{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T15:04:02Z","timestamp":1766588642452,"version":"3.48.0"},"posted":{"date-parts":[[2025,12,20]]},"group-title":"Genetic and Genomic Medicine","reference-count":21,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T00:00:00Z","timestamp":1766188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  PTEN hamartoma tumor syndrome (PHTS) is a cancer predisposition disorder caused by germline\n                  <jats:italic>PTEN<\/jats:italic>\n                  variants, yet its full clinical spectrum remains poorly defined due to reliance on highly selected cohorts. Accordingly, PHTS is underrecognized and its prevalence underestimated. Leveraging genomic and electronic health record data from 414,830 participants in the All of Us (AoU) Research Program, we identified 55 individuals with pathogenic or likely pathogenic\n                  <jats:italic>PTEN<\/jats:italic>\n                  variants, the majority of whom lacked a prior PHTS diagnosis, underscoring underrecognition in the general population. PHTS affects \u223c1\/7500 individuals in this US cohort, which is about 26-folds higher than historical estimates for\n                  <jats:italic>PTEN<\/jats:italic>\n                  -related disorder. Compared with carriers of other cancer-related gene variants and noncarriers,\n                  <jats:italic>PTEN<\/jats:italic>\n                  variant carriers exhibited the highest cancer prevalence and significantly younger ages at first cancer diagnosis. Phenotype enrichment revealed expected overgrowth-related features as well as previously unreported associations, including adenotonsillar hypertrophy, sleep apnea, acanthosis nigricans, and extreme obesity, suggesting broader systemic involvement than classically appreciated. Variant spectra were consistent across the population-based and clinically-ascertained PHTS cohorts. These findings demonstrate that PHTS is more prevalent, more heterogeneous, and more often undiagnosed than current clinical practice reflects, emphasizing the value of population-scale genomics for comprehensive characterization and earlier detection of PHTS.\n                <\/jats:p>","DOI":"10.64898\/2025.12.19.25342661","type":"posted-content","created":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T01:30:14Z","timestamp":1766280614000},"source":"Crossref","is-referenced-by-count":0,"title":["Population-based Characterization of PTEN Hamartoma Tumor Syndrome"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2784-038X","authenticated-orcid":false,"given":"Gideon","family":"Idumah","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chloe","family":"Bautista","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6389-3059","authenticated-orcid":false,"given":"Lamis","family":"Yehia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0338-5239","authenticated-orcid":false,"given":"Ying","family":"Ni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025122407000894000_2025.12.19.25342661v2.1","unstructured":"Yehia L , Eng C. PTEN Hamartoma Tumor Syndrome. In: GeneReviews((R)) (eds Adam MP , et al.) (1993)."},{"key":"2025122407000894000_2025.12.19.25342661v2.2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-052218-125823"},{"key":"2025122407000894000_2025.12.19.25342661v2.3","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2283"},{"key":"2025122407000894000_2025.12.19.25342661v2.4","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101339"},{"key":"2025122407000894000_2025.12.19.25342661v2.5","doi-asserted-by":"publisher","DOI":"10.1007\/s10689-013-9674-3"},{"key":"2025122407000894000_2025.12.19.25342661v2.6","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/jnci\/djac188","article-title":"Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome","volume":"115","year":"2023","journal-title":"J Natl Cancer Inst"},{"key":"2025122407000894000_2025.12.19.25342661v2.7","doi-asserted-by":"crossref","first-page":"e239705","DOI":"10.1001\/jamanetworkopen.2023.9705","article-title":"Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants","volume":"6","year":"2023","journal-title":"JAMA Netw Open"},{"key":"2025122407000894000_2025.12.19.25342661v2.8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.53.6656"},{"key":"2025122407000894000_2025.12.19.25342661v2.9","unstructured":"Hendricks LAJ , et al. The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS). Genet Med, 101467 (2025)."},{"key":"2025122407000894000_2025.12.19.25342661v2.10","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.024646"},{"key":"2025122407000894000_2025.12.19.25342661v2.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.12.036"},{"key":"2025122407000894000_2025.12.19.25342661v2.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.10.009"},{"key":"2025122407000894000_2025.12.19.25342661v2.13","doi-asserted-by":"crossref","unstructured":"White SL , et al. Population prevalence of the major thyroid cancer-associated syndromes. J Clin Endocrinol Metab, (2025).","DOI":"10.1210\/clinem\/dgaf236"},{"key":"2025122407000894000_2025.12.19.25342661v2.14","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5200289"},{"key":"2025122407000894000_2025.12.19.25342661v2.15","doi-asserted-by":"crossref","unstructured":"Idumah G , Newell D , Hadrys M , Ribaudo I , Ni Y , Arbesman J . Pathogenic Germline Variants in Cancer Susceptibility Genes. JAMA, (2025).","DOI":"10.1101\/2025.03.28.25324849"},{"key":"2025122407000894000_2025.12.19.25342661v2.16","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2011.20"},{"key":"2025122407000894000_2025.12.19.25342661v2.17","doi-asserted-by":"crossref","unstructured":"Drissen M , Schieving JH , Schuurs-Hoeijmakers JHM , Vos JR , Hoogerbrugge N . Red flags for early recognition of adult patients with PTEN Hamartoma Tumour Syndrome. Eur J Med Genet 64, 104364 (2021).","DOI":"10.1016\/j.ejmg.2021.104364"},{"key":"2025122407000894000_2025.12.19.25342661v2.18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsr1809937"},{"key":"2025122407000894000_2025.12.19.25342661v2.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04558-8"},{"key":"2025122407000894000_2025.12.19.25342661v2.20","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41698-025-00847-3","article-title":"Extended spectrum of cancers in PTEN hamartoma tumor syndrome","volume":"9","year":"2025","journal-title":"NPJ Precis Oncol"},{"key":"2025122407000894000_2025.12.19.25342661v2.21","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23636"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2025.12.19.25342661","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T15:00:20Z","timestamp":1766588420000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2025.12.19.25342661"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,20]]},"references-count":21,"URL":"https:\/\/doi.org\/10.64898\/2025.12.19.25342661","relation":{},"subject":[],"published":{"date-parts":[[2025,12,20]]},"subtype":"preprint"}}