Abstract
PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN variants, exhibits marked phenotypic heterogeneity, most notably cancer, neurodevelopmental disorders (NDD), or both. The basis for this divergence, even among carriers of identical PTEN variants, remains poorly defined. We performed whole-genome sequencing of 599 individuals with PHTS and family members, complemented by analyses of PTEN variant carriers from the All of Us Research Program. Analyses included both targeted evaluation of genes previously implicated in cancer and NDD and agnostic genome-wide single-variant and rare-variant burden testing. The analytic cohort comprised 543 PHTS probands, including individuals with NDD (n = 171), cancer (n = 221), both phenotypes (n = 21), or neither (n = 130) at the time of enrollment. Pathogenic or likely pathogenic variants in cancer-associated genes were identified in 37 (6.8%), most frequently in MITF, DICER1, and BRCA2, while 43 (7.9%) harbored variants in NDD-related genes, including DHCR7, POLG, and ARSA. Such secondary variants were less common in PTEN variant carriers in All of Us. Genome-wide analyses identified candidate modifier loci functionally linked to PTEN, including in ZNF713, TPTE2P1, and PDPK1. These findings demonstrate that PHTS phenotypes are shaped by complex gene–gene interactions beyond PTEN alone, informing mechanisms underlying the cancer–NDD dichotomy and advancing precision risk stratification.
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Data availability
The data generated in this study will be publicly available in the database of Genotypes and Phenotypes (dbGaP) upon acceptance. All of Us (AoU) data analyses were performed using the AoU Controlled Tier Dataset v8 dataset and executed using the AoU Research Workbench. All other raw data are available from the corresponding author on reasonable request.
Code availability
All software versions are indicated within the Methods. All custom scripts related to this study are available from the corresponding author upon reasonable request. All other bioinformatics and statistical tools are publicly available and are described within the manuscript text.
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Acknowledgements
We are sincerely indebted to the generosity of the families and patients in PTEN clinics across the United States who contributed their time and effort to this study. We thank the clinical research team at the PTEN Multidisciplinary Clinic and Center of Excellence at the Cleveland Clinic for administrative support. We would also like to thank the PTEN Hamartoma Tumor Syndrome Foundation and the PTEN Research Foundation for their continued support in PTEN research. We gratefully acknowledge All of Us participants for their contributions, without whom this research would not have been possible. We also thank the National Institutes of Health’s All of Us Research Program for making available the participant data examined in this study. This work has been partly funded by the PTEN Research Foundation, a charity governed by English law (charity number 117358) to Professor Charis Eng under grant number CCF-19-001. We are also grateful for other funding sources, including the American Cancer Society (RPG-02-151-01-CCE and Clinical Research Professorship), National Institute of Child Health and Human Development (R01HD105049), Breast Cancer Research Foundation, Doris Duke Distinguished Clinical Scientist Award, the Ambrose Monell Foundation, and the Zacconi Center of PTEN Research Excellence (all to C.E.). C.E. was the Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic and an American Cancer Society Clinical Research Professor. The Developmental Synaptopathies Consortium (U54NS092090) is part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN) and is supported by the RDCRN Data Management and Coordinating Center (DMCC) (U2CTR002818). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) and National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH).
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L.Y. and C.E. conceptualized and designed the project. L.Y., L.L., G.I., V.M., and Y.N. performed the experimental procedures and data analyses. L.Y., Y.N., and C.E. interpreted the data. A.H., J.A.M., D.M.R., M.S., and C.E. performed patient accrual and phenotyping. C.E. and Y.N. supervised the project. All authors drafted, critically revised, and gave final approval of the paper. L.Y. and L.L. are co-first authors of this study. C.E. passed away on the 13th day of August 2024.
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T.W.F. has received funding or research support from, acted as a consultant to, received travel support from, and/or received a speaker’s honorarium from the PTEN Research Foundation, SYNGAP Research Fund, Malan Syndrome Foundation, ADNP Kids Research Foundation, Quadrant Biosciences, Autism Speaks, Impel NeuroPharma, F. Hoffmann-La Roche AG Pharmaceuticals, the Cole Family Research Fund, Simons Foundation, Ingalls Foundation, Forest Laboratories, Ecoeos, IntegraGen, Kugona LLC, Shire Development, Bristol-Myers Squibb, Roche Pharma, MaraBio, Scioto Biosciences, Linus Biotechnology, National Institutes of Health, and the Brain and Behavior Research Foundation, has equity options in Quadrant Biosciences/Autism Analytica, MaraBio, has an investor stake in Autism EYES LLC, is employed by CentralReach, and is a co-owner of iSCAN-R and AI-Measures. C.E. was an Associate Editor for npj Genomic Medicine but played no role in the peer-review or decision to publish this manuscript. All other authors declare no competing financial or non-financial interests.
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Yehia, L., Li, L., Idumah, G. et al. Genomic modifiers of malignant and neurodevelopmental phenotypes in individuals with PTEN hamartoma tumor syndrome. npj Genom. Med. (2026). https://doi.org/10.1038/s41525-026-00556-1
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DOI: https://doi.org/10.1038/s41525-026-00556-1
