Biallelic MCM10 Deficiency Presenting with Natural Killer Cell Deficiency, Poikiloderma and EBV-Associated Malignancy.
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PURPOSE: Defects in components of the CDC45-MCM2-7-GINS (CMG) helicase complex have been associated with natural killer (NK) cell deficiency in rare inborn errors of immunity. Pathogenic biallelic variants in MCM10 have been reported in a limited number of individuals with severe immunologic and developmental phenotypes. We aimed to further delineate the clinical and immunologic spectrum of MCM10 deficiency. METHODS: Singleton exome sequencing, RNA splicing analysis, flow cytometry-based immunophenotyping, telomere length assessment, radiation sensitivity testing, and in silico analysis of publicly available single-cell RNA sequencing datasets were performed. RESULTS: A six-year-old boy presented with poikiloderma, photosensitivity, growth failure, and immune dysregulation. Exome sequencing identified a homozygous canonical splice-site variant in MCM10 (c.930 + 2T > A), resulting in an in-frame deletion of 17 amino acids within the oligonucleotide/oligosaccharide-binding (OB)-fold domain, confirmed at the RNA level.Immunophenotyping showed near-absent NK cells with increased NK-T cells and terminally differentiated CD8 T cells. While karyotype, telomere length, and radiation sensitivity were normal, limited MCM10 expression in replicating NK cells is suspected. During follow-up, the patient developed an aggressive Epstein-Barr virus-positive squamous cell carcinoma of the tongue, an exceedingly rare childhood malignancy. CONCLUSION: This case expands the phenotypic spectrum of MCM10-related inborn errors of immunity and supports a critical role for MCM10 in NK-cell development and immune homeostasis. The occurrence of a virus-associated malignancy suggests susceptibility and impaired immune surveillance. Together with previously described defects in CMG-complex components, these findings are consistent with an emerging group of DNA replication-associated immune disorders.