Case Report: The revelation of a new pathogenic variant in the POT1 gene in a patient with a pediatric high-grade glioma and a renal cell carcinoma

This study aimed to describe and molecularly characterize a rare case of early-onset multiple primary tumors associated with a novel germline protection of telomeres 1 (POT1) gene pathogenic variant, associated with POT1 tumor predisposition syndrome (POT1-TPD), a rare autosomal dominant disorder characterized by an increased risk for various tumors, including gliomas. A custom clinical exome panel for genes associated with Cancer Predisposition Syndromes was performed on DNA extracted from blood. RNA sequencing and genome-wide DNA methylation profiling were conducted on tumors. We report the case of a female patient diagnosed at age 12 with a diffuse glioma harboring a ROS1 fusion. At age 18, she developed a renal cell carcinoma. Genetic germline testing revealed a heterozygous germline POT1 variant, c.910dupG (p.Asp304fs*8), classified as pathogenic. Segregation analysis demonstrated paternal inheritance of the variant. The same POT1 variant was identified in both tumor tissues in a heterozygous state. This is the first reported case of a young adult carrying a new pathogenic POT1 variant who developed a pediatric high-grade glioma and a renal tumor in early adulthood. This report expands the clinical spectrum of POT1-associated tumors with early-onset and underscores the relevance of genetic testing for patient management and family counseling.