Population-based characterization of PTEN hamartoma tumor syndrome

Background PTEN hamartoma tumor syndrome (PHTS) is a hereditary cancer predisposition disorder caused by changes in the PTEN gene. Its true prevalence and full range of clinical features are not well understood. This study aims to define how common this condition is and to better describe its health effects in the general population. Methods We analyzed genetic and electronic health record (EHR) data from 414,830 All of Us Research Program participants to identify carriers of pathogenic/likely pathogenic (P/LP) germline PTEN variants, characterizing their cancer history, age at first diagnosis, clinical phenotypes, and variant spectrum. We compared P/LP carriers with carriers of PTEN variants of uncertain significance (VUS), and compared the All of Us PTEN variant spectrum with that of a clinically ascertained Cleveland Clinic PHTS cohort. Results We identified 55 individuals with P/LP PTEN variants, most without a prior PHTS diagnosis. The condition affects ~1 in 7500 people, 26-fold higher than previously reported and consistent with recent population-based estimates. Among 46 carriers with EHR data, 20 (43.5%) had at least one cancer diagnosis (median age 46 years). Phenotype enrichment revealed expected overgrowth-related features and previously under-reported associations, including adenotonsillar hypertrophy, sleep apnea, acanthosis nigricans, and extreme obesity. PTEN VUS carriers showed lower odds of cancer than P/LP carriers (OR, 0.31; 95% CI 0.16–0.61; P < 0.001) and an older age at first cancer diagnosis (61 vs. 46 years, P < 0.001). Variant spectra were consistent between the population-based and clinically-ascertained cohorts. Conclusions These findings show that PHTS is more common, heterogeneous, and often undiagnosed than current clinical practice reflects, emphasizing the value of population-scale genomics for comprehensive characterization and earlier detection of PHTS.