MYB Haploinsufficiency Causes Familial Autoimmune Cytopenias

MYB is a transcription factor and master regulator of hematopoiesis with a central role at multiple stages of B and T cell development. We identified ten heterozygous germline MYB variants in seven families and four unrelated singletons. The variants segregated with autoimmune cytopenias, including Evans syndrome, in three five-generation pedigrees. In our cohort of 41 carriers, 22 were affected by autoimmune cytopenias, while one had isolated B cell lymphopenia and neutropenia. All ten variants are absent or ultra-rare in population databases and segregate with disease in the kindreds in an autosomal-dominant pattern with incomplete penetrance. In silico analyses predict that the variants are likely to perturb MYB function. Carriers of select alleles (p.R81X, c.1587+1G>C, p.S407Vfs*13, and c.528-1G>T) from whom biospecimens were available exhibited elevated fetal hemoglobin levels, consistent with reduced MYB function given its established role as a fetal hemoglobin repressor. For the p.R81X and p.S407Vfs*13 alleles, we demonstrated reduced protein expression in activated CD8+ T cells, supporting MYB haploinsufficiency as the underlying mechanism. High-resolution immunophenotyping of carriers of the p.R81X, c.1587+1G>C, and p.S407Vfs*13 alleles revealed expanded T-bet-positive B cells and expanded CD4+ and CD8+ terminal effector T cells, suggesting that reduced MYB function affects lymphocyte differentiation pathways relevant to immune regulation. Together, the segregation, computational, functional, and immunophenotypic data establish damaging germline MYB variants as a dominantly inherited cause of autoimmune cytopenias, expand the spectrum of inborn errors of immunity, and support an immunoregulatory role for MYB in activated lymphocytes.