Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype

Abstract

Background Autosomal recessive, loss-of-function mutations in DOCK8 cause a combined immunodeficiency characterized by atopy, recurrent infections, and cancer susceptibility. A genotype-phenotype explanation for the variable disease expression is lacking. Objective We investigated whether reversions contributed to the variable disease expression. Methods Patients followed at the NIH Clinical Center were studied. We performed detailed genetic analyses and intracellular flow cytometry to detect DOCK8 protein expression within lymphocyte subsets. Results We identified 17 out of 34 DOCK8-deficient patients who had germline mutations with variable degrees of reversion due to 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 in NK cells, but less so in naïve T cells 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. Conclusions In 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 may modulate disease phenotype over time.

The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency

“…However, a possible somatic reversion of the germline mutation may be present. 22 Eventually, genes mutated in the DOCK8-sufficient patients, such as PGM3 , 7–9 will be identified, and the diagnostic sequencing strategy can be expanded to include more genes (see the Online Repository for exclusion of other candidate genes in some of our families that do not have mutations in either DOCK8 or PGM3 ). In addition, a recent report 22 has demonstrated that in some patients DOCK8 gene expression can be reestablished in one or more subsets of cells through somatic reversion.…”

Genomics of Immune Diseases and New Therapies

“…DNA sequence analysis of selected cell populations can also uncover somatic mutations (SM) such as FAS gene mutations that are present in a subpopulation of CD4-, CD8- T cells but not in the germline of certain autoimmune lymphoproliferative syndrome (ALPS) patients (23). Somatic reversion can also ameliorate disease phenotype by “correcting” the genetic defect in appropriate cell lineages (24). …”

DOCK8 regulates lymphocyte shape integrity for skin antiviral immunity

“…However, these viruses can reemerge from latency to cause disease in up to 30% of the population (Higgins et al, 1993;Kilkenny and Marks, 1996;Harpaz et al, 2008). In contrast to normal individuals, DOCK8-deficient patients with autosomalrecessive loss-of-function mutations in DOCK8 have impaired cellular and humoral immunity (Engelhardt et al, 2009;Zhang et al, 2009;Su et al, 2011;Jing et al, 2014) that manifests as extreme susceptibility to skin and other infections (Chu et al, 2012). Patients often suffer from disseminated and persistent viral skin infections including those caused by HSV, varicella-zoster virus, human papillomavirus, and molluscum contagiosum.…”