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

Vrijenhoek T, Kraaijeveld K, Elferink M, de Ligt J, Kranendonk E, Santen G, Nijman IJ, Butler D, Claes G, Costessi A, Dorlijn W, van Eyndhoven W, Halley DJ, van den Hout MC, van Hove S, Johansson LF, Jongbloed JD, Kamps R, Kockx CE, de Koning B, Kriek M, Lekanne Dit Deprez R, Lunstroo H, Mannens M, Mook OR, Nelen M, Ploem C, Rijnen M, Saris JJ, Sinke R, Sistermans E, van Slegtenhorst M, Sleutels F, van der Stoep N, van Tienhoven M, Vermaat M, Vogel M, Waisfisz Q, Marjan Weiss J, van den Wijngaard A, van Workum W, Ijntema H, van der Zwaag B, van IJcken WF, den Dunnen J, Veltman JA, Hennekam R, Cuppen E - Eur. J. Hum. Genet. (2015)

Bottom Line: Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient.We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results.Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus

Overview of the diagnostic process. The diagnostic process of nine samples with cardiomyopathies varied substantially among CGCs. Each colored line represents the process the nine patients went through in a particular CGC. The ‘metro stops' represent choices that the various CGCs made in the intake, sequencing, analysis and reporting phase.
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fig1: Overview of the diagnostic process. The diagnostic process of nine samples with cardiomyopathies varied substantially among CGCs. Each colored line represents the process the nine patients went through in a particular CGC. The ‘metro stops' represent choices that the various CGCs made in the intake, sequencing, analysis and reporting phase.

Mentions: The centers were completely autonomous in their choices for sample intake, sequencing approach, data analysis and clinical interpretation, which resulted in a wide routing spectrum for the patient samples across centers (Figure 1). Critical choices in each phase of the diagnostic process – intake, sequencing, data analysis and interpretation, and reporting − determined the route in each center.


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

Vrijenhoek T, Kraaijeveld K, Elferink M, de Ligt J, Kranendonk E, Santen G, Nijman IJ, Butler D, Claes G, Costessi A, Dorlijn W, van Eyndhoven W, Halley DJ, van den Hout MC, van Hove S, Johansson LF, Jongbloed JD, Kamps R, Kockx CE, de Koning B, Kriek M, Lekanne Dit Deprez R, Lunstroo H, Mannens M, Mook OR, Nelen M, Ploem C, Rijnen M, Saris JJ, Sinke R, Sistermans E, van Slegtenhorst M, Sleutels F, van der Stoep N, van Tienhoven M, Vermaat M, Vogel M, Waisfisz Q, Marjan Weiss J, van den Wijngaard A, van Workum W, Ijntema H, van der Zwaag B, van IJcken WF, den Dunnen J, Veltman JA, Hennekam R, Cuppen E - Eur. J. Hum. Genet. (2015)

Overview of the diagnostic process. The diagnostic process of nine samples with cardiomyopathies varied substantially among CGCs. Each colored line represents the process the nine patients went through in a particular CGC. The ‘metro stops' represent choices that the various CGCs made in the intake, sequencing, analysis and reporting phase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4538197&req=5

fig1: Overview of the diagnostic process. The diagnostic process of nine samples with cardiomyopathies varied substantially among CGCs. Each colored line represents the process the nine patients went through in a particular CGC. The ‘metro stops' represent choices that the various CGCs made in the intake, sequencing, analysis and reporting phase.
Mentions: The centers were completely autonomous in their choices for sample intake, sequencing approach, data analysis and clinical interpretation, which resulted in a wide routing spectrum for the patient samples across centers (Figure 1). Critical choices in each phase of the diagnostic process – intake, sequencing, data analysis and interpretation, and reporting − determined the route in each center.

Bottom Line: Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient.We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results.Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, Centre for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus