Biallelic deficiencies of CD27 and its ligand CD70 underlie selective susceptibility to Epstein-Barr virus (EBV) infection and its acute and chronic complications, underscoring their nonredundant roles in anti-EBV immunity. To date, 16 pathogenic CD27 variants have been reported. Here, we describe three patients from two unrelated families, homozygous for a new loss-of-function (LOF) CD27 variant, resulting in the substitution of serine 70 with proline (S70P). All three patients presented with EBV viremia and lymphoproliferative disease, with variable immune dysregulation or recurrent otosinopulmonary infections. One patient developed EBV-associated malignancy. Functional studies demonstrated that the S70P variant impaired surface expression of CD27 and abolished CD70 binding, rendering complete LOF when overexpressed in vitro. Endogenous CD27 expression from patients was absent ex vivo.
Together, S70P represents a novel pathogenic variant causing autosomal recessive (AR) CD27 deficiency, characterized by a unified susceptibility to EBV yet distinct clinical manifestations, ranging from chronic viremia to malignancy.
