Next-generation sequencing-based genome diagnostics across clinical genetics centers: implementation choices and their effects

T Vrijenhoek, K Kraaijeveld, M Elferink, J de Ligt, E Kranendonk, G Santen, IJ Nijman, D Butler, G Claes, A Costessi, W Dorlijn, W van Eyndhoven, Dicky Halley, Mirjam Van den Hout - van Vroonhoven, S van Hove, LF Johansson, JDH Jongbloed, R Kamps, Christel Kockx, B de KoningM Kriek, RLD Deprez, H Lunstroo, M Mannens, OR Mook, M Nelen, C Ploem, M Rijnen, Jasper Saris, R Sinke, E Sistermans, Marjon van Slegtenhorst, Frank Sleutels, N van der Stoep, Marianne Tienhoven, M Vermaat, M Vogel, Q Waisfisz, JM Weiss, A van den Wijngaard, W van Workum, H Ijntema, B Van der Zwaag, Wilfred van Ijcken, J den Dunnen, JA Veltman, R Hennekam, E Cuppen

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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.
Original languageUndefined/Unknown
Pages (from-to)1142-1150
Number of pages9
JournalEuropean Journal of Human Genetics
Issue number9
Publication statusPublished - 2015

Research programs

  • EMC MGC-02-13-02
  • EMC MGC-02-96-01

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