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Eur J Hum Genet. 2015 Sep;23(9):1142-50. doi: 10.1038/ejhg.2014.279. Epub 2015 Jan 28.

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

Author information

1
Department of Medical Genetics, Centre for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
2
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
3
Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
4
Department of Public Health, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
5
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
6
BaseClear, Leiden, The Netherlands.
7
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
8
Agilent Technologies Netherlands B.V., Amstelveen, The Netherlands.
9
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
10
Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands.
11
Illumina Inc., Eindhoven, The Netherlands.
12
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
13
Department of Human Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
14
Roche Nimblegen Inc., Madison, WI, USA.
15
Life Technologies Europe B.V., Bleiswijk, The Netherlands.
16
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
17
ServiceXS, Leiden, The Netherlands.
18
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.

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.

PMID:
25626705
PMCID:
PMC4538197
DOI:
10.1038/ejhg.2014.279
[Indexed for MEDLINE]
Free PMC Article

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