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

Terry Vrijenhoek*, Ken Kraaijeveld, Martin Elferink, Joep de Ligt, Elcke Kranendonk, Gijs Santen, Isaac J. Nijman, Derek Butler, Godelieve Claes, Adalberto Costessi, Wim Dorlijn, Winfried van Eyndhoven, Dicky J. J. Halley, Mirjam C. G. N. van den Hout, Steven van Hove, Lennart F. Johansson, Jan D. H. Jongbloed, Rick Kamps, Christel E. M. Kockx, Bart de KoningMarjolein Kriek, Ronald Lekanne Dit Deprez, Hans Lunstroo, Marcel Mannens, Olaf R. Mook, Marcel Nelen, Corrette Ploem, Marco Rijnen, Jasper J. Saris, Richard Sinke, Erik Sistermans, Marjon van Slegtenhorst, Frank Sleutels, Nienke van der Stoep, Marianne van Tienhoven, Martijn Vermaat, Maartje Vogel, Quinten Waisfisz, Janneke Marjan Weiss, Arthur van den Wijngaard, Wilbert van Workum, Helger Ijntema, Bert van der Zwaag, Wilfred F. J. van IJcken, Johan den Dunnen, Joris A. Veltman, Raoul Hennekam, Edwin Cuppen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 languageEnglish
Pages (from-to)1142-1150
JournalEuropean Journal of Human Genetics
Issue number9
Publication statusPublished - Sept 2015

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