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Mobile element insertions (MEIs) contribute to genomic diversity, but they can be responsible for human disease in some cases. Initial clinical testing ( BRCA1 , BRCA2 and PALB2 ) in a 40-year-old female with unilateral breast cancer did not detect any pathogenic variants. Subsequent reanalysis for MEIs detected a novel likely pathogenic insertion of the retrotransposon element (RE) c.7894_7895insSVA in BRCA2 . This case highlights the importance of bioinformatic pipeline optimization for the detection of MEIs in genes associated with hereditary cancer, as early detection can significantly impact clinical management., Competing Interests: Conflict of interestJ.N. received funding from AstraZeneca for breast and ovarian cancer research unrelated to the current study. L.Y., R.T., and W.B.-F. are salaried employees of GeneDx/OPKO Health. The remaining authors declare no competing interests., (© The Author(s) 2020.)

Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways 1 . Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development 2,3 . However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.