UMMS Affiliation

New England Newborn Screening Program; Department of Pediatrics, Division of Pediatric Genetics

Publication Date


Document Type



Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Diagnosis | Genetic Phenomena | Genetics and Genomics | Health Services Administration | Immune System Diseases | Maternal and Child Health | Medical Genetics | Pediatrics


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. 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. 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). 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. Functional studies are often required in these cases to confirm a pathogenic variant. 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. Pathogenic IL2RG variants were subsequently confirmed by functional assay of gamma chain signaling and maternal X-inactivation studies. We propose that such tests can facilitate confirmation of suspected cases of X-linked SCID in newborns when initial genetic testing is inconclusive. Early identification of pathogenic IL2RG variants is especially important to ensure eligibility for gene therapy.


X-linked severe combined immunodeficiency (SCID), functional assays, gamma chain signaling, interleukin 2 receptor gamma (IL2RG), maternal X-inactivation studies, newborn screening

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Copyright © 2019 Purswani, Meehan, Kuehn, Chang, Dasso, Meyer, Ujhazi, Csomos, Lindsay, Alberdi, Joychan, Trotter, Duff, Ellison, Bleesing, Kumanovics, Comeau, Hale, Notarangelo, Torgersen, Ochs, Sriaroon, Oshrine, Petrovic, Rosenzweig, Leiding and Walter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

DOI of Published Version



Front Pediatr. 2019 Apr 5;7:55. doi: 10.3389/fped.2019.00055. eCollection 2019. Link to article on publisher's site

Journal/Book/Conference Title

Frontiers in pediatrics


Full author list omitted for brevity. For the full list of authors, see article.

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Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.