Malignancies are often observed in pediatric patients with combined immunodeficiency and it is the most prevalent cause of death after infections in these patients.
Here, we report clinical, immunological and genetic evaluation in two young sisters that presented with combined immunodeficiency, where one patient developed EBV related B cell lymphoma and the other had systemic EBV infection and suspected lymphoma.
By whole exome sequencing we identified a novel homozygous missense c.721G>A mutation in exon 5 of UNG gene, generating a p.V241I mutant protein. The mutation led to a significant loss of UNG expression. Immunodeficiency associated with mutations in the UNG is rare and is known to present as hyper IgM syndrome 5 . Nevertheless, our patients displayed clinical and laboratory signs of combined immunodeficiency severe T cell lymphopenia, poor proliferative reaction to mitogens, abnormal T cell repertoire, and restriction and clonal expansions of the TRG repertoire of the gdT cells. class-switch recombination was grossly not impaired. The analysis of the IGH repertoire revealed abnormal IGHV gene usages and somatic hyper mutation (SHM) pattern.
Our findings demonstrate for the first time, the importance of UNG in T cell development and its role in protecting against the development of B cell lymphomas in humans. We believe that thesenew insights will help in unveiling yet unknown functions of UNG in adaptive immunity.