{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T15:37:01Z","timestamp":1789832221360,"version":"4.0.1"},"reference-count":25,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T00:00:00Z","timestamp":1750464000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Li\u2013Fraumeni syndrome (LFS) is a rare autosomal\u2010dominant cancer\u2010predisposition syndrome caused by germline pathogenic or likely pathogenic variants (P\/LPVs) in the <jats:italic>TP53<\/jats:italic> gene. Classical autosomal\u2010dominant inheritance predicts a 50% transmission rate of <jats:italic>TP53<\/jats:italic> P\/LPV from each carrier parent to their offspring. However, clinical observations suggest higher\u2010than\u2010expected carrier proportions, indicating a potential transmission ratio distortion (TRD). The objective of this study was to investigate TRD in Israeli LFS families.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data from families with an LFS diagnosis who were followed at Sheba Medical Center between 2015 and 2024 were reviewed. Families that had complete clinical data and offspring were included. Pedigree analyses classified carriers as confirmed, obligate, or probable. Observed carrier proportions were compared with the expected 50% rate using one\u2010sample <jats:italic>t<\/jats:italic>\u2010tests.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among 171 individuals from 20 families, 100 (58.5%) were identified as <jats:italic>TP53<\/jats:italic> P\/LPV confirmed or obligatory carriers, significantly exceeding the expected 50% inheritance rate (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.027). A second analysis, which included 11 probable carriers, resulted in a carrier proportion of 64.9% (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.001). TRD was observed across all phenotypic groups. No significant differences in TRD were observed by sex or variant type.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study revealed significant TRD in <jats:italic>TP53<\/jats:italic> P\/LPV inheritance among Israeli LFS families. A potential mechanism involves the role of <jats:italic>TP53<\/jats:italic> in the cell cycle, in which reduced TP53 function may enhance embryonic cell proliferation, offering a survival or implantation advantage. TRD in LFS has implications for genetic counseling, reproductive decision making, and clinical management. These findings underscore the need for further research to validate TRD across diverse populations and elucidate the underlying mechanisms.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.35943","type":"journal-article","created":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T13:03:37Z","timestamp":1750511017000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Transmission ratio distortion of germline <i>TP53<\/i> variants in Li\u2013Fraumeni syndrome families"],"prefix":"10.1002","volume":"131","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8926-4154","authenticated-orcid":false,"given":"Naama","family":"Halpern","sequence":"first","affiliation":[{"name":"The Jusidman Cancer Center Sheba Medical Center  Ramat Gan Israel"},{"name":"Faculty of Medical and Health Sciences School of Medicine Tel\u2010Aviv University  Tel\u2010Aviv 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Tel\u2010Aviv University  Tel\u2010Aviv Israel"},{"name":"The Recanati Genetics Unit Rabin Medical Center Beilinson Hospital  Petah Tikva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inbal","family":"Kedar","sequence":"additional","affiliation":[{"name":"The Recanati Genetics Unit Rabin Medical Center Beilinson Hospital  Petah Tikva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagit","family":"Shani","sequence":"additional","affiliation":[{"name":"Preimplantation Genetic Diagnosis Center Danek Gertner Institute of Human Genetics Sheba Medical Center  Ramat Gan Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eitan","family":"Friedman","sequence":"additional","affiliation":[{"name":"Faculty of Medical and Health Sciences School of Medicine Tel\u2010Aviv University  Tel\u2010Aviv Israel"},{"name":"The Meirav High\u2010Risk Clinic, Sheba Medical Center  Ramat Gan 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