{
  "abstract": "Background Pathogenic variants in the protection of telomerase 1 ( POT1) gene are associated with predisposition to a broad spectrum of malignancies, although the specific genotype–phenotype correlation has not yet been fully elucidated. To further characterise the phenotypic spectrum, we describe six families with germline POT1 variants and evaluate existing literature to highlight the possible association between variants in POT1, telomere dysregulation and predisposition to malignant central nervous system (CNS) tumours.Methods Genetic analyses were performed using an Illumina sequencing platform. All variants were examined by in silico analysis in Alamut as well as Rare Exome Variant Ensemble Learner (REVEL), and one variant was additionally examined by RNA analysis.Telomere length assessment was performed through RepeatDX Europe.Results We identified four missense and two frameshift POT1 germline variants: c.255G>C, p.(Lys85Asn), c.322G>A, p.(Gly108Arg), c.323G>A, p.(Gly108Glu), c.676C>T, p.(His226Tyr), c.707del, p.(Gly236Glufs*16) and c.709del, p.(Ser237Alafs*15). The variants c.255G>C and c.322G>A were observed in two patients with astrocytoma and c.676C>T in a patient with oligodendroglioma, corresponding to the most prevalent CNS tumour histopathology described in POT1 carriers in previous publications. Longer telomeres were found in probands with the CNS tumour phenotype.Conclusion Our findings support a possible association between pathogenic POT1 germline variants and increased risk of CNS tumours mainly oligodendroglioma, astrocytoma and glioblastoma. We highlight the potential importance of missense variants and telomeric measurement in tailoring of surveillance and advocate further studies to guide future personalised surveillance strategies.",
  "authors": [
    {
      "affiliations": [
        "Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark"
      ],
      "name": "Emilie Neerup Nielsen"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark"
      ],
      "name": "Anne Marie Jelsig"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Copenhagen University Hospital, Copenhagen, Denmark"
      ],
      "name": "Jon Foss-Skiftesvik"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Zealand University Hospital Roskilde, Roskilde, Denmark"
      ],
      "name": "Zuzana Lohse"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Zealand University Hospital Roskilde, Roskilde, Denmark"
      ],
      "name": "Susanne Timshel"
    },
    {
      "affiliations": [
        "Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark"
      ],
      "name": "Line Borgwardt"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark",
        "Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Thomas Van Overeem Hansen"
    },
    {
      "affiliations": [
        "Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark",
        "Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark"
      ],
      "name": "Karin A W Wadt"
    }
  ],
  "title": "Exploring the spectrum of central nervous system tumours in carriers of germline POT1 variants",
  "uid": "f7e46e78-690c-540e-ada0-a30e3ff91ac3"
}