Abstract
Several inborn errors of immunity are caused by defects in the general
DNA repair machinery as exemplified by the T-B- RS-SCID condition owing
to impaired resolution of programmed DNA double strands breaks
introduced by RAG1/2 during V(D)J recombination. The genome instability
generally associated with these conditions results in an increased
propensity to develop malignancies requiring genotoxic based anti-cancer
treatments. Moreover, the extent of immune deficiency often calls for
hematopoietic stem cell transplantation as a definitive treatment, thus
also demanding genotoxic based conditioning regimen prior to
transplantation. In both cases, the underlying general DNA repair
defects may result in catastrophic iatrogenic consequences. It is
therefore of paramount importance to assess the functionality of the DNA
repair apparatus prior to any genotoxic treatment when the exact
molecular cause of the disease is unknown. For this purpose, two simple
assays can be used on patient’s derived peripheral blood lymphocytes. 1)
The PROMIDISα biomarker, based on the next generation sequencing
analysis of the TCRα will highlight specific signatures of DNA repair
deficiencies. 2) Direct analysis of the sensitivity of peripheral
lymphocytes to ionizing radiations will formally identify patients at
risk to develop toxicity towards genotoxic based treatments.