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

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 DunnenJeroen F J Laros, Morris A Swertz, Marielle E van Gijn

OnderzoeksoutputAcademicpeer review

26 Citaten (Scopus)
188 Downloads (Pure)


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.

Originele taal-2English
Pagina's (van-tot)2230-2238
Aantal pagina's9
TijdschriftHuman Mutation
Nummer van het tijdschrift12
Vroegere onlinedatum21-aug.-2019
StatusPublished - dec.-2019

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