Poli, CeciliaEbstein, FrédéricNicholas, Sarah K.Guzman, Marietta M. deForbes, Lisa R.Chinn, Ivan K.Mace, Emily M.Vogel, Tiphanie P.Carisey, Alexandre F.Benavides, FelipeCoban-Akdemir, Zeynep H.Gibbs, Richard A.Jhangiani, Shalini N.Muzny, Donna M.Carvalho, Claudia M. B.Schady, Deborah A.Jain, MahimRosenfeld, Jill A .Emrick, LisaLewis, Richard A.Lee, BrendanUndiagnosed Diseases Network membersZieba, Barbara A.Küry, SébastienKrüger, ElkeLupski, James R.Bostwick, Bret L.Orange, Jordan S.2022-05-272022-05-272018Poli MC, Ebstein F, Nicholas SK, de Guzman MM, Forbes LR, Chinn IK, Mace EM, Vogel TP, Carisey AF, Benavides F, Coban-Akdemir ZH, Gibbs RA, Jhangiani SN, Muzny DM, Carvalho CMB, Schady DA, Jain M, Rosenfeld JA, Emrick L, Lewis RA, Lee B; Undiagnosed Diseases Network members, Zieba BA, Küry S, Krüger E, Lupski JR, Bostwick BL, Orange JS. Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome. Am J Hum Genet. 2018 Jun 7;102(6):1126-1142. doi: 10.1016/j.ajhg.2018.04.010. Epub 2018 May 24.https://doi.org/10.1016/j.ajhg.2018.04.010http://hdl.handle.net/11447/6152The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.enPIDPOMPPOMP-related autoinflammation and immune dysregulation diseasePRAIDAutoinflammatory syndromeCore particle proteasome 20SDominant negativeInterferonopathyNonsense-mediated decayPrimary immune deficiencyArticle