BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency

Abstract

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.

Clinical efficacy of a next‐generation sequencing gene panel for primary immunodeficiency diagnostics

“…This deletion contained the genes MDN1 , BACH2, MAP3K7, CASP8AP2, and GJA10. Haploinsufficiency of the transcription factor BACH2 has recently been described to cause immunodeficiency with autoimmunity, which is a similar clinical phenotype to that of P1, making this the likely cause of the participant's PID …”

“…Haploinsufficiency of the transcription factor BACH2 has recently been described to cause immunodeficiency with autoimmunity, which is a similar clinical phenotype to that of P1, making this the likely cause of the participant's PID. 41 Two participants (P7 and P26) had 2 reportable variants identified. We assessed whether these 2 gene variants were likely to contribute to a blended phenotype of 2 distinct phenotypes that overlap within the individuals, or potentially contributed in a digenic mechanism for disease.…”

“…Many of these missing genes have subsequently been shown to be prevalent in cohorts of PID patients . Another disadvantage is highlighted by the results of P1, in whom a monogenic diagnosis was not reached with the PID gene panel, but an aCGH identified a large structural variant including the BACH2 gene as the cause of the patient's condition . Large structural variants are not detectable from NGS gene panels, and although bioinformatics software exists to investigate for structural variants in NGS WES data it remains challenging due to the PCR amplification of DNA during library preparation and need for read de‐duplication.…”

Zero tolerance! A perspective on monogenic disorders with defective regulatory T cells and IBD‐like disease

“…As described in the report by Afzali et al, BACH2 haploinsufficiency causes a syndrome of BACH2‐related immunodeficiency and autoimmunity (BRIDA), characterized by bowel inflammation and immunoglobulin deficiency. BRIDA patients had a significant reduction in FoxP3 expression in their Treg cells . Similarly, Bach2 heterozygous mice have reduced FoxP3 + Tregs .…”

Measuring “Intolerance to Mutation” in Human Genetics

“…pLI is also increasingly used in clinical annotation and in databases of mouse models as indicative of haploinsufficiency and dosage sensitivity [46][47][48][49][50] . In fact, however, pLI and related measures are not directly informative about dominance effects on fitness, let alone about the degree of haploinsufficiency with respect to a phenotype, and instead reflect only the strength of selection acting in heterozygotes.…”