Two novel variants in signal transduction and activator of transcription 1 (STAT1) coiled-coil region cause STAT1 gain of function in an infant presenting with Pneumocystis jiroveci pneumonia (PJP) and CMV viremia

Gain-of-function (GOF) mutations in STAT1 are associated with a diverse phenotype, including chronic mucocutaneous candidiasis and autoimmunity. We report a 5-month-old boy presenting with PJP, CMV viremia, and immune-mediated hepatitis with novel compound heterozygous in-frame deletions in the coiled-coil region of STAT1. Next generation sequencing (Prevention Genetics), flow cytometry, quantitative PCR. A 5-month-old male presented with PJP and CMV viremia. Immune phenotyping revealed mild T cell lymphopenia (CD3+: 1,029 cells/mcL, CD4+: 686 cells/mcL, CD8+: 258 cells/mcL) and normal T cell proliferation to mitogens. B and NK cell numbers were normal or high. Sequencing of genomic DNA revealed novel biallelic variants in the coiled-coil region of STAT1 (c.496_504del, p.Leu166_Asp168del, heterozygous; c.489_497del, p.Glu164_Leu166del, heterozygous). Neither variant is in gnomAD, and surprisingly, neither variant was found in either parent. Functional assays were consistent with STAT1 gain-of-function. The patient had increased IFN-g and IFN-a-mediated STAT1 phosphorylation and low Th17 cell percentage (0.09%). There was also increased expression of downstream IFN-stimulated genes: flow cytometry showed baseline surface expression of CD64 and CD169 and quantitative PCR showed increased expression of IFI44, ISG15, and Ly6E compared to healthy controls. We report PJP, CMV viremia, and immune-mediated hepatitis in a patient with novel compound heterozygous STAT1 variants. These variants are closely positioned in the coiled-coil domain, where numerous GOF mutations have been reported previously. To the best of our knowledge, this is the first report of an in-frame deletion causing increased STAT1 activity. Work is ongoing to determine whether one or both variants is pathogenic.