Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational “transcriptotype” that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.

自身免疫性疾病可由免疫的单基因错误引起。我们描述了一名患者，其早期发病的多器官免疫功能失调是由JAK1中的镶嵌，功能获得性突变（S703I）导致的，该突变编码的激酶对于信号传导> 25种细胞因子下游必不可少。通过定制的单细胞RNA测序，我们以单细胞分辨率检查了镶嵌性。我们发现JAK1转录主要限于跨不同细胞的单个等位基因，引入了不同于基因型的突变“转录型”的概念。从功能上讲，该突变增加了JAK1活性并激活了与其相​​关的催化结构域无关的配对JAK。S703I JAK1不仅对于细胞因子信号传导是超形态的，而且还是新形态的，因为它可以使信号传导级联不受JAK1规范地介导。鉴于这些结果，该患者接受了JAK抑制剂托法替尼治疗，从而迅速解决了临床疾病。这些发现为同时结合基本生物学原理的个性化医学提供了平台。