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Purpose <p>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 <i>MCM10</i> 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 <i>MCM10</i> deficiency.</p> Methods <p>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.</p> Results <p>A six-year-old boy presented with poikiloderma, photosensitivity, growth failure, and immune dysregulation. Exome sequencing identified a homozygous canonical splice-site variant in <i>MCM10</i> (c.930 + 2T &gt; 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.</p> Conclusion <p>This case expands the phenotypic spectrum of <i>MCM10</i>-related inborn errors of immunity and supports a critical role for <i>MCM10</i> 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.</p>

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Biallelic MCM10 Deficiency Presenting with Natural Killer Cell Deficiency, Poikiloderma and EBV-Associated Malignancy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Yael Hoffman,
  • Alina Kurolap,
  • Hila Ledermann Nahmias,
  • Adi Mory,
  • Tal Freund,
  • Avraham Unterman,
  • Uri Hamiel,
  • Hagit Baris Feldman,
  • Daphna Marom,
  • David Hagin

摘要

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.