BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency

Nat Immunol. 2017 Jul;18(7):813-823. doi: 10.1038/ni.3753. Epub 2017 May 22.


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.

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use
  • Adult
  • Autoimmune Diseases / complications
  • Autoimmune Diseases / genetics*
  • Basic-Leucine Zipper Transcription Factors / genetics*
  • Colitis / complications
  • Colitis / genetics
  • Colitis / pathology
  • Female
  • Fever / complications
  • Fever / drug therapy
  • Fever / genetics
  • Haploinsufficiency
  • Heterozygote
  • Humans
  • Immunologic Deficiency Syndromes / complications
  • Immunologic Deficiency Syndromes / genetics*
  • Lymphopenia / complications
  • Lymphopenia / genetics
  • Male
  • Middle Aged
  • Mutation
  • Pancytopenia / complications
  • Pancytopenia / drug therapy
  • Pancytopenia / genetics
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Recurrence
  • Respiratory Tract Infections / complications
  • Respiratory Tract Infections / diagnostic imaging
  • Respiratory Tract Infections / genetics
  • Splenomegaly / complications
  • Splenomegaly / genetics
  • Syndrome
  • Tomography, X-Ray Computed
  • Young Adult


  • Adrenal Cortex Hormones
  • BACH2 protein, human
  • Basic-Leucine Zipper Transcription Factors