Clinical and Genetic Analysis of Li-Fraumeni Syndrome with Novel TP53 Mutations

Abstract Objective Mutations in the TP53 gene can cause Li-Fraumeni syndrome (LFS), an autosomal dominant genetic syndrome that increases susceptibility to various tumors. This study aims to explore the clinical and pathological features as well as the genetic characteristics of LFS to provide a theoretical basis for genetic counseling in affected families. Methods We conducted a retrospective analysis of clinical data and family history in three LFS cases with TP53 germline mutations. High-throughput sequencing technology was used to screen for hereditary tumor-related genes in the probands, and Sanger sequencing was used to confirm and analyze candidate pathogenic variant sites in their family members. Results Three different types of TP53 mutation variants were found in our study. The first family, spanning four generations and consisting of 30 individuals, included 9 adults diagnosed with 8 different types of cancer. Genetic testing revealed the TP53 c.642_643delTA p.H214Qfs*7 mutation in this family, showing that the age of onset tended to become younger in successive generations. The second family, with two patients having four different malignant tumors, carried the TP53 c.742C > T p.R248W mutation. This family had an average diagnosis age younger than the first family. The third proband, a 13-year-old boy, carried the TP53 c.844C > T p.R282W mutation and had no family history, indicating that this may be a new TP53 germline mutation in his family. Conclusion Our study identified and reported the pathogenic variant TP53 p.H214Qfs*7 frameshift mutation for the first time, expanding the mutation spectrum of the TP53 gene. We recommend timely genetic counseling and TP53 germline mutation testing for patients with childhood tumors or multiple familial tumors. Systematic monitoring of individuals carrying these mutations is crucial for early intervention to prevent primary and secondary tumors.