Novel heterozygous SPI1c.538C>T p.(Leu180Phe) variant causes PU.1 haploinsufficiency leading to agammaglobulinemia

PU.1 is an Ets family transcription factor crucial for hematopoietic cell fate. Complete PU.1 deficiency lethally arrests lympho- and myelopoiesis in mice. Individuals with SPI1 heterozygous loss-of-function variants exhibit disrupted gene expression patterns associated with B cell development. We identified the vertical transmission of a heterozygous SPI1c.538C>T p.(L180F) variant in a Finnish family. The index patient and his mother had severe bacterial infections, agammaglobulinemia, and low myeloid and plasmacytoid dendritic cell counts. The variant carrier sister had slightly reduced B cell counts, isolated IgA deficiency, and reduced dendritic cell counts. All individuals had diminished PU.1 protein expression in monocytes. In vitro studies showed that PU.1 L180F variant is less expressed and predominantly located in the cytoplasm. PU.1 WT mainly interacts with chromatin and centrosome-associated proteins, while the L180F variant showed fewer interactions. Our findings describe a novel PU.1 variant leading to agammaglobulinemia with variable penetrance.