Inborn errors of immunity and somatic variant phenocopies disrupting human JAK-STAT signaling

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling cascade is an evolutionarily conserved signal transduction pathway that regulates many vital cellular processes, including immune function and hematopoiesis. Human genetic variants that disrupt JAK-STAT signaling are being found to cause a rapidly increasing number of diseases, including both germline-encoded inborn errors of immunity (IEI) and acquired somatic variants causing a 'phenocopy' of the IEI. Multiple genetic mechanisms are responsible for this growing group of JAK-STAT diseases including loss-of-function (LOF), gain-of-function (GOF), and dominant negative (DN) effects. In this review, we discuss the clinical presentation and pathogenesis of all currently described JAK/STAT defects, as well as providing an overview of the guiding principles to consider in diagnosing and treating these conditions.