Over many years, while studying DOCK8-deficient patients who were evaluated at the NIH Clinical Center, we observed that they often differed from each other in their spectrum of disease and disease severity. Detailed genetic evaluations revealed that the phenotypic variability in some patients was associated with the presence and degree of somatic reversion. This occurred to a high frequency among our patient population who did not have homozygous or overlapping large deletions, due to mechanisms involving homologous recombination. We developed an intracellular flow cytometric method to rapidly diagnose DOCK8 deficiency and assess for somatic reversion, which showed that reversion occurs mostly in T cells and sometimes NK cells. Our results indicate that in most patients somatic reversion may improve but is inadequate to cure disease. However, rare patients who are clinically doing well and have high levels of reversion might benefit from ongoing monitoring, which could influence decisions regarding treatment with hematopoietic cell transplantation. In FY2014, we also participated in two collaborative studies related to DOCK8 deficiency. In the first, we helped to show that the neurological symptoms in DOCK8-deficient patients, which are often attributed to vasculitis, can result from viral reactivation after vaccination with varicella-zoster virus. However, this occurred in the additional setting of immunodeficiency and additional immunosuppressant medications. In the second collaborative study, we helped to show that DOCK8-deficient patients and mice have impaired NKT cell development, which could contribute to the patients'immunodeficiency.
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