CIDs are caused by defects in T cell development and activation as well as compromised B cell activation with or without impaired B cell development. Phenotypes of CIDs are diverse, including infection, malignancy, allergy, autoimmunity and auto-inflammation. In order to identify the genetic basis of PID patients, we screened a panel of PID related genes by targeted next-generation sequencing.
By targeted NGS we identified a novel CARMIL2 mutation. Expression of CARMIL2 at protein level was characterized by flow cytometry and Western blot analysis. Functional analyzes were performed using flow cytometry.
We report a novel homozygous splice site mutation in CARMIL2 gene in 3 affected individuals from a consanguineous family that presented with selective antibody deficiency, psoriasis, molluscum contagiosum as well as warts.
CARMIL2 expression was absent in naïve CD4+ T cells of all patients. Absolute numbers of CD4+ T cells and the proportion of CD4+ naïve T cells were increased, while percentages of CD4+ T memory and CD4+ T follicular-like T cells were reduced. The phosphorylation of NFκB subunit p65 in CD4+ T cells was abolished indicating the contribution of CARMIL2 in activation of NF-κB signaling.
These cases underline the role of CARMIL2 in immunity and suggest that CARMIL2 mutations should be considered in patients with disseminated and/or persistent warts. Differences in clinical and immunological phenotypes among our patients highlight the variable clinical presentations of CARMIL2-deficiency and suggest the pathogenic relevance of additional genetic and/or epigenetic modifying factors.