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

Authors:
Ivo F A C Fokkema Kasper J van der Velde Mariska K Slofstra Claudia A L Ruivenkamp Maartje J Vogel Rolph Pfundt Marinus J Blok Ronald H Lekanne Deprez Quinten Waisfisz Kristin M Abbott Richard J Sinke Rubayte Rahman Isaäc J Nijman Bart de Koning Gert Thijs Nienke Wieskamp Ruben J G Moritz Bart Charbon Jasper J Saris Johan T den Dunnen Jeroen F J Laros Morris A Swertz Marielle E van Gijn

Hum Mutat 2019 12 3;40(12):2230-2238. Epub 2019 Sep 3.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

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.

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http://dx.doi.org/10.1002/humu.23896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900155PMC
December 2019

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