{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T07:51:56Z","timestamp":1776844316293,"version":"3.51.2"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T00:00:00Z","timestamp":1693440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:italic>NTHL1<\/jats:italic> tumor syndrome is an autosomal recessive rare disease caused by biallelic inactivating variants in the <jats:italic>NTHL1<\/jats:italic> gene and which presents a broad tumor spectrum. To contribute to the characterization of the phenotype of this syndrome, we studied 467 index patients by KASP assay or next-generation sequencing, including 228 patients with colorectal polyposis and 239 patients with familial\/personal history of multiple tumors (excluding multiple breast\/ovarian\/polyposis). Three <jats:italic>NTHL1<\/jats:italic> tumor syndrome families were identified in the group of patients with polyposis and none in patients with familial\/personal history of multiple tumors. Altogether, we identified nine affected patients with polyposis (two of them diagnosed after initiating colorectal cancer surveillance) with biallelic pathogenic or likely pathogenic <jats:italic>NTHL1<\/jats:italic> variants, as well as two index patients with one pathogenic or likely pathogenic <jats:italic>NTHL1<\/jats:italic> variant in concomitance with a missense variant of uncertain significance. Here we identified a novel inframe deletion classified as likely pathogenic using the ACMG criteria, supported also by tumor mutational signature analysis. Our findings indicate that the <jats:italic>NTHL1<\/jats:italic> tumor syndrome is a multi-tumor syndrome strongly associated with polyposis and not with multiple tumors without polyposis.<\/jats:p>","DOI":"10.3389\/fgene.2023.1254908","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T13:03:14Z","timestamp":1693486994000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Combined germline and tumor mutation signature testing identifies new families with NTHL1 tumor syndrome"],"prefix":"10.3389","volume":"14","author":[{"given":"Carla","family":"Pinto","sequence":"first","affiliation":[]},{"given":"Joana","family":"Guerra","sequence":"additional","affiliation":[]},{"given":"Manuela","family":"Pinheiro","sequence":"additional","affiliation":[]},{"given":"Carla","family":"Escudeiro","sequence":"additional","affiliation":[]},{"given":"Catarina","family":"Santos","sequence":"additional","affiliation":[]},{"given":"Pedro","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"Miguel","family":"Porto","sequence":"additional","affiliation":[]},{"given":"Carla","family":"Bartosch","sequence":"additional","affiliation":[]},{"given":"Jo\u00e3o","family":"Silva","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Peixoto","sequence":"additional","affiliation":[]},{"given":"Manuel R.","family":"Teixeira","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2023,8,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/s41439-019-0077-3","article-title":"A new family with a homozygous nonsense variant in NTHL1 further delineated the clinical phenotype of NTHL1-associated polyposis","volume":"6","author":"Altaraihi","year":"2019","journal-title":"Hum. 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