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Early-onset autoimmune disease due to a heterozygous loss-of-function mutation in TNFAIP3 (A20)
  1. Christopher J A Duncan1,
  2. Emma Dinnigan1,
  3. Rachel Theobald1,
  4. Angela Grainger1,
  5. Andrew J Skelton2,
  6. Rafiqul Hussain3,
  7. Joseph D P Willet1,
  8. David J Swan1,
  9. Jonathan Coxhead3,
  10. Matthew F Thomas4,
  11. Julian Thomas5,
  12. Veena Zamvar6,
  13. Mary A Slatter7,
  14. Andrew J Cant7,
  15. Karin R Engelhardt1,
  16. Sophie Hambleton1,7
  1. 1Primary Immunodeficiency Group, Institute for Cellular Medicine, Newcastle University, UK
  2. 2Bioinformatics Support Unit, Institute for Cellular Medicine, Newcastle University, UK
  3. 3Genomic Core Facility, Institute for Genetic Medicine, Newcastle University, UK
  4. 4Department of Paediatric Respiratory Medicine, Great North Children’s Hospital, Royal Victoria Infirmary, UK
  5. 5Department of Paediatric Gastroenterology, Great North Children’s Hospital, Royal Victoria Infirmary, UK
  6. 6Department of Paediatric Gastroenterology, Leeds General Infirmary, UK
  7. 7Department of Paediatric Immunology and Stem Cell Transplant Unit, Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, UK
  1. Correspondence to Prof Sophie Hambleton, Primary Immunodeficiency Group, Institute for Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne NE2 4HH, UK; sophie.hambleton{at}

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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).

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Table 1

Immunological and clinical parameters

Ethical 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 …

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