BackgroundIn a considerable number of patients with a suspected hereditary tumor syndrome (HTS), no underlying germline mutation is detected in the most likely affected genes. The present study aimed to establish and validate a large gene panel for HTS, and determine its diagnostic yield and clinical utility.MethodsThe study cohort comprised 173 patients with suspected, but unexplained, HTS (group U) and 64 HTS patients with a broad spectrum of known germline mutations (group K). All patients in group U presented with early age at onset, multiple tumors, and/or a familial clustering of various tumor types; no germline mutation had been identified during routine diagnostics. Sequencing of leukocyte DNA was performed for the 94 HTS genes of the Illumina TruSight™Cancer Panel and 54 additional HTS genes.ResultsThe sensitivity of the panel to identify known germline variants was 99.6%. In addition to known mutations, a total of 192 rare, potentially pathogenic germline variants in 86 genes were identified. Neither the proportion of rare variants per patient (group K: 0.9 variants; group U: 0.8 variants) nor the proportion of variants in the most frequently mutated, moderately penetrant genes CHEK2 and ATM showed significant inter-group difference. Four of the five patients from group U with a truncating CHEK2 mutation had thyroid cancer, pointing to a broader tumor spectrum in patients with pathogenic CHEK2 variants. In 22% of patients from group K, a further potential causative variant was identified. Here, the most interesting finding was an NF1 nonsense mutation in a child with a known TP53 frameshift mutation. In 17% of patients from group U, potential causative variants were identified. In three of these patients (2%), mutations in PMS2, PTEN, or POLD1 were considered to be causative. In both groups, incidental findings with presumptive predictive value were generated.ConclusionsThe gene panel identified the genetic cause in some prescreened, unexplained HTS patients and generated incidental findings. Some patients harbored predicted pathogenic mutations in more than one established HTS gene, rendering interpretation of the respective alterations challenging. Established moderate risk genes showed an almost equal distribution among patients with known and unexplained disease.

中文翻译：

---

遗传性肿瘤综合征综合基因组的诊断率和临床效用

背景在相当多的疑似遗传性肿瘤综合征 (HTS) 患者中，在最可能受影响的基因中未检测到潜在的种系突变。本研究旨在建立和验证 HTS 的大型基因组，并确定其诊断率和临床效用。方法研究队列包括 173 名疑似但无法解释的 HTS（U 组）患者和 64 名具有广谱 HTS 的患者。已知的种系突变（K组）。U组所有患者发病年龄早，肿瘤多发，和/或各种肿瘤类型的家族聚集；在常规诊断过程中未发现种系突变。对 Illumina TruSight™Cancer Panel 的 94 个 HTS 基因和另外 54 个 HTS 基因进行了白细胞 DNA 测序。结果panel识别已知种系变异的敏感性为99.6%。除已知突变外，共鉴定了 86 个基因中的 192 种罕见的、潜在致病的种系变异。每名患者的罕见变异比例（K 组：0.9 个变异；U 组：0.8 个变异）和最频繁突变的中度外显基因 CHEK2 和 ATM 的变异比例均未显示出显着的组间差异。U 组 5 名具有截短 CHEK2 突变的患者中有 4 名患有甲状腺癌，这表明具有致病性 CHEK2 变异的患者的肿瘤谱更广。在来自 K 组的 22% 的患者中，确定了进一步的潜在致病变异。在这里，最有趣的发现是一个具有已知 TP53 移码突变的儿童的 NF1 无义突变。在 U 组 17% 的患者中，确定了潜在的致病变异。在其中三名患者（2%）中，PMS2、PTEN 或 POLD1 的突变被认为是致病因素。在这两组中，产生了具有假定预测价值的偶然发现。结论基因小组确定了一些预先筛选的、无法解释的 HTS 患者的遗传原因并产生了偶然发现。一些患者在多个已建立的 HTS 基因中具有预测的致病突变，这使得对各自改变的解释具有挑战性。已建立的中度风险基因在患有已知和无法解释疾病的患者中显示出几乎相等的分布。产生了具有假定预测价值的偶然发现。结论基因小组确定了一些预先筛选的、无法解释的 HTS 患者的遗传原因并产生了偶然发现。一些患者在多个已建立的 HTS 基因中具有预测的致病突变，这使得对各自改变的解释具有挑战性。已建立的中度风险基因在患有已知和无法解释疾病的患者中显示出几乎相等的分布。产生了具有假定预测价值的偶然发现。结论基因小组确定了一些预先筛选的、无法解释的 HTS 患者的遗传原因并产生了偶然发现。一些患者在多个已建立的 HTS 基因中具有预测的致病突变，这使得对各自改变的解释具有挑战性。已建立的中度风险基因在患有已知和无法解释疾病的患者中显示出几乎相等的分布。