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We present the description of <jats:italic>SMAD4<\/jats:italic> mosaicism in a 30\u2010year\u2010old man who had caecum adenocarcinoma, 11 juvenile colon polyps and epistaxis since childhood. We conducted NGS polyposis and CRC panel analysis on DNA extracted from two polyps, revealing a likely pathogenic <jats:italic>SMAD4<\/jats:italic> variant: NM_005359.5:c. 1600C&gt;T, p.(Gln534*). This variant was then identified at a very low frequency on blood and normal colonic tissue, by targeted visualization of previously obtained NGS data. These findings support the presence of a likely pathogenic mosaic <jats:italic>SMAD4<\/jats:italic> variant that aligns with the patient's phenotype. Given the relatively frequent occurrence of de novo <jats:italic>SMAD4<\/jats:italic> mutations, somatic mosaicism could account for a significant proportion of sporadic JPS patients with unidentified pathogenic variants. This case underscores the diagnosis challenge of detecting mosaicism and emphasizes the importance of somatic analyses.<\/jats:p>","DOI":"10.1002\/ajmg.a.63648","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T13:35:20Z","timestamp":1714656920000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp><i>SMAD4<\/i><\/scp> mosaicism in juvenile polyposis: Essential contribution of somatic analysis in diagnosis"],"prefix":"10.1002","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4123-7790","authenticated-orcid":false,"given":"Sabine","family":"Vautier","sequence":"first","affiliation":[{"name":"Department of Genetics Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen  Rouen France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacques","family":"Mauillon","sequence":"additional","affiliation":[{"name":"Department of Genetics Univ 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