Thymus dysfunction in the 22q11 deletion syndrome

Abstract: Introduction: The 22q11.2 deletion syndrome (22q11DS) is associated with heterogeneous clinical findings, including T-cell immunodeficiency resulting from thymus hypoplasia. Newborn screening programs based on the quantification of T-cell receptor excision circles (TRECs) identify infants with severe combined immunodeficiency, as well as a number of infants with 22q11DS. Aim: To study the outcome of TRECs at birth in infants with 22q11DS, and to investigate if low numbers of TRECs are predictive of persistent thymus dysfunction in individuals with 22q11DS. Method: TRECs were retrospectively quantified by PCR using the original newborn screening cards from 48 infants with 22q11DS (Paper I). A follow-up of individuals with low numbers of TRECs (22q11Low, N=10), normal numbers of TRECs (22q11Normal, N=10) and matched healthy controls (N=10), was performed, including quantification of TRECs, flow cytometry for characterization of lymphocyte subsets, deep sequencing of T-cell receptor repertoires, and PCR for assessment of telomere lengths (Paper II). High-density arrays were used for autoantibody profiling (Paper III). Results: A considerable proportion of infants with 22q11DS had abnormal numbers of TRECs at birth (Paper I). At follow-up (median age 16 years), the 22q11Low group had lower TRECs, lower proportions of naïve T cells, aberrant T-cell receptor repertoires (Paper II) and more autoantibodies (Paper III), as compared to the 22q11Normal group and to healthy controls. Many autoantibody specificities were shared between the two 22q11DS groups. Conclusion: Newborn screening with TRECs identifies a subpopulation of infants with 22q11DS, in whom low numbers of TRECs at birth are associated with long-term immune aberrations, necessitating follow-up.