CD132; CIDX; IL-2RG; IMD4; P64; SCIDX; SCIDX1
The IL2RG gene is associated with X-linked recessive severe combined immunodeficiency (MedGen UID: 220906).
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An estimated 20% – 28% of severe combined immunodeficiency (SCID) is caused by pathogenic variants identified in IL2RG (PMID: 8410508, 25138334).
The IL2RG gene encodes the common gamma chain which is a subunit for several receptors that are important for lymphocyte development and function. Upon ligand binding to the IL2 receptor, the gamma subunit interacts with the JAK3 tyrosine kinase to transduce the signal (PMID: 26235889).
X-linked severe combined immunodeficiency (X-SCID)
MedGen UID: 220906
X-linked severe combined immunodeficiency (X-SCID) is a disorder of profound impairment in cellular and humoral immunity caused by pathogenic variants in the IL2RG gene (PMID: 9058718). If not recognized during the neonatal period (either through newborn screening or due to a family history), males with X-SCID come to medical attention at 3-6 months of age when maternal antibody levels diminish, and affected infants experience severe bacterial, fungal, and viral infections, and failure to thrive (PMID: 25937517). Infections are recurrent, persistent, and life threatening. Presenting symptoms often include absent tonsils and lymph nodes, chronic diarrhea, fevers, sepsis, and pneumonia (PMID: 28747913, 25937517). The immunophenotype of X-SCID is characterized by near absent T cells, low or absent natural killer (NK) cells, and normal or increased numbers of nonfunctional B cells (T-, B+, NK-; PMID: 20301584).
A milder form of IL2RG-related SCID is known as atypical or “leaky” X-SCID. Leaky SCID is characterized by the presence of T and B cells with little or absent NK cells and is caused by hypomorphic mutations in IL2RG (PMID: 20301584, 25138334). Symptoms of leaky SCID include infantile-onset immune dysregulation, rashes, splenomegaly, gastrointestinal malabsorption, and poor growth (PMID: 18559672, 17598841, 25042067). Like typical SCID, leaky SCID can also be fatal if left untreated (PMID: 20301584).
Revertant somatic mosaicism, in which a pathogenic allele is spontaneously corrected, has been reported in several males with atypical late-onset X-SCID (PMID: 26407811).
In 2008, state newborn screening programs began screening for SCID, enabling early identification of babies requiring further clinical evaluation. SCID is currently included in the newborn screening programs of 44 states, and 4 additional states have pilot programs (Immune Deficiency Foundation. http://primaryimmune.org. Accessed August 2017). In the US, over 95% of infants are covered by newborn screening protocols, which identify individuals with SCID by measurement of low T-cell receptor excision circles (TREC; PMID: 22285280 ). Clinical evaluation and molecular testing is used to confirm newborn screening results. Early identification of asymptomatic infants by newborn screening and subsequent treatment with hematopoietic cell transplant (HCT) or gene therapy results in significantly improved outcomes (PMID: 25937517, 26235889).
SCID is an infantile-onset primary immunodeficiency syndrome that results in T-lymphocyte and B-lymphocyte dysfunction. Some subtypes of SCID may also result in defective NK cell function. Flow cytometry results may inform the subtype of SCID; however different genetic subtypes have the same lymphocyte subset profile, and several forms of SCID share a clinical presentation. An infant with HIV may present similarly to an infant with SCID; however, T cells are generally present in those with HIV (PMID: 20301584). An abnormal SCID newborn screen can be indicative of other genetic syndromes, including 22q11.2 deletion syndrome, Jacobsen syndrome, Trisomy 21, and CHARGE syndrome, as well as other non-genetic conditions including extreme prematurity, congenital heart defects, and intrauterine growth retardation (PMID: 25138334).
The IL2RG gene (OMIM: 308380) encodes the common gamma chain, an important subunit of several interleukin receptors, which are central to lymphocyte development and function. Upon ligand binding to the IL2 receptor, the gamma subunit interacts with the JAK3 tyrosine kinase for signal transduction (PMID: “(external)26235889”:http://ncbi.nlm.nih.gov/pubmed/26235889; NCBI. https://www.ncbi.nlm.nih.gov/gene/3561. Accessed August 2017).
Pathogenic variants in the IL2RG gene follow X-linked recessive inheritance. A female with a pathogenic variant has a 50% chance of passing the variant on to her offspring. Males who inherit a pathogenic variant will be affected, and females who inherit a pathogenic variant will be carriers. Males with a pathogenic variant will pass it to all of their daughters, who will be carriers, while none of their sons will inherit the variant. Pathogenic variants may be inherited from a carrier mother or may occur de novo. Germline mosaicism has been reported in mothers of individuals with X-SCID, therefore negative carrier status in the mother does not eliminate the recurrence risk in future pregnancies (PMID: 9049783). With a positive result, it is possible to identify at-risk relatives who can pursue testing for the specific familial variant.
Identification of at-risk, asymptomatic newborns and reconstitution of the immune system with HCT provides a cure for individuals with X-SCID (PMID: 25937517). HCT within the first 3-4 months of life is associated with better outcomes, fewer pre- and post-transplant infections, and faster engraftment compared with cases where HCT is delayed (PMID: 15032591). Outcomes are best when grafts are received from an HLA-matched, related donor; however, transplants from unrelated matched donors and haploidentical donors are also successful (PMID: 25075835). Pre-transplant conditioning regimens vary by donor type and transplant center. Between the time of diagnosis and HCT, individuals with SCID are monitored intensively and treated with immunoglobulin replacement, prophylactic antibiotics, and avoidance of transfusions, immunizations, and exposure to infectious environments. Guidelines for long-term follow-up for individuals with SCID who have undergone HCT have been developed by an international consortium (PMID: 28479164).
Experimental gene therapy for X-SCID is considered for individuals who are not eligible for HCT or for whom the transplant was not successful. With novel methods of gene editing, correcting the gene defects may lead to new treatment options for these individuals (PMID: 28270364). Clinical trials utilizing gene therapy are ongoing.
Review date: August 2017
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Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
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