Novel STAT1 gain-of-function variant in a patient with Bechet’s like clinical phenotype

Abstract

Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that mediates cellular responses to interferons (IFNs), multiple cytokines and growth factors in diverse cell types. STAT1 gain-of-function (GOF) variants are predominantly associated with chronic mucocutaneous candidiasis (CMC), with majority of the variants confined to the coiled-coil domain (CCD) and the DNA-binding domain (DBD) of STAT1. Here, we present the case of a female child with a novel STAT1 variant who presented with recurrent, severe aphthous ulcers and cutaneous ulceration, but with absence of CMC. She first presented at age 1 year with recurrent fevers. She later developed recurrent oral ulcers, genital ulcers, skin lesions including frequent periungual edema and erythema with rare pustules or hemorrhagic crust, ulcers of the digits and extremities, ulcerative scalp lesions with occasional pustules, and perioral and nasal scaly pink papules consistent with periorofacial dermatitis. She was diagnosed with Bechet’s syndrome and started on colchicine which led to clinical improvement of her ulcers and skin disease. Clinical sequencing and research-based exome sequencing (ES) revealed a de novo novel heterozygous missense mutation (c.1676A>G, p.Glu559Gly) localized in the linker domain of STAT1, without other candidate genes to explain her clinical phenotype. Immunophenotyping revealed reduced memory and class-switched memory B cells and a unique finding of elevated levels of TCRab-positive double negative T cells (~13–20%). A functional STAT1 phosphorylation assay revealed significantly higher levels of STAT1 phosphorylation in patient monocytes after stimulation with IFNγ (25 ng/mL) compared to controls. An elevated level of total STAT1 protein at baseline and after IFNγ stimulation was also detected in the patient cells, providing strong supporting evidence for the pathogenicity of the identified variant. This novel variant and few similar cases reported previously expands the growing clinical phenotype of STAT1 GOF disease to include a Behcet’s-like clinical phenotype in the absence of CMC.