Skewed offspring distribution of <i>TP53</i> pathogenic variants in Israeli Li-Fraumeni syndrome families.

10604 Background: Li-Fraumeni Syndrome (LFS) [OMIM #151623] is an autosomal dominant cancer predisposition syndrome caused primarily by germline pathogenic (PV) or likely pathogenic variants (LPV) in the TP53 gene. Classical autosomal dominant (AD) inheritance predicts a 50% risk of inheritance for offspring of TP53 PV/LPV carriers. However, clinical observations in Israeli LFS families suggest a higher-than-expected prevalence of TP53 PV/LPV carriers among offspring. This study aims to further investigate this phenomenon. Methods: Relevant clinical data from 36 LFS families followed at Sheba Medical Center's high-risk clinic (2015–2024) were reviewed under an IRB-approved protocol. Twenty families met inclusion criteria after excluding those with incomplete clinical data or carriers without offspring. Detailed pedigree analyses were conducted to determine the carrier status of all offspring of confirmed and obligate TP53 mutation carriers. Probable carriers were defined as individuals who fulfilled two criteria: (1) a diagnosis of an LFS-associated malignancy, and (2) being a first-degree relative of a confirmed carrier. Deceased parents with LFS-associated malignancies, whose partners had normal TP53 sequencing and whose offspring tested positive for TP53 PV/LPV, were also considered obligate carriers. A t-test was used to compare the observed proportion of TP53 PV/LPV carriers among offspring with the expected 50% inheritance rate for AD conditions. Results: A total of 174 individuals met the study criteria and were either genotyped for the family-specific TP53 PV/LPV or assigned obligatory or probable carrier status. Of these, 115 (66.1%) were identified as TP53 PV/LPV carriers, either through genotyping (n= 87), obligatory (n= 13) or probable carrier designation (n= 15). This observed proportion was significantly higher than the expected 50% based on AD inheritance (p&lt;0.0001). Out of the TP53 PV/LPV carriers, 67 (58.3%) individuals were healthy at the time of genotyping, and 62 (53.9%) were male. Conclusions: Our findings reveal a significant skewing of TP53 variant inheritance in Israeli LFS families, with a higher-than-expected prevalence of carriers among offspring. To our knowledge, this phenomenon has not been previously reported in LFS. A potential mechanism for this skewing may involve TP53's role in cell cycle regulation and apoptosis. Reduced TP53 protein levels could confer a selective advantage during early embryonic development by enhancing cell proliferation, potentially improving embryonic survival and implantation success. If corroborated in larger and ethnically diverse LFS cohorts, this finding could have implications for genetic counseling, particularly in reproductive decision-making for LFS families. Further research is needed to validate these findings and explore the underlying biological mechanisms driving this skewing.