Schematic representation of the risk for developing HLH in relation to different models of genetic deficiency. Individuals with biallelic null mutations invariably develop HLH early in life, whereas hypomorphic mutations can be associated with late-onset HLH or cancer. Recently, it was suggested that monoallelic null mutations may represent a risk factor for developing cancer. Here, Sepulveda and colleagues elegantly show that polygenic monoallelic mutations add up, being associated with an intermediate risk of developing HLH. Likely, such polygenic combinations of mutations also increase the risk of cancer.