A novel spi1 mutation in a patient with agammaglobulinemia

Agammaglobulinemia is a primary immunodeficiency characterized by a low number or absence of mature B lymphocytes and consequently by immunoglobulin deficiency. In 2021, six patients with pathogenic variants in SPI1 gene associated with agammaglobulinemia type 10 (PU.MA) were described for the first time. This gene encodes the pioneer transcription factor PU.1, which plays an important role in the differentiation of B lymphocytes, monocytes, and conventional dendritic cells. Here we present a female patient with a novel mutation in SPI1 gene which has not been previously found in patients with PU.MA. Case description: A 37-year-old female patient with frequent middle ear infections in early childhood was diagnosed with agammaglobulinemia at the age of 15 when she started immunoglobulin replacement therapy (IgRT). One year later, an allogeneic hematopoietic stem cell transplant from a healthy sibling donor was performed. Unfortunately, chimerism analysis found no DNA material from the donor in the patient's blood, suggesting graft rejection, so she remained dependent on antibody replacement therapy. Years later, she was diagnosed with protein-losing enteropathy, and despite escalating doses of IgRT, IgG levels remained low. Subsequently, the patient developed persistent COVID -19 viremia and bacterial meningoencephalitis. Clinical exome sequencing using the TruSight (Illumina) panel was performed and in comparision with the human reference genome (hg19), has revealed a heterozygous mutation in exon 4 of the SPI1 gene. This mutation is characterized by the insertion of 2 nucleotides (c.441dup), a reading frame shift, and the insertion of a premature stop codon. According to the American College of Medical Genetics and Genomics, this mutation is described as a likely pathogenic-class 2 (PVS1_Very Strong). Conclusion: From analysis of previous literature, we concluded that the mutant sequence in exon 4 encodes the PEST region of the pioneer transcription factor PU.1, which is responsible for interaction with other transcription factors. Immunophenotyping of peripheral blood cells did not reveal CD19+ B cells, suggesting that a differentiation arrest may have developed between the prepro-B and pro-B stages, where there is a high requirement for PU.1 activity. Nextgeneration sequencing can be a very useful tool to uncover the causes of rare primary immunodeficiencies, but further analysis is needed to explain the relationship between patient genotype and clinical presentation