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Li–Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome usually associated with  TP53  germline alterations. Its genetic basis in  TP53  wild-type pedigrees is less understood. Using whole-genome sequencing, we identified a germline hemizygous deletion ablating  CDKN2A–CDKN2B  in a  TP53  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  CDKN2A -encoded tumour suppressors p14 ARF  and p16 INK4A  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  CDKN2A  variants suggested associations of germline  CDKN2A  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  CDKN2A–CDKN2B  locus in an LFS family. These findings highlight the potential contribution of germline  CDKN2A  deletions to cancer predisposition and the importance of interrogating the full extent of  CDKN2A  locus in clinical testing gene panels.

Germline hemizygous deletion of CDKN2A–CDKN2B locus in a patient presenting with Li–Fraumeni syndrome