# Heritability and Transcriptional Impact of JAK3, STAT5A and STAT6 Variants in a Tyrolean Family

## TL;DR

This study explores how rare genetic variants in immune-related genes affect gene activity in a family without causing obvious health issues.

## Contribution

The study identifies germline variants in JAK3, STAT5A, and STAT6 and investigates their transcriptional effects in a family without clinical symptoms.

## Key findings

- Rare JAK3P151R, JAK3R925S, STAT5AV494L, and STAT6Q633H variants were found in a three-generation family.
- Not all carriers of these variants showed the same immune transcriptome activation.
- Germline variants may have context-dependent effects influenced by other genetic and environmental factors.

## Abstract

The Janus Kinase (JAK) and Signal Transducers and Activators of Transcription (STAT) pathways regulate a range of biological processes, including immune response and 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. This study addresses an important issue in population genetics: the context-dependent effects and incomplete penetrance of rare genetic variants in immune pathways. Here we identify the rare JAK3P151R, JAK3R925S, STAT5AV494L, and STAT6Q633H variants in an extended family spanning three generations, integrate in silico analyses and 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 physiological manifestations in the carriers. As individual variants, not all persons carrying a specific variant showed the same immune transcriptome. The presence of activated basal transcriptomes was limited to some, but not all, individuals carrying the above variants. A next step in understanding the role of germline variants will be to understand how and why other factors, including both other germline variants and environmental and developmental factors, influence the likelihood of expression of an activated basal transcriptome.