A mathematical model predicting the frequency of aberrant rearrangements in the T-cell receptor gene

The T-cell receptor (TCR) genetic loci undergo an orderly process of recombination in ontogeny in order to generate a diverse array of antigen receptors. Normally occurring, outof-frame and incomplete rearrangements produce non-productive TCR transcripts. Abnormalities in the rearrangement process occur at very low frequencies but may predominate in inborn errors of recombination. Detecting these abnormalities in surviving pools of lymphocytes is difficult and typically focuses on identification of abnormally rearranged alleles or on detecting abnormalities in recombinase proteins. Thus, there currently exists no rapid screening method to identify aberrant V(D)J recombination. To address this issue, a mathematical model was developed to predict the error rate from the measured proportions of different non-productive TCR alleles. Since the proportions of different nonproductive rearrangements vary in a characteristic fashion in response to abnormalities in the recombination process, the mathematical model presented here provides a tool to indirectly assess the error rate of TCR recombination. The model was applied to a group of patients with Omennʹs syndrome, most of whom had an unknown primary defect. The results indicate that these patients had a >90% rate of aberrant TCR recombination.