National external quality assessment for next-generation sequencing-based diagnostics of primary immunodeficiencies

Kim Elsink, Manon M. H. Huibers, Iris H. I. M. Hollink, Lars T. van der Veken, Robert F. Ernst, Annet Simons, Evelien Zonneveld-Huijssoon, Annemieke H. van der Hout, Kristin M. Abbott, Alexander Hoischen, Marc Pieterse, Taco W. Kuijpers, Joris M. van Montfrans, Marielle E. van Gijn*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    Dutch genome diagnostic centers (GDC) use next-generation sequencing (NGS)-based diagnostic applications for the diagnosis of primary immunodeficiencies (PIDs). The interpretation of genetic variants in many PIDs is complicated because of the phenotypic and genetic heterogeneity. To analyze uniformity of variant filtering, interpretation, and reporting in NGS-based diagnostics for PID, an external quality assessment was performed. Four main Dutch GDCs participated in the quality assessment. Unannotated variant call format (VCF) files of two PID patient analyses per laboratory were distributed among the four GDCs, analyzed, and interpreted (eight analyses in total). Variants that would be reported to the clinician and/or advised for further investigation were compared between the centers. A survey measuring the experiences of clinical laboratory geneticists was part of the study. Analysis of samples with confirmed diagnoses showed that all centers reported at least the variants classified as likely pathogenic (LP) or pathogenic (P) variants in all samples, except for variants in two genes (PSTPIP1andBTK). The absence of clinical information complicated correct classification of variants. In this external quality assessment, the final interpretation and conclusions of the genetic analyses were uniform among the four participating genetic centers. Clinical and immunological data provided by a medical specialist are required to be able to draw proper conclusions from genetic data.

    Original languageEnglish
    Pages (from-to)20-28
    Number of pages9
    JournalEuropean Journal of Human Genetics
    Issue number1
    Publication statusPublished - Jan-2021



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