X-linked Severe Combined Immunodeficiency via the IL2RG Gene

Severe combined immunodeficiency (SCID) affects one in 75,000 births and is a heterogeneous disorder that arises through genetic defect in genes associated with lymphocyte development and function. To date, there are over 20 genes known to cause SCID through an autosomal recessive manner, with mutations in the IL2RG gene being the only X-linked form of the disease (Allenspach et al. 2013). Categorization of T-cell, B-cell and Natural Killer (NK) cell levels are used to distinguish between subtypes of SCID, but genetic testing is essential in specifically defining the molecular defect leading to disease. X-linked SCID accounts for 40-50% cases of SCID with patients showing impaired B-cell function and diminished T-cell and NK cell levels. SCID due to mutations in the JAK3 or IL7R genes is phenotypically identical to X-SCID. X-SCID is characterized by failure to thrive, absence of tonsils/lymph nodes, candidiasis, recurrent and persistent infections due to cellular and humoral immunodeficiency. Bone marrow transplant or gene therapy is required to correct disease with patients succumbing to disease by two years of age without therapeutic intervention (Gaspar et al. 2013). Genetic testing can also be used to distinguish X-SCID from other X-linked immunodeficiencies including agammaglobulinemia (Test #1650), Wiskott-Aldrich syndrome (Test #440), and hyper IgM syndrome (Test #1613). Infants with human immunodeficiency virus infection may also mirror symptoms of X-SCID (Allenspach et al. 2013).

There are 23 monogenic causative genes involved with autosomal recessive forms of SCID. Mutation in the IL2RG gene is the only X-linked form of SCID. Female carriers are asymptomatic. Nearly 200 mutations have been described throughout the IL2RG gene with exons 3-5 being hotspots. Missense mutations are found most frequently (40%) followed by nonsense (24%), splice site alterations (19%), and small insertions/deletions (17%) with each mutation type being fully penetrant for disease (Puck et al. 1997; Piirilä et al. 2006). Maternal mosaicism for IL2RG mutations exists in ~13% cases of X-SCID. Similarly, somatic reversion in subsets of immune precursor cells have been reported to result in patients with variable clinical phenotype (Speckmann et al. 2008). The IL2RG gene encodes the common gamma chain of the interleukin receptor 2, a key membrane receptor required for cytokine signaling to promote T-cell, B-cell, and NK cell development (Noguchi et al. 1993; Allenspach et al. 2013).

Two independent reports identified mutations in the IL2RG gene in 87 of 103 patients presenting with X-SCID (Puck et al. 1997). Analytical sensitivity to detect mutations within the IL2RG gene using this methodology is >95% (Hacein-Bey et al. 1996).

Gross deletions have only been reported in a single case of X-SCID (Hacein-Bey et al. 1996).

This test provides full coverage of all coding exons of the IL2RG gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.