BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency

Transcriptional programs guiding lymphocyte differentiation depend on precise expression and timing of transcription factors (TFs). BACH2 is a TF essential for T- and B-lymphocytes and is associated with an archetypal super-enhancer (SE). Single nucleotide variants in the BACH2 locus associate with multiple autoimmune diseases but BACH2 mutations causing Mendelian monogenic primary immunodeficiency have not previously been identified. We describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) resulting from BACH2 haploinsufficiency. Patients had lymphocyte maturation defects, causing immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. Analogous lymphocyte defects existed in Bach2 heterozygous mice. More generally, we found that genes causing monogenic haploinsufficient diseases are substantially enriched for TFs and SE-architecture. These observations show a new feature of SE-architecture in Mendelian diseases of immunity, that heterozygous mutations in SE-regulated genes identified on whole exome/genome sequencing may have greater significance than recognized.