Role of a Rare Variant in APC Gene Promoter 1B Region in Classic Familial Adenomatous Polyposis
Role of a Rare Variant in APC Gene Promoter 1B Region in Classic Familial Adenomatous Polyposis
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APC 基因启动子 1B 区域罕见变异在经典家族性腺瘤性息肉病中的作用
DOI：
10.1159/000509234
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发表时间：
2020-07
期刊：
影响因子：
3.2
通讯作者：
Ying Yuan
中科院分区：
文献类型：
--
作者：
Mengyuan Yang;Lila Zhu;Lizhen Zhu;Dong Xu;Ying Yuan
家族性腺瘤性息肉病（FAP）最常见的原因是大肠腺瘤性息肉病（APC）基因的种系变异。虽然大多数FAP患者都能检测到明确的致病性变异，但仍有大量的FAP患者存在变异阴性，我们利用139个基因的下一代测序（NGS）面板和多重连接依赖探针扩增（MLPA）检测FAP患者的致病性变异，并发现了一个变异阴性的家系。通过全外显子组测序（WES），我们确定了APC基因非编码区的点变异。最后，我们使用桑格测序分析其家系共分离和双荧光素酶报告基因（DLR）检测来评估其功能。进行MLPA后，该家系仍为变异阴性。有趣的是，通过WES，一个点变量c。3例患者APC基因启动子1B区190 G>A阳性。此外，在桑格测序筛查该家系时发现了一个变异携带者。通过DLR分析，我们进一步证实了变异体c.- 190 G>A引起APC下游转录的显著抑制。APC启动子1B区190 G>A）的突变可导致典型表型的FAP，但非编码区的这种变异可能被常规遗传学检测所遗漏。因此，利用覆盖更大区域的测序技术可以帮助我们进一步探索变异阴性FAP病例的发病机制。
Familial adenomatous polyposis (FAP) is most commonly caused by germline variants in the adenomatous polyposis coli (APC) gene. Although definite pathogenic variants could be detected in the majority of individuals with FAP, there are still numerous variant-negative FAP patients.We utilized a 139-gene next-generation sequencing (NGS) panel and multiplex ligation-dependent probe amplification (MLPA) to detect pathogenic variants in FAP patients and found a variant-negative pedigree. Through whole-exome sequencing (WES), we identified a point variant in the noncoding region in the APC gene. Finally, we used Sanger sequencing to analyze its pedigree cosegregation and a dual-luciferase reporter (DLR) assay to assess its function.With the exception of 2 variants of undetermined significance (VUS), WES showed no pathogenic or likely pathogenic variants. After performing MLPA, the pedigree was still variant-negative. Interestingly, through WES, a point variant c.-190G>A located in the promoter 1B region of the APC gene was identified in 3 affected individuals. Moreover, a variant carrier was found during screening of the family with Sanger sequencing. Through the DLR assay, we further confirmed that the variant c.-190G>A caused significant suppression of downstream transcription of APC.The variant (c.-190G>A) in the APC promoter 1B region is able to cause FAP with a classic phenotype, but this kind of variant in the noncoding region could be missed by conventional genetic testing. Thus, utilizing sequencing technologies covering a larger area can help us to further explore the pathogenesis in variant-negative FAP cases.
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