Somatic genetic reversion of large duplication event in IL2RG in siblings

Deleterious mutations in the common gamma chain (γC, CD132) are associated with X-linked severe combined immunodeficiency (X-SCID) characterized by a T-B+NK- phenotype. Hypomorphic variants in the IL2RG gene have also been associated with a milder or atypical SCID phenotype. Milder phenotypes can also occur when somatic genetic rescue occurs in the setting of severe IL2RG mutations. Spontaneous somatic variants particularly in hematologic disorders can occur particularly in genes with known selection pressure including IL2RG. Here, we report the clinical and molecular findings from two brothers with atypical X-SCID phenotype including hypogammaglobulinemia, elevated IgM, T cell lymphopenia and extensive verruca plana. One brother required splenectomy secondary to a benign vascular tumor and had recurrent pancreatitis consistent with primary sclerosing cholangitis. Both brothers developed recurrent suppurative pneumonia resulting in early bronchiectasis in their first decade. Next generation sequencing initially was negative, yet reanalysis found a large duplication event in exon 3 of IL2RG gene with somatic genetic rescue events that occurred twice in two brothers. Functional studies revealed a unique mosaic pattern in each affected sibling when stimulating peripheral blood mononuclear cells with IL-2 or IL-21 resulting in bimodal phospho-STAT5 or phospho-STAT3 respectively. The genetic analysis revealed the maternal allele was heterozygous as expected, although the ratio of these events and clonal analysis revealed cell type skewing. Our data demonstrate an atypical SCID phenotype in two brothers secondary to the combination of a large duplication event in the IL-2RG gene partially rescued by somatic genetic rescue. Although previous somatic reversion cases have been reported involving the IL2RG genetic locus, our cases demonstrate a large duplication reversion event with recurrence. Our case highlights the unique selection pressure to amplify rare genetic events at the IL2RG locus.