A novel POT1-TPD presentation: A germline pathogenic POT1 variant discovered in a patient with newly diagnosed posterior fossa ependymoma.

Introduction: POT1 tumor predisposition (POT1-TPD) is an autosomal dominant disorder characterized by increased lifetime malignancy risk. Melanoma, angiosarcoma, and chronic lymphocytic leukemia are the most frequently reported malignancies [1]. Protection of telomeres protein 1 (POT1) is part of the shelterin protein complex to maintain/protect telomeres [2]. Proposed mechanisms for oncogenesis with POT1 loss of function include telomere elongation and DNA damage response causing genomic instability [3]. Ependymomas are a heterogeneous group representing one-third of pediatric brain tumors and are locally aggressive with frequent recurrence [4].

Case Presentation: A healthy 3-year-old male presented with worsening vertigo, headaches, and emesis. Radiographic studies demonstrated a midline posterior fossa mass in the fourth ventricle. Following a gross total resection, pathology demonstrated a posterior fossa ependymoma, group A. Next generation sequencing (NGS) using our institution's clinically validated panel, "CinCSeq," identified a POT1 splice site variant (c.1164-1G>A; variant allele fraction 46 %). Paired germline testing via the Molecular Characterization Initiative confirmed this variant as heterozygous in the patient. Genetic testing confirmed the POT1 pathogenic variant in his mother, who has a history of multiple nevi. The patient completed treatment with focal proton radiotherapy with no evidence of disease recurrence to date.

Discussion: To our knowledge, this represents the first documented pediatric ependymoma patient with a familial, germline POT1 pathogenic variant. Somatic POT1 mutational frequency, as determined by NGS in over 60,000 solid tumors, is 2.94 %. Among this cohort, 48 cases were ependymomas with one non-benign POT1 mutation [5]. Alterations of telomere maintenance have been reported in intracranial ependymomas previously through increased human telomerase reverse transcriptase (hTERT) expression [6,7]. This case sheds light on a potential new predisposition for ependymoma development and the expanding phenotype of POT1-TPD. We recognize the POT1 pathogenic variant may have been discovered incidentally in this case. Further research is needed to advance our understanding of the association between POT1 genetic alterations and ependymomas.