Unlocking Precision in Hereditary Paraganglioma-Pheochromocytoma Syndrome Testing with POAga

Certain genes, such as SDHD and SDHAF2, are associated with Hereditary Paraganglioma-Pheochromocytoma (PGL/PCC) syndromes. Pathogenic variants in these genes significantly increase the lifetime risk for PGL/PCC. However, a unique characteristic of these genes is a parent-of-origin (PofO) effect. This means that disease risk depends on whether the variant is inherited from the mother or the father. For SDHD and SDHAF2, susceptibility to paragangliomas and pheochromocytomas is observed almost exclusively when the variants are paternally inherited. While rare cases of maternally inherited SDHD-related tumor susceptibility have been reported, these are either phenocopies where the tumor is unrelated to the inherited variant or the result of complex somatic tumour events.

Accurately determining the parent-of-origin (PofO) of pathogenic variants in SDHD and SDHAF2 is crucial for providing accurate risk assessments and tailoring screening strategies. Lifelong screening and surveillance strategies are recommended in individuals with paternally inherited variants. Traditionally, determining PofO relies on cascade testing, which involves testing at-risk relatives to establish variant segregation. However, this approach faces practical barriers, such as unknown, unavailable, deceased, or reluctant relatives who decline genetic testing. This often results in cases where the parental origin remains unknown. In current clinical practice, this lack of PofO information for SDHD and SDHAF2 can lead to unnecessary lifelong screening for carriers of maternally inherited variants, causing undue stress for patients and strain on the healthcare system.

To address these critical challenges, Evident Genomics has developed Parent-of-Origin-Aware Genomic Analysis (POAga).  POAga is a novel and innovative technology that can accurately determine the parental origin of a genetic variant without requiring parental data.  This approach is currently for research use only and is not as yet a clinically accredited test.