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.
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.
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.
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.