TY - JOUR T1 - Early-onset autoimmune disease due to a heterozygous loss-of-function mutation in <em>TNFAIP3</em> (A20) JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 783 LP - 786 DO - 10.1136/annrheumdis-2016-210944 VL - 77 IS - 5 AU - Christopher J A Duncan AU - Emma Dinnigan AU - Rachel Theobald AU - Angela Grainger AU - Andrew J Skelton AU - Rafiqul Hussain AU - Joseph D P Willet AU - David J Swan AU - Jonathan Coxhead AU - Matthew F Thomas AU - Julian Thomas AU - Veena Zamvar AU - Mary A Slatter AU - Andrew J Cant AU - Karin R Engelhardt AU - Sophie Hambleton Y1 - 2018/05/01 UR - http://ard.bmj.com/content/77/5/783.abstract N2 - Rare Mendelian disorders increasingly contribute to our understanding of the genetic architecture of autoimmune disease and the key molecular pathways governing its pathogenesis. Early-onset autoimmune disease can arise through activating mutations in inflammatory signalling pathways or loss-of-function mutations in immunoregulatory proteins.We investigated the molecular basis of complex autoimmunity—characterised by the onset of insulin-dependent diabetes, cytopaenias, hepatitis, enteropathy and interstitial lung disease at age 10—in a 14-year-old boy of healthy non-consanguineous British parents. Immunological analysis revealed lymphopaenia with no naive T cells and a high proportion of activated T cells (table 1). Pathogenic variants in STAT3 and FOXP3 were excluded. The clinical course was refractory to intensive immunosuppression with prednisolone, sirolimus, tacrolimus, infliximab or rituximab, necessitating haematopoietic stem cell transplantation. Twenty-one months post-transplant, he is thriving off all immunosuppressive medication with complete remission of autoimmune disease (except diabetes).View this table:In this windowIn a new windowTable 1 Immunological and clinical parametersEthical approval was granted (ref: 10/H0906/22) and written informed consent provided prior to study commencement. By whole exome sequencing of peripheral blood genomic DNA (Illumina MiSeq) and downstream bioinformatic filtering (Ingenuity Variant Analysis), we identified a single biologically plausible variant—a novel de novo heterozygous 2 bp deletion in tumour necrosis factor-alpha-induced protein 3 (TNFAIP3, figure 1A). TNFAIP3 encodes the ubiquitin-editing enzyme A20, a negative regulator of the nuclear factor-κB (NF-κB) pathway.1 A20 removes K63-linked ubiquitin chains from key adaptor proteins, replacing them with K48-linked polyubiquitin chains, to trigger proteasomal degradation and termination of the NF-κB activation cascade.2 Polymorphisms in … ER -