Germline Hemizygous Deletion of Locus in a Patient Presenting with Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome usually associated with germline alterations. Its genetic basis in wild-type pedigrees is less understood. Using whole-genome sequencing, we identified a germline hemizygous deletion ablating in a wild-type patient presenting with high-grade sarcoma, laryngeal squamous cell carcinoma and a family history suggestive of LFS. Patient-derived cells demonstrated reduced basal gene and protein expression of the -encoded tumour suppressors p14 and p16 with concomitant decrease in p21 and faster cell proliferation, implying potential deregulation of p53-mediated cell cycle control. Review of 13 additional patients with pathogenic variants suggested associations of germline mutations with an expanded spectrum of non-melanoma familial cancers. To our knowledge, this is the first report of a germline gross deletion of the locus in an LFS family. These findings highlight the potential contribution of germline deletions to cancer predisposition and the importance of interrogating the full extent of locus in clinical testing gene panels.