De Novo RHOG Variant in a Patient with Combined Immunodeficiency and Extensive Viral Infections: A Potential New Disease Mechanism

Background RHOG encodes a small GTPase involved in cytoskeletal dynamics, T cell activation, and immune synapse formation. Variants in RHOG have been implicated in combined immunodeficiencies affecting both cellular and humoral responses, although clinical reports remain scarce. Case Presentation We report a pediatric patient with a clinical diagnosis of common variable immunodeficiency (CVID), presenting with recurrent respiratory infections and widespread viral warts. Immunologic evaluation revealed combined immunodeficiency with defects in both T and B cell compartments. Exome sequencing identified a heterozygous missense variant in RHOG (c.34G>A; p.Gly12Arg), located within the conserved GTP-binding domain. The variant is absent from population databases including gnomAD and is predicted to be deleterious (Revel score: 0.906) (PM2_Supporting, PP3_Moderate). Parental and sibling testing confirmed that the variant arose de novo, supporting a causative role (PM6_Supporting). Discussion Based on American College of Medical Genetics and Genomics/ClinGen criteria, the variant meets multiple supporting and moderate-level criteria: PM6 (de novo in a patient with consistent phenotype), PM2 (absent from controls), and PP3 (multiple in silico tools predict damaging effect). This strengthens its classification as a variant of uncertain significance. The clinical phenotype is consistent with the emerging role of RHOG in human immunity. Conclusion This case adds new evidence supporting RHOG as a candidate gene for combined immunodeficiency with viral susceptibility. Functional validation is required to confirm the mechanism and establish RHOG deficiency as a distinct clinical entity.