Dutch genome diagnostic laboratories accelerated and improved variant interpretation and increased accuracy by sharing data.

Fokkema IFAC1, van der Velde KJ2, Slofstra MK2, Ruivenkamp CAL3, Vogel MJ4, Pfundt R5, Blok MJ6, Lekanne Deprez RH7, Waisfisz Q8, Abbott KM9, Sinke RJ9, Rahman R10, Nijman IJ11, de Koning B12, Thijs G13, Wieskamp N14, Moritz RJG6, Charbon B15, Saris JJ16, den Dunnen JT1, Laros JFJ1,3, Swertz MA2, van Gijn ME9,17.

Author information

1: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
2: Genomics Coordination Center & Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
3: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
4: Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
5: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
6: Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands.
7: Department of Clinical Genetics, Academic Medical Center, Amsterdam UMC, Amsterdam, The Netherlands.
8: Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
9: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
10: Department of Research IT, Netherlands Cancer Institute, Amsterdam, The Netherlands.
11: Center for Molecular Medicine, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
12: Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands.
13: DGG - Genomics Software Solutions, Agilent Technologies, Leuven, Belgium.
14: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
15: Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
16: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
17: Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

Abstract

Each year diagnostic laboratories in the Netherlands profile thousands of individuals for heritable disease using next generation sequencing (NGS). This requires pathogenicity classification of millions of DNA variants on the standard 5-tier scale. To reduce time spent on data interpretation and increase data quality and reliability, the nine Dutch labs decided to publicly share their classifications. Variant classifications of nearly 100,000 unique variants were catalogued and compared in a centralized MOLGENIS database. Variants classified by more than one center were labeled as "consensus" when classifications agreed, and shared internationally with LOVD and ClinVar. When classifications opposed (LB/B versus LP/P), they were labeled "conflicting", while other non-consensus observations were labeled "no consensus". We assessed our classifications using the InterVar software to compare to ACMG 2015 guidelines, showing 99.7% overall consistency with only 0.3% discrepancies. Differences in classifications between Dutch labs or between Dutch labs and ACMG were mainly present in genes with low penetrance or for late onset disorders and highlight limitations of the current 5-tier classification system. The data sharing boosted the quality of DNA diagnostics in Dutch labs, an initiative we hope will be followed internationally. Recently, a positive match with a case from outside our consortium resulted in a more definite disease diagnosis. This article is protected by copyright. All rights reserved.