| Abstract: | We present, on behalf of EuroGentest and the European Society of Human Genetics, guidelines for the evaluation and validation of next-generation sequencing (NGS) applications for the diagnosis of genetic disorders. The work was performed by a group of laboratory geneticists and bioinformaticians, and discussed with clinical geneticists, industry and patients'' representatives, and other stakeholders in the field of human genetics. The statements that were written during the elaboration of the guidelines are presented here. The background document and full guidelines are available as supplementary material. They include many examples to assist the laboratories in the implementation of NGS and accreditation of this service. The work and ideas presented by others in guidelines that have emerged elsewhere in the course of the past few years were also considered and are acknowledged in the full text. Interestingly, a few new insights that have not been cited before have emerged during the preparation of the guidelines. The most important new feature is the presentation of a ‘rating system'' for NGS-based diagnostic tests. The guidelines and statements have been applauded by the genetic diagnostic community, and thus seem to be valuable for the harmonization and quality assurance of NGS diagnostics in Europe.Next-generation sequencing (NGS) allows for the fast generation of thousands to millions of base pairs of DNA sequence of an individual patient. The relatively fast emergence and the great success of these technologies in research herald a new era in genetic diagnostics. However, the new technologies bring challenges, both at the technical level and in terms of data management, as well as for the interpretation of the results and for counseling. We believe that all these aspects warrant consideration of what the precise role of NGS in diagnostics will be, today and tomorrow. Before even embarking on acquisition of machines and skills for performing NGS in diagnostics, many issues have to be dealt with. It is in this context that we propose the guidelines. These guidelines mostly deal with NGS testing in the context of rare and mostly monogenic diseases. They mainly focus on the targeted analysis of gene panels, either through specific capture assays, or by extracting data from whole-exome sequencing. In principle, whole-genome sequencing may – and shortly will – also be used to extract similar information. In that case, the guidelines would still apply, but because whole-genome sequencing would also allow detecting other molecular features of disease, they would have to be extended accordingly.The different aspects of NGS and diagnostics were discussed during three workshops. The first took place in Leuven, 25–26 February 2013. The preliminary views were presented during the EuroGentest Scientific Meeting in Prague, 7–8 March 2013. The second was an editorial workshop in Leuven, 1–2 October 2013, where the different people involved in writing the document came together to discuss the layout of the document and prepare the first draft. The first draft was finalized prior to the third meeting in Nijmegen, 21–22 November, 2013. To the latter meeting, a larger group of stakeholders was invited. They were invited to comment on the draft, and on the statements presented therein. The comments were included in a new version, which was circulated among the editorial group, prior to publication on the EuroGentest and European Society of Human Genetics websites. Eventually, the document was presented to the Board of the European Society of Human Genetics, for endorsement. Endorsement was formally obtained on 1 July 2015.The statements that emerged during the writing of the guidelines are briefly presented in this paper. They are more extensively explained in the full version of the guidelines, available as supplementary material. The supplementary material also includes definitions, general recommendations and importantly, a number of practical examples and templates. |
