{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T20:42:23Z","timestamp":1788813743266,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T00:00:00Z","timestamp":1747180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The majority of early-onset colorectal cancers (EOCRCs) are not substantiated by germline variants in the main CRC predisposition genes (the \u201cDIGE\u201d panel). To identify potentially novel EOCRC-specific predisposition genes, we analyzed 585 cancer pathway genes in an EOCRC patient cohort (n = 87, diagnosis \u2264 40 years, DIGE-), and compared their variant spectrum to the GnomAD cancer-free database. We identified high-impact variants (HVs) in 15 genes significantly over-represented in EOCRC. Among the 32 unrelated patients with a CRC family history (i.e., with a potentially dominant transmission pattern), 9 presented HVs in ten genes, four of which had a DNA repair function. We subsequently sequenced these 15 genes in a cohort of 82 late-onset CRCs (diagnosis \u2265 50 years, DIGE-) and found variants in 11 of these genes to be specific to EOCRC. We then screened these 11 genes in our patient database (n = 6482), which only contained 2% of EOCRCs (DIGE-), and identified two other EOCRC cases diagnosed after our cohort constitution, with HVs in RECQL4 and NUTM1. Altogether, we found that 37.5% and 18.75% of patients carrying heterozygous NUTM1 and RECQL4 HVs, respectively, in our database were diagnosed with EOCRC. Our work has identified a pattern of germline variants not previously associated with EOCRC.<\/jats:p>","DOI":"10.3390\/ijms26104672","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T03:59:29Z","timestamp":1747195169000},"page":"4672","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Germline Sequencing of Familial and Sporadic Early-Onset Colorectal Cancer: A Novel Pattern of Genes"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7595-7243","authenticated-orcid":false,"given":"Pierre","family":"Vande Perre","sequence":"first","affiliation":[{"name":"Oncogenetics Laboratory, Oncopole Claudius Regaud, IUCT-Oncopole, 31059 Toulouse, France"},{"name":"DIAD Team, INSERM U1037, Centre de Recherches en Canc\u00e9rologie de Toulouse, 31100 Toulouse, France"},{"name":"Oncogenetics Department, Oncopole Claudius Regaud, IUCT-Oncopole, 31059 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1517-4156","authenticated-orcid":false,"given":"Ayman","family":"Al Saati","sequence":"additional","affiliation":[{"name":"Oncogenetics Laboratory, Oncopole Claudius Regaud, IUCT-Oncopole, 31059 Toulouse, France"},{"name":"DIAD Team, INSERM U1037, Centre de Recherches en Canc\u00e9rologie de Toulouse, 31100 Toulouse, France"},{"name":"Facult\u00e9 de Sant\u00e9, Universit\u00e9 de Toulouse, 31400 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bastien","family":"Cabarrou","sequence":"additional","affiliation":[{"name":"Biostatistics & Health Data Science Unit, Oncopole Claudius Regaud, IUCT-Oncopole, 31059 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Plenecassagnes","sequence":"additional","affiliation":[{"name":"Bioinformatic Department, Oncopole Claudius Regaud, IUCT-Oncopole, 31059 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