The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.

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We thank all subjects and healthy donors for their support, and we thank H. Matthews and C. Neurwirth for coordinating control blood samples. This research was supported by the Intramural Research Programs of NIAMS, the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Clinical Center, and National Human Genome Research Institute, National Institutes of Health. This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. This work was supported by the Crohn's & Colitis Foundation of America (A.D.J.L. and H.H.U.), the US National Institutes of Health (grant KHL125593A to M.K.), the Sigrid Juselius and Emil Aaltonen Foundations (both to J.G.), the Wellcome Trust (grant 097261/Z/11/Z to B.A.; grant 105663/Z/14/Z to R.R.), the European Molecular Biology Organization (grant ALTF 11602012 to A.N.H.), a Marie Curie fellowship (FP7-PEOPLE-2012-IEF, proposal 330621, to A.N.H.), the Imperial College National Institute for Health Research (NIHR) Biomedical Research Centre (N.C. and P.K.), the Oxford NIHR Biomedical Research Centre (H.H.U.), the Chelsea & Westminster Hospital Charity (C.O'B.), the UK Biotechnology and Biological Sciences Research Council (BB/N0077941/1 to R.R. and M.F.S.), Cancer Research UK (C52623/A22597 to R.R.), the Westminster Medical School Research Trust (P.K.), the Biotechnology and Biological Sciences Research Council (grant BBS/E/B/000C0407 to M.A.L. and I.V.), the Cambridge Trust (I.V.), the Leona M. and Harry B. Helmsley Charitable Trust and ESPGHAN (H.H.U.), the MRC Clinical Sciences Centre (CSC) (T.J.A.) and the CSC Genomics Core Laboratory, and by MRC transition funding (T.J.A.). We acknowledge the contribution of the BRC Gastrointestinal biobank–Oxford IBD cohort study, which is supported by the NIHR Oxford Biomedical Research Centre. We thank G. Vahedi, E. Mathé, S. Parker, C. Kanellopoulou and S. Muljo for critical reading of the manuscript; J. Kabat for help with confocal image analysis; and S.S. De Ravin and H. Malech for advice on the use of MaxCyte. Molecular graphics and analyses were done with the UCSF Chimera package, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311). This study used high-performance computational capabilities of Helix Systems at the NIH (http://helix.nih.gov).

Author information

Author notes

    • Behdad Afzali
    • , Juha Grönholm
    •  & Jana Vandrovcova

    These authors contributed equally to this work.

    • Nichola Cooper
    •  & Arian D J Laurence

    These authors jointly supervised this work.


  1. Lymphocyte Cell Biology Section (Molecular Immunology and Inflammation Branch), Biodata Mining and Discovery Section and Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Behdad Afzali
    • , Hong-Wei Sun
    • , Fred P Davis
    • , Alejandro V Villarino
    • , Ira W Palmer
    • , Joshua Kaufman
    • , Norman R Watts
    • , Paul T Wingfield
    •  & John J O'Shea
  2. MRC Centre for Transplantation, King's College London, London, UK.

    • Behdad Afzali
  3. Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, Biological Imaging Section (Research Technologies Branch) and Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Juha Grönholm
    • , Yu Zhang
    • , Olena Kamenyeva
    • , Ivan J Fuss
    • , Warren Strober
    •  & Michael J Lenardo
  4. Molecular Neuroscience, Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK.

    • Jana Vandrovcova
  5. Department of Medicine, Imperial College London, London, UK.

    • Jana Vandrovcova
    • , Charlotte O'Brien
    • , Ahmad Khoder
    • , Anwar Sayed
    • , Timothy J Aitman
    • , Peter Kelleher
    •  & Nichola Cooper
  6. Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK.

    • Ine Vanderleyden
    • , Mohammed F Sadiyah
    • , Michelle A Linterman
    •  & Rahul Roychoudhuri
  7. Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK.

    • Ahmed N Hegazy
    • , Julia Keith
    • , Holm H Uhlig
    •  & Arian D J Laurence
  8. Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

    • Ahmed N Hegazy
  9. Department of Biochemistry and Department of Computer Science, Purdue University, West Lafayette, Indiana, USA.

    • Majid Kazemian
  10. Imperial BRC Genomics Facility, Hammersmith Hospital, London, UK.

    • Dalia Kasperaviciute
    •  & Michael Mueller
  11. Merck Research Laboratories, Merck & Co. Inc., Boston, Massachusetts, USA.

    • Jason D Hughes
    •  & Joshua McElwee
  12. Clinical Research Directorate/CMRP, Leidos Biomedical Research Inc., NCI at Frederick, Frederick, Maryland, USA.

    • Kim Montgomery-Recht
  13. National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Nicholas P Restifo
  14. Department of Paediatrics, University of Oxford, Oxford, UK.

    • Holm H Uhlig
  15. Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Timothy J Aitman
  16. Department of Haematology, Northern Centre for Cancer Care, Newcastle upon Tyne, UK.

    • Arian D J Laurence


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B.A., J.G. and J.V. designed and performed experiments, analyzed data and wrote the manuscript. C.O'B., I.V., F.P.D., A.K., A.N.H., J. Keith, M.F.S., A.S., R.R., M.A.L., O.K., H.-W.S. and Y.Z. performed experiments and/or analyzed data. I.J.F., W.S., T.J.A., P.K. and N.C. provided patient samples and clinical and scientific input. K.M.-R. coordinated patient samples. Patient sequencing and sequence analysis were carried out by J.V., N.C., T.J.A., D.K., M.M., J.D.H., J.M. and Y.Z. A.V.V., N.R.W., H.H.U. and M.K. provided scientific input. P.T.W., I.W.P. and J. Kaufman provided scientific input, performed protein chemistry experiments and analyzed data. N.P.R. provided murine reagents for these experiments. M.J.L., J.J.O'S., N.C. and A.D.J.L. provided scientific input, supervised the project and wrote the manuscript.

Competing interests

H.H.U. declares industrial project collaboration (unrelated to the current study) with Lilly, UCB Pharma and Vertex Pharmaceuticals. Travel support was received from Actelion and MSD.

Corresponding authors

Correspondence to Behdad Afzali or Nichola Cooper.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8, Supplementary Tables 1 and 2, and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 3

    Associated super-enhancer (SE) structures in haplosufficient genes and in genes causing haploinsufficiency and autosomal recessive diseases. Gene IDs in each tab are demarcated by tissue as containing (marked as ‘1’) or not containing (marked as ‘0’) an associated SE structure.

  2. 2.

    Supplementary Table 4

    Uniform Resource Locators (URLs) for source data used in Supplementary Table 3.

  3. 3.

    Supplementary Table 5

    Haplosufficient and haploinsufficient genes that have genome-wide association study (GWAS) ‘hits’. Listed are gene identifiers. Please note that BACH2 is included in the haploinsufficient gene list here.


  1. 1.

    Confocal images from a healthy donor.

    Movie from confocal images of lymphocytes of a healthy donor. Green, BACH2; Blue, Hoechst stain.

  2. 2.

    Confocal images from patient B.II.1.

    Movie from confocal images of lymphocytes of BACH2E788K mutant patient. Green, BACH2; Blue, Hoechst stain.

  3. 3.

    Confocal images from wild-type BACH2 transfected HEK293T cells.

    Movies from confocal images of HEK293T cells transfected with Flag-tagged wild-type BACH2. Green, Flag; Blue, Hoechst stain

  4. 4.

    Confocal images from BACH2E786K-transfected HEK293T cells.

    Movies from confocal images of HEK293T cells transfected with Flag-tagged BACH2E786K. Green, Flag; Blue, Hoechst stain.

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