Novel STAT1 Gain-of-Function Mutation Presenting as Combined Immunodeficiency
To the Editor:
Heterozygous STAT1 gain-of-function (GOF) mutation represents a broad spectrum of clinical presentations beyond chronic mucocutaneous candidiasis (CMC), encompassing not only fungal, but also bacterial, viral infections and autoimmune manifestations. Most STAT1 GOF mutations are located in the coiled-coil (CCD) and DNA-binding domains (DBD)  resulting in hyper-phosphorylation of STAT1, thereby enhancing target gene expression. Here, we present a patient with a de novo novel heterozygous STAT1 GOF mutation that presented with a complex clinical phenotype with progressive combined immunodeficiency (CID) without classical fungal infections or autoimmune features. This case highlights a phenotypic disease expansion alongside presentation of a novel STAT1 GOF mutation and emphasizes the importance of whole exome sequencing (WES) in diagnosis of primary immunodeficiency diseases.
KeywordsSTAT1 gain of function Chronic mucocutaneous candidiasis Combined immunodeficiency Common variable immunodeficiency Hematopoietic stem cell transplant
Signal transducer and activator of transcription 1
Chronic mucocutaneous candidiasis
Whole exome sequencing
High resolution computed tomography
Common variable immunodeficiency
Immunoglobulin replacement therapy
Hematopoietic stem cell transplant
Graft versus host disease
The authors would like to thank Drs. James R. Lupski, Richard A. Gibbs, and Zeynep H. Coban Akdemir for whole exome sequencing and bioinformatics support. We greatly appreciate the support of Dr. Jordan Orange and the Texas Children’s Hospital Jeffrey Modell Diagnostic and Research Center. We also appreciate the help of Ms. Tram N. Cao and Ms. Anaid G. Reyes for research coordination.
This study received financial support from the Chao Physician Scientist Junior Faculty Award, Jeffrey Modell Foundation Diagnostic and Research Center for Primary Immunodeficiencies, and NIH-NHGRI/NHLBI award UM1HG006542 (Baylor-Hopkins Center for Mendelian Genomics).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest
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