title: Next-generation sequencing-based genome diagnostics across clinical genetics centers: implementation choices and their effects.
abstract: 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.
authors: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Terry
authors: T
authors: Vrijenhoek
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Ken
authors: K
authors: Kraaijeveld
authors: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Martin
authors: M
authors: Elferink
authors: Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: Joep
authors: J
authors: de Ligt
authors: Department of Public Health, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors: Elcke
authors: E
authors: Kranendonk
authors: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Gijs
authors: G
authors: Santen
authors: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Isaac J
authors: IJ
authors: Nijman
authors: BaseClear, Leiden, The Netherlands.
authors: Derek
authors: D
authors: Butler
authors: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Godelieve
authors: G
authors: Claes
authors: BaseClear, Leiden, The Netherlands.
authors: Adalberto
authors: A
authors: Costessi
authors: Agilent Technologies Netherlands B.V., Amstelveen, The Netherlands.
authors: Wim
authors: W
authors: Dorlijn
authors: Agilent Technologies Netherlands B.V., Amstelveen, The Netherlands.
authors: Winfried
authors: W
authors: van Eyndhoven
authors: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Dicky J J
authors: DJ
authors: Halley
authors: Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Mirjam C G N
authors: MC
authors: van den Hout
authors: Illumina Inc., Eindhoven, The Netherlands.
authors: Steven
authors: S
authors: van Hove
authors: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Lennart F
authors: LF
authors: Johansson
authors: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Jan D H
authors: JD
authors: Jongbloed
authors: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Rick
authors: R
authors: Kamps
authors: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Christel E M
authors: CE
authors: Kockx
authors: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Bart
authors: B
authors: de Koning
authors: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Marjolein
authors: M
authors: Kriek
authors: Department of Human Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors: Ronald
authors: R
authors: Lekanne Dit Deprez
authors: Roche Nimblegen Inc., Madison, WI, USA.
authors: Hans
authors: H
authors: Lunstroo
authors: Department of Human Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors: Marcel
authors: M
authors: Mannens
authors: Department of Human Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors: Olaf R
authors: OR
authors: Mook
authors: Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: Marcel
authors: M
authors: Nelen
authors: Department of Public Health, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors: Corrette
authors: C
authors: Ploem
authors: Life Technologies Europe B.V., Bleiswijk, The Netherlands.
authors: Marco
authors: M
authors: Rijnen
authors: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Jasper J
authors: 000000019232267X
authors: JJ
authors: Saris
authors: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Richard
authors: R
authors: Sinke
authors: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors: Erik
authors: E
authors: Sistermans
authors: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Marjon
authors: M
authors: van Slegtenhorst
authors: Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Frank
authors: F
authors: Sleutels
authors: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Nienke
authors: N
authors: van der Stoep
authors: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Marianne
authors: M
authors: van Tienhoven
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Martijn
authors: 0000000265541380
authors: M
authors: Vermaat
authors: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Maartje
authors: M
authors: Vogel
authors: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors: Quinten
authors: Q
authors: Waisfisz
authors: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors: Janneke
authors: J
authors: Marjan Weiss
authors: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors: Arthur
authors: A
authors: van den Wijngaard
authors: ServiceXS, Leiden, The Netherlands.
authors: Wilbert
authors: W
authors: van Workum
authors: Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: Helger
authors: H
authors: Ijntema
authors: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Bert
authors: B
authors: van der Zwaag
authors: Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Wilfred F J
authors: 0000000204218301
authors: WF
authors: van IJcken
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Johan
authors: 0000000263041710
authors: J
authors: den Dunnen
authors: Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: Joris A
authors: JA
authors: Veltman
authors: 1] Department of Human Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands [2] Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors: Raoul
authors: R
authors: Hennekam
authors: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Edwin
authors: E
authors: Cuppen
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics; D024722:Cardiac Myosins / Q000235:genetics; D009202:Cardiomyopathies / Q000175:diagnosis* / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D059472:Exome; D015870:Gene Expression; D005820:Genetic Testing / Q000592:standards*; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000295:instrumentation / Q000379:methods / Q000592:standards*; D006801:Humans; D007258:Informed Consent / Q000331:legislation & jurisprudence; D059021:Laboratory Proficiency Testing / Q000706:statistics & numerical data; D020930:MAP Kinase Kinase Kinases / Q000235:genetics; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics; D009426:Netherlands; D017346:Protein Serine-Threonine Kinases; D000099211:Phospholamban; D000099163:Myosin Binding Protein C
chemical_list: D002135:Calcium-Binding Proteins; D024722:Cardiac Myosins; D002352:Carrier Proteins; D020930:MAP Kinase Kinase Kinases; D018995:Myosin Heavy Chains; D017346:Protein Serine-Threonine Kinases; D000099211:Phospholamban; D000099163:Myosin Binding Protein C; C501641:MYH7 protein, human; C481078:TNNI3K protein, human
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