BACH2 – Immunodeficiency 60

BACH2 haploinsufficiency causes an autosomal dominant primary immunodeficiency characterized by antibody deficiency and immune dysregulation. Two unrelated probands have been reported with heterozygous missense variants in BACH2 (c.2362G>A (p.Glu788Lys) and c.71T>C (p.Leu24Pro)) (PMID:28530713, PMID:37148421). Familial segregation identified one additional relative harboring the c.G1727T (p.Arg576Leu) variant with subclinical immunological findings (PMID:37148421). Affected individuals present with decreased circulating antibody concentration (HP:0004313), intestinal inflammation, selective IgA deficiency, and, in one case, early-onset systemic lupus erythematosus and juvenile dermatomyositis.

Mechanistically, BACH2 mutations disrupt protein stability by interfering with homodimerization or causing aggregation, consistent with haploinsufficiency (PMID:28530713). Bach2+/- mice exhibit analogous lymphocyte-maturation defects leading to immunoglobulin deficiency, supporting functional concordance (PMID:28530713). Patient-derived cells show reduced BACH2 expression and deficient repression of the BACH2 target BLIMP1, further validating loss-of-function (PMID:37148421).

Key Take-home: BACH2 haploinsufficiency should be considered in patients presenting with primary antibody deficiency and immune dysregulation.

References

• Nature immunology • 2017 • BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. PMID:28530713
• Journal of clinical immunology • 2023 • An early-onset SLE patient with a novel paternal inherited BACH2 mutation. PMID:37148421

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