• Huie Jing, Qian Zhang, Yu Zhang, Brenna J Hill, Christopher G Dove, Erwin W Gelfand, T Prescott Atkinson, Gulbu Uzel, Helen F Matthews, Peter J Mustillo, David B Lewis, Fotini D Kavadas, I Celine Hanson, Ashish R Kumar, Raif S Geha, Daniel C Douek, Steven M Holland, Alexandra F Freeman, and Helen C Su.
• Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
• J. Allergy Clin. Immunol. 2014 Jun 1;133(6):1667-75.

BackgroundAutosomal recessive loss-of-function mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency characterized by atopy, recurrent infections, and cancer susceptibility. A genotype-phenotype explanation for the variable disease expression is lacking.ObjectiveWe investigated whether reversions contributed to the variable disease expression.MethodsPatients followed at the National Institutes of Health's Clinical Center were studied. We performed detailed genetic analyses and intracellular flow cytometry to detect DOCK8 protein expression within lymphocyte subsets.ResultsWe identified 17 of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion caused by somatic repair. Somatic repair of the DOCK8 mutations resulted from second-site mutation, original-site mutation, gene conversion, and intragenic crossover. Higher degrees of reversion were associated with recombination-mediated repair. DOCK8 expression was restored primarily within antigen-experienced T cells or natural killer cells but less so in naive T or B cells. Several patients exhibited multiple different repair events. Patients who had reversions were older and had less severe allergic disease, although infection susceptibility persisted. No patients were cured without hematopoietic cell transplantation.ConclusionsIn patients with DOCK8 deficiency, only certain combinations of germline mutations supported secondary somatic repair. Those patients had an ameliorated disease course with longer survival but still had fatal complications or required hematopoietic cell transplantation. These observations support the concept that some DOCK8-immunodeficient patients have mutable mosaic genomes that can modulate disease phenotype over time.Published by Mosby, Inc.

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