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

K Elsink, MMH Huibers, Iris Hollink, LT van der Veken, RF Ernst, A Simons, E Zonneveld-Huijssoon, AH van der Hout, KM Abbott, A Hoischen, M Pieterse, TWJ Kuijpers, JM van Montfrans, ME van Gijn

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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 (PSTPIP1 and BTK). 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 - 2021

Bibliographical note

Funding Information:
Funding The external quality assessment (EQA) is part of the Genetics First: next-generation sequencing for cost-effective PID diagnostics project. This project is funded by ZonMw (grant No. 846002001).

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to European Society of Human Genetics.

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