Vrijenhoek Terry, Kraaijeveld Ken, Elferink Martin, de Ligt Joep, Kranendonk Elcke, Santen Gijs, Nijman Isaac J, Butler Derek, Claes Godelieve, Costessi Adalberto, Dorlijn Wim, van Eyndhoven Winfried, Halley Dicky J J, van den Hout Mirjam C G N, van Hove Steven, Johansson Lennart F, Jongbloed Jan D H, Kamps Rick, Kockx Christel E M, de Koning Bart, Kriek Marjolein, Lekanne Dit Deprez Ronald, Lunstroo Hans, Mannens Marcel, Mook Olaf R, Nelen Marcel, Ploem Corrette, Rijnen Marco, Saris Jasper J, Sinke Richard, Sistermans Erik, van Slegtenhorst Marjon, Sleutels Frank, van der Stoep Nienke, van Tienhoven Marianne, Vermaat Martijn, Vogel Maartje, Waisfisz Quinten, Marjan Weiss Janneke, van den Wijngaard Arthur, van Workum Wilbert, Ijntema Helger, van der Zwaag Bert, van IJcken Wilfred F J, den Dunnen Johan, Veltman Joris A, Hennekam Raoul, Cuppen Edwin
Department of Medical Genetics, Centre for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Eur J Hum Genet. 2015 Sep;23(9):1142-50. doi: 10.1038/ejhg.2014.279. Epub 2015 Jan 28.
Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants. Reported pathogenic mutations were consistent for all but one patient. Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient. The other provided an alternative diagnosis, identifying another variant as causal than the other centers. Ethical and legal analysis showed that informed consent procedures in all centers were generally adequate for diagnostic NGS applications that target a limited set of genes, but not for exome- and genome-based diagnosis. We propose changes to further improve and align these procedures, taking into account the blurring boundary between diagnostics and research, and specific counseling options for exome- and genome-based diagnostics. We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results. Moreover, there is an increasing interdependence of clinic, diagnostics and research departments for comprehensive diagnostic genome care. Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care.
将下一代DNA测序（NGS）技术应用于常规诊断基因组医疗需要做出战略选择。我们没有对这些选择的后果进行理论探讨，而是基于对9名预先选定的心肌病患者的基因检测，比较了荷兰8个临床遗传中心基于NGS的诊断实践。我们强调了关键的实施选择，包括实验室和医学专家、生物信息学家和研究人员对诊断基因组医疗的具体贡献，以及这些如何影响变异的解读和报告。除一名患者外，所有报告的致病突变都是一致的。在诊断结果不一致的两个中心中，一个报告称“未发现致病变异”，从而对该患者诊断不足。另一个提供了替代诊断，确定了一个与其他中心不同的致病变异。伦理和法律分析表明，所有中心的知情同意程序对于针对有限基因集的诊断性NGS应用总体上是足够的，但对于基于外显子组和基因组的诊断则不够。我们建议做出改变以进一步改进和统一这些程序，同时考虑到诊断与研究之间模糊的界限，以及基于外显子组和基因组诊断的特定咨询选项。我们得出结论，替代诊断可能意味着在解读测序结果时为得出阳性诊断存在一定程度的“贪心”。此外，临床、诊断和研究部门在全面的诊断基因组医疗方面的相互依存度越来越高。因此，我们邀请临床遗传学家、医生、研究人员、生物信息学专家和患者重新考虑他们在未来诊断基因组医疗中的角色和地位。
