@article{c3d85dc4d3714250adf7b996a0b839fa,
title = "An Integrated Deep-Mutational-Scanning Approach Provides Clinical Insights on PTEN Genotype-Phenotype Relationships",
abstract = "Germline variation in PTEN results in variable clinical presentations, including benign and malignant neoplasia and neurodevelopmental disorders. Despite decades of research, it remains unclear how the PTEN genotype is related to clinical outcomes. In this study, we combined two recent deep mutational scanning (DMS) datasets probing the effects of single amino acid variation on enzyme activity and steady-state cellular abundance with a large, well-curated clinical cohort of PTEN-variant carriers. We sought to connect variant-specific molecular phenotypes to the clinical outcomes of individuals with PTEN variants. We found that DMS data partially explain quantitative clinical traits, including head circumference and Cleveland Clinic (CC) score, which is a semiquantitative surrogate of disease burden. We built logistic regression models that use DMS and CADD scores to separate clinical PTEN variation from gnomAD control-only variation with high accuracy. By using a survival-like analysis, we identified molecular phenotype groups with differential risk of early cancer onset as well as lifetime risk of cancer. Finally, we identified classes of DMS-defined variants with significantly different risk levels for classical hamartoma-related features (odds ratio [OR] range of 4.1–102.9). In stark contrast, the risk for developing autism or developmental delay does not significantly change across variant classes (OR range of 5.4–12.4). Together, these findings highlight the potential impact of combining DMS datasets with rich clinical data and provide new insights that might guide personalized clinical decisions for PTEN-variant carriers.",
keywords = "ASD, PHTS, PTEN, PTEN hamartoma tumor syndrome, autism, autism spectrum disorder, cancer, deep mutational scanning, genotype-phenotype, multiplex assay for variant effect",
author = "Mighell, {Taylor L.} and Stetson Thacker and Eric Fombonne and Charis Eng and O'Roak, {Brian J.}",
note = "Funding Information: We thank A.C. Adey, D.M. Fowler, K.A. Matreyek, J. Zonana, G. Mandel, P.J. Stork, K.M. Wright, I.N. Smith, and M. Seyfi for helpful discussions. We thank Martha Atherton and the Atherton Foundation for their support of the NARSAD awards. This work was supported, in part, by a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation through the NARSAD-Atherton Foundation Young Investigator Award (22935 to B.J.O.), a Sloan Research Fellowship in Neurosciences ( Alfred P. Sloan Foundation ; FG-2015-65608 to B.J.O.), the Ambrose Monell Foundation (to C.E.), the Zacconi Program of PTEN Research Excellence (to C.E.), and internal funds (C.E. and B.J.O.). T.L.M received support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development ( F31HD095571 ). T.L.M. is an ARCS scholar ( Achievement Rewards for College Scientists Foundation , Inc., Oregon Chapter), and B.J.O. is a Klingenstein-Simons Fellow (Esther A. and Joseph Klingenstein Fund, Simons Foundation ). C.E. is the Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic and is an American Cancer Society (ACS) clinical research professor. Funding Information: We thank A.C. Adey, D.M. Fowler, K.A. Matreyek, J. Zonana, G. Mandel, P.J. Stork, K.M. Wright, I.N. Smith, and M. Seyfi for helpful discussions. We thank Martha Atherton and the Atherton Foundation for their support of the NARSAD awards. This work was supported, in part, by a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation through the NARSAD-Atherton Foundation Young Investigator Award (22935 to B.J.O.), a Sloan Research Fellowship in Neurosciences (Alfred P. Sloan Foundation; FG-2015-65608 to B.J.O.), the Ambrose Monell Foundation (to C.E.), the Zacconi Program of PTEN Research Excellence (to C.E.), and internal funds (C.E. and B.J.O.). T.L.M received support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F31HD095571). T.L.M. is an ARCS scholar (Achievement Rewards for College Scientists Foundation, Inc. Oregon Chapter), and B.J.O. is a Klingenstein-Simons Fellow (Esther A. and Joseph Klingenstein Fund, Simons Foundation). C.E. is the Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic and is an American Cancer Society (ACS) clinical research professor. Publisher Copyright: {\textcopyright} 2020 American Society of Human Genetics",
year = "2020",
month = jun,
day = "4",
doi = "10.1016/j.ajhg.2020.04.014",
language = "English (US)",
volume = "106",
pages = "818--829",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",
}