Low Yield of Genetic Testing in Serrated Polyposis Syndrome.

Abstract

Introduction: Serrated polyposis syndrome (SPS) is clinically defined by the presence of multiple serrated polyps in the colon and rectum and is associated with increased colorectal cancer risk. SPS is the most prevalent polyposis condition however its genetic basis remains poorly characterised. The British Society of Gastroenterology recommends gene panel testing for all SPS patients to rule out other polyposis conditions. This study aimed to evaluate the diagnostic yield of genetic testing in SPS patients.

Methods: We conducted a retrospective, cross-sectional analysis using the Polyposis Registry from St. Mark's Hospital, London, a national referral centre in the United Kingdom. SPS patients who underwent genetic testing between 4 April 2009 to 9 February 2024 and met the SPS WHO criteria were included. Genetic variants were identified from test reports, and clinical data was extracted from medical records.

Results: In total, 573 people with SPS were identified in our registry, of whom 258 underwent genetic testing. Of these, 119 underwent target gene testing and 139 underwent multi-gene panel testing (MGPT). No pathogenic variants were detected through targeted genetic testing. On MGPT, pathogenic germline variants were found in four patients (2.9%), including three with Lynch syndrome (two with PMS2, one with MSH2) and one with an RNF43 variant.

Conclusion: Genetic testing demonstrated a low diagnostic yield in this SPS cohort, suggesting undefined genetic risk or involvement of other pathophysiological factors. Therefore, genetic testing appears to have limited utility in SPS patients and may primarily identify those with an incidental diagnosis of Lynch syndrome.