Two Unique Cases of X-linked SCID: A Diagnostic Challenge in the Era of Newborn Screening

Abstract

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.

Hemophagocytic syndrome associated with Mycobacterium bovis in a patient with X-SCID: a case report

“…This might explain the low lymphocyte count in our patient. Several reports confirmed that the mutations in IL2RG gene lead to X-SCID, an immunodeficiency disease, characterized by low lymphocyte counts [4,10,11]. Some studies reported that immunodeficiency might be one of the risk factors related to HPS [12,13].…”

“…However, HPS induced by Mycobacterium tuberculosis complex infection is extremely rare, and HPS related to M. bovis in children is not yet reported [ 2 , 3 ]. X-linked severe combined immunodeficiency (X-SCID) is also a rare, life-threatening immunodeficiency disease caused by genes mutations [ 4 ]. Thus, an extremely rare case of patient with X-SCID also presenting HPS due to M. bovis has been reported in this study.…”

Immunity and Genetics at the Revolving Doors of Diagnostics in Primary Immunodeficiencies

“…In such cases, the reliability of flow cytometry-based functional assays (e.g., measure of WASP protein, analysis of gamma chain signaling, assessment of superoxide production), together with the results of XCI studies in the mother, can allow making a diagnosis guiding more complex genomic analyses, for example to search for gene inversions, promoter mutations, and other rare genomic changes. The possibility of false negative exome-sequencing results was reported for WAS [ 10 ], X-SCID [ 95 ], and chronic granulomatous disease (CGD) [ 96 ]. Conversely, for some PIDs, also flow cytometry can yield false negative results, as reported about the expression of SAP protein in XLP [ 97 ].…”

Immune Reconstitution After Gene Therapy Approaches in Patients With X-Linked Severe Combined Immunodeficiency Disease

“…Due to the presence of maternal T-cells or leaky production of oligoclonal cells, total T-cell numbers might initially be significant, so the analysis of subpopulations including naïve T-cells and recent thymic emigrants (RTE) is crucial (23,25). The final diagnosis of SCID-X1 is established by the identification of pathogenic variants in the IL2RG gene, although sometimes this requires confirmation by other studies, such as functional assays, especially in atypical SCID-X1 (26). The expression of gc is not conclusive, as it can be normal (but nonfunctional) in some patients (10).…”