Ambry Genetics, Aliso Viejo, CA.
JCO Precis Oncol. 2024 Mar;8:e2300404. doi: 10.1200/PO.23.00404.
Patients with germline pathogenic variants (PVs) in develop tens (attenuated familial adenomatous polyposis [AFAP]) to innumerable (classic FAP) adenomatous polyps in their colon and are at significantly increased lifetime risk of colorectal cancer. Up to 10% of FAP and up to 50% of patients with AFAP who have undergone DNA-only multigene panel testing (MGPT) do not have an identified PV in . We seek to demonstrate how the addition of RNA sequencing run concurrently with DNA can improve detection of germline PVs in individuals with a clinical presentation of AFAP/FAP.
We performed a retrospective query of individuals tested with paired DNA-RNA MGPT from 2021 to 2022 at a single laboratory and included those with a novel PV located in intronic regions infrequently covered by MGPT, a personal history of polyposis, and family medical history provided. All clinical data were deidentified in this institutional review board-exempt study.
Three novel variants were identified in six families and were shown to cause aberrant splicing because of the creation of a deep intronic cryptic splice site that leads to an RNA transcript subject nonsense-mediated decay. Several carriers had previously undergone DNA-only genetic testing and had received a negative result.
Here, we describe how paired DNA-RNA MGPT can be used to solve missing heritability in FAP families, which can have important implications in family planning and treatment decisions for patients and their families.
携带胚系致病性变异（PVs）的患者在结肠中会出现数十个（低危家族性腺瘤性息肉病 [AFAP]）到无数个（经典 FAP）腺瘤性息肉，终生结直肠癌风险显著增加。多达 10%的 FAP 患者和多达 50%的接受仅 DNA 多基因panel 检测（MGPT）的 AFAP 患者在 中没有发现 PV。我们旨在展示在具有 AFAP/FAP 临床表现的个体中，同时进行 DNA 和 RNA 测序如何提高胚系 PV 的检测率。
我们对 2021 年至 2022 年在一家实验室进行 DNA-RNA 配对 MGPT 检测的个体进行了回顾性查询，并纳入了那些具有位于 MGPT 较少覆盖的内含子区域的新 PV、多发性息肉病的个人病史和提供的家族病史的个体。在这项经机构审查委员会豁免的研究中，所有临床数据均被去识别化。
在六个家族中发现了三个新的 变体，这些变体被证明会导致异常剪接，因为创建了一个深内含子隐蔽剪接位点，导致 RNA 转录物被无意义介导的衰变。一些携带者之前已经接受了仅 DNA 的基因检测，结果为阴性。
在这里，我们描述了如何使用配对的 DNA-RNA MGPT 来解决 FAP 家族中的遗传缺失问题，这对患者及其家属的计划生育和治疗决策具有重要意义。
