PDF(Pubmed)
Abstract：
Juvenile polyposis syndrome (JPS) is an inherited autosomal dominant condition that predisposes to the development of juvenile polyps throughout the gastrointestinal (GI) tract, and it poses an increased risk of GI malignancy. Germline causative variants were identified in the SMAD4 gene in a subset (20%) of JPS cases. Most SMAD4 germline genetic variants published to date are missense, nonsense, and frameshift mutations. SMAD4 germline alterations predicted to result in aberrant splicing have rarely been reported. Here, we report two unrelated Italian families harboring two different SMAD4 intronic variants, c.424+5G>A and c.425-9A>G, which are clinically associated with colorectal cancer and/or juvenile GI polyps. In silico prediction analysis, in vitro minigene assays, and RT-PCR showed that the identified variants lead to aberrant SMAD4 splicing via the exonization of intronic nucleotides, resulting in a premature stop codon. This is expected to cause the production of a truncated protein. This study expands the landscape of SMAD4 germline genetic variants associated with GI polyposis and/or cancer. Moreover, it emphasizes the importance of the functional characterization of SMAD4 splicing variants through RNA analysis, which can provide new insights into genetic disease variant interpretation, enabling tailored genetic counseling, management, and surveillance of patients with GI polyposis and/or cancer.
摘要：
青少年息肉病综合征（JPS）是一种遗传性常染色体显性疾病，易于在整个胃肠道（GI）中发展青少年息肉，它会增加胃肠道恶性肿瘤的风险。在JPS病例的一个子集（20％）中的SMAD4基因中鉴定了种系致病变异。迄今为止发表的大多数SMAD4种系遗传变异都是错误的，胡说，和移码突变。预测会导致异常剪接的SMAD4种系改变很少有报道。这里,我们报告了两个不相关的意大利家族，它们拥有两种不同的SMAD4内含子变体，c.424+5G>A和c.425-9A>G，临床上与结直肠癌和/或青少年胃肠道息肉相关。在硅预测分析中，体外小基因测定，和RT-PCR显示，鉴定的变体通过内含子核苷酸的外显子化导致异常的SMAD4剪接，导致提前终止密码子。预期这将导致截短的蛋白质的产生。这项研究扩展了与GI息肉病和/或癌症相关的SMAD4种系遗传变异的前景。此外，它强调了通过RNA分析对SMAD4剪接变体进行功能表征的重要性，这可以提供对遗传疾病变异解释的新见解，提供量身定制的遗传咨询，管理,以及对胃肠道息肉病和/或癌症患者的监测。
