Somatic mosaicism in two unrelated patients with X-linked chronic granulomatous disease characterized by the presence of a small population of normal cells

X-linked chronic granulomatous disease (X-CGD) is a primary immunodeficiency disease of phagocytes caused by mutations in the cytochrome b558β (CYBB) gene. We, for the first time, detected somatic mosaicism in two unrelated male patients with X-CGD caused by de novo nonsense mutations (p.Gly223X and p.Glu462X) in the CYBB gene. In each patient, a small subset of granulocytes was normal in terms of respiratory burst (ROB) activity, gp91phox expression, and CYBB sequences. Cells with wild-type CYBB sequence were also detected in buccal swab specimens and in peripheral blood mononuclear cells. The normal cells were shown to be of the patient origin by fluorescent in situ hybridization analysis of X/Y chromosomes, and by HLA DNA typing. Two possible mechanisms for this somatic mosaicism were considered. The first is that the de novo disease-causing mutations in CYBB occurred at an early multicellular stage of embryogenesis with subsequent expansion of the mutated cells, leaving some unmutated cells surviving. The second possibility is that the de novo mutations occurred in oocytes which was followed by reversion of the mutations in a small subset of cells in early embryogenesis. ► We, for the first time, report somatic mosaicism in two male patients with X-CGD. ► Cells with normal DNA sequence also had normal gp91phox expression and ROB activity. ► Cells with normal DNA sequence were also present in buccal swab specimens and PBMC. ► FISH and HLA DNA typing studies indicate these cells are of the patient origin. ► De novo mutations or reversion of mutations during embryogenesis may have occurred.