Wagener Rabea, Walter Carolin, Surowy Harald M, Brandes Danielle, Soura Stavrieta, Alzoubi Deya, Yasin Layal, Fischer Ute, Dugas Martin, Borkhardt Arndt, Brozou Triantafyllia
Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty.
Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf.
J Pediatr Hematol Oncol. 2023 Mar 1;45(2):e244-e248. doi: 10.1097/MPH.0000000000002475. Epub 2022 May 3.
Application of next-generation sequencing may lead to the detection of secondary findings (SF) not related to the initially analyzed disease but to other severe medically actionable diseases. However, the analysis of SFs is not yet routinely performed. We mined whole-exome sequencing data of 231 pediatric cancer patients and their parents who had been treated in our center for the presence of SFs. By this approach, we identified in 6 children (2.6%) pathogenic germline variants in 5 of the noncancer-related genes on the American College of Medical Genetics and Genomics (ACMG) SF v3.0 list, of which the majority were related to cardiovascular diseases ( RYR2 , MYBPC3 , KCNQ1 ). Interestingly, only the patient harboring the KCNQ1 variant showed at the time point of the analysis signs of the related Long QT syndrome. Moreover, we report 3 variants of unknown significance which, although not classified as pathogenic, have been reported in the literature to occur in individuals with the respective disease. While the frequency of patients with SFs is low, the impact of such findings on the patients' life is enormous, with regard to the potential prevention of life-threatening diseases. Hence, we are convinced that such actionable SF should be routinely analyzed.
应用下一代测序技术可能会检测到与最初分析的疾病无关，但与其他严重的、具有医学可干预性的疾病相关的次要发现（SF）。然而，对次要发现的分析尚未常规进行。我们挖掘了在我们中心接受治疗的231名儿科癌症患者及其父母的全外显子测序数据，以寻找次要发现。通过这种方法，我们在6名儿童（2.6%）中发现了美国医学遗传学与基因组学学会（ACMG）次要发现v3.0列表中5个非癌症相关基因的致病种系变异，其中大多数与心血管疾病相关（RYR2、MYBPC3、KCNQ1）。有趣的是，在分析时，只有携带KCNQ1变异的患者表现出相关长QT综合征的症状。此外，我们报告了3个意义未明的变异，尽管未被分类为致病变异，但在文献中已有报道在患有相应疾病的个体中出现。虽然次要发现患者的频率较低，但就潜在预防危及生命的疾病而言，这些发现对患者生活的影响是巨大的。因此，我们坚信这种具有可干预性的次要发现应该常规进行分析。
