Heritability and transcriptional impact of JAK3, STAT5A and STAT6 variants in a Tyrolean family

The Janus Kinase (JAK) and Signal Transducers and Activators of Transcription (STAT) pathway regulate a range of biological processes, including hematopoiesis. While a major research focus has been on somatic human mutations in disease, less is known about the heritability of germline variants and their physiological impact. Here we identify the rare JAK3P151R, JAK3R925S, STAT5AV494L and STAT6Q633H variants in an extended family spanning three generations and integrate in silico analyses, AlphaFold 3 structural predictions and investigate the immune transcriptomes in probands carrying one or more variants. All four variants are inherited through the germline without any evident clinical or gross physiological manifestations in the carriers. As individual variants, not all persons carrying a specific variant showed the same immune transcriptome. However, the presence of activated basal transcriptomes was limited to individuals carrying one of the four variants above. A next step in understanding the role of germline variants will be to understand how and why other factors including both other germline variants as well as environmental and developmental factors influence the likelihood of expression of an activated basal transcriptome.