![]() With advances in genetic sequencing technology, pathogenic variants have been discovered in over 20 genes that cause classic or leaky SCID phenotypes ( 3, 4). 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. ![]() 14Division of Allergy and Immunology, Massachusetts General Hospital for Children, Boston, MA, United States.13Department of Pediatrics, University of Washington & Seattle Children's Research Institute, Seattle, WA, United States.12National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, United States.11New England Newborn Screening Program, University of Massachusetts Medical School, Worcester, MA, United States.10New England Newborn Screening Program and Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, United States.9ARUP Laboratories, Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States.8Department of Pathology, University of Utah, Salt Lake City, UT, United States.7Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.6Dearborn Allergy & Asthma Clinic, PC, Dearborn, MI, United States.5Division of Allergy and Immunology, Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States.4Department of Biology, University of Tampa, Tampa, FL, United States.3Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, United States.2Division of Allergy and Immunology, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL, United States.1Johns Hopkins All Children's Hospital, St.Ochs 13 Panida Sriaroon 1,2 Benjamin Oshrine 1 Aleksandra Petrovic 13 Sergio D. Meyer 1 Boglarka Ujhazi 2 Krisztian Csomos 2 David Lindsay 5 Taylor Alberdi 2 Sonia Joychan 6 Jessica Trotter 2 Carla Duff 2 Maryssa Ellison 2 Jack Bleesing 7 Attila Kumanovics 8,9 Anne M. Pooja Purswani 1 † Cristina Adelia Meehan 2 † Hye Sun Kuehn 3 Yenhui Chang 1 Joseph F.
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