23 research outputs found
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