Transmission ratio distortion of germline TP53 variants in Li-Fraumeni syndrome families

Li-Fraumeni syndrome (LFS) is a rare autosomal-dominant cancer-predisposition syndrome caused by germline pathogenic or likely pathogenic variants (P/LPVs) in the TP53 gene. Classical autosomal-dominant inheritance predicts a 50% transmission rate of TP53 P/LPV from each carrier parent to their offspring. However, clinical observations suggest higher-than-expected carrier proportions, indicating a potential transmission ratio distortion (TRD). The objective of this study was to investigate TRD in Israeli LFS families.

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-sample t-tests.

Among 171 individuals from 20 families, 100 (58.5%) were identified as TP53 P/LPV confirmed or obligatory carriers, significantly exceeding the expected 50% inheritance rate (p = .027). A second analysis, which included 11 probable carriers, resulted in a carrier proportion of 64.9% (p < .001). TRD was observed across all phenotypic groups. No significant differences in TRD were observed by sex or variant type.

This study revealed significant TRD in TP53 P/LPV inheritance among Israeli LFS families. A potential mechanism involves the role of TP53 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.