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. 2019 Dec;40(12):2230-2238.
doi: 10.1002/humu.23896. Epub 2019 Sep 3.

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

Ivo F A C Fokkema  1 , Kasper J van der Velde  2 , Mariska K Slofstra  2 , Claudia A L Ruivenkamp  3 , Maartje J Vogel  4 , Rolph Pfundt  5 , Marinus J Blok  6 , Ronald H Lekanne Deprez  7 , Quinten Waisfisz  8 , Kristin M Abbott  9 , Richard J Sinke  9 , Rubayte Rahman  10 , Isaäc J Nijman  11 , Bart de Koning  6 , Gert Thijs  12 , Nienke Wieskamp  13 , Ruben J G Moritz  4 , Bart Charbon  2 , Jasper J Saris  14 , Johan T den Dunnen  1 , Jeroen F J Laros  1   3 , Morris A Swertz  2 , Marielle E van Gijn  9   11
Affiliations

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

Ivo F A C Fokkema et al. Hum Mutat. 2019 Dec.

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 vs. LP/P), they were labeled "conflicting", while other nonconsensus 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.

Keywords: NGS; data sharing; database; diagnostics; whole-exome sequencing.

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Figures

Figure 1
Figure 1
Overview of VKGL variant classifications. Data is split depending on whether a variant was classified and submitted to the database by two or more labs, or by only one lab. VKGL, Vereniging Klinisch Genetische Laboratoriumdiagnostiek
Figure 2
Figure 2
Flowchart describing the steps and results of the VKGL‐InterVar discrepancy analysis. VKGL, Vereniging Klinisch Genetische Laboratoriumdiagnostiek
Figure 3
Figure 3
Total number of VKGL classifications per gene plotted against the total number of discrepancies with InterVar classifications. A linear regression shows a significant but only slight trend, explaining <9% of the observed variation
See this image and copyright information in PMC

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