenic IL2RG variants were subsequently confirmed by functional assay of gamma chain signaling and maternal X-inactivation studies. We present here two unique examples of X-linked SCID with variable immune phenotypes, where IL2R gamma chain expression was detected and no pathogenic variant was identified on initial genetic testing. Functional studies are often required in these cases to confirm a pathogenic variant. Therefore, it is important to extend evaluation to non-coding areas of a SCID gene if the exon-based sequencing is inconclusive and there is strong suspicion that a variant in that gene is the cause for disease. As a challenge, both IL2RG and ADA genes are highly polymorphic and a gene–based diagnosis may be difficult if the variant is of unknown significance or if it is located in non-coding areas of the genes that are not routinely evaluated with exon-based genetic testing (e.g., introns, promoters, and the 5′and 3′ untranslated regions). In western countries, X-linked interleukin 2 receptor gamma chain (IL2RG) and adenosine deaminase (ADA) deficiency SCID are two of the most common types of SCID and can be treated by GT. In the era of newborn screening (NBS) for severe combined immunodeficiency (SCID) and the possibility of gene therapy (GT), it is important to link SCID phenotype to the underlying genetic disease.
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