NTHL1肿瘤综合征是一种由NTHL1基因的双等位失活变异引起的常染色体隐性罕见疾病，在肿瘤谱方面表现出广泛多样性。为了对该综合征的表型进行描述性研究，我们通过KASP分析或下一代测序对467名索引患者进行了研究，其中包括228名患有结肠息肉症的患者和239名有家族/个人史中患有多种肿瘤(不包括多发性乳腺/卵巢/息肉)的患者。在患有息肉症的患者群中，发现了三个NTHL1肿瘤综合征家族，而在有家族/个人史中患有多种肿瘤的患者中未发现。总共鉴定出9例患有息肉症的患者(其中两例在开始结肠癌监测后被诊断)，其具有双等位致病性或可能致病性NTHL1变异，以及两个索引患者与一个未确定意义的错义变异同时存在一个致病性或可能致病性NTHL1变异。在这里，我们鉴定了一个新的帧内缺失，根据ACMG标准被分类为可能致病性，这也得到了肿瘤突变特征分析的支持。我们的研究结果表明，NTHL1肿瘤综合征是一种与息肉强相关的多肿瘤综合征，而不是与无息肉的多肿瘤相关。 版权所有©2023年Pinto、Guerra、Pinheiro、Escudeiro、Santos、Pinto、Porto、Bartosch、Silva、Peixoto和Teixeira。

NTHL1 tumor syndrome is an autosomal recessive rare disease caused by biallelic inactivating variants in the NTHL1 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 NTHL1 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 NTHL1 variants, as well as two index patients with one pathogenic or likely pathogenic NTHL1 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 NTHL1 tumor syndrome is a multi-tumor syndrome strongly associated with polyposis and not with multiple tumors without polyposis.Copyright © 2023 Pinto, Guerra, Pinheiro, Escudeiro, Santos, Pinto, Porto, Bartosch, Silva, Peixoto and Teixeira.