Table 3.

Overview of the primary challenges and recommendations to harmonise reporting of the NGS-based diagnostic tests for rare neurological disorders.

Quality measure	Challenges observed during the scheme provision	Recommendations for harmonisation
Information on the details of the test performed	A proportion of the laboratories failed to clearly present the sequencing platform, or the capture reagent used to enrich the sequencing targets. Information on the bioinformatic software used to process data is not reported by some laboratories.	The sequencing platform and the capture kit along with the version should be provided in the report. If an in-house capture is used, the laboratory should enable the access to the list of targeted regions in the genome. The essential elements of bioinformatic pipeline should also be included in the report. Especially, the information pertaining to detection of non-SNV variation should be provided, for example – details on detection of copy number variation or repeat expansions.
Provision of quality parameters of the sequencing experiment	The NGS experimental quality parameters are not reported consistently across laboratories.	Report the estimate of depth of coverage and the percentage of target regions covered at a defined depth threshold for variant calling
Definition of the reportable range	The genes and the variation spectrum assessed is inconsistently reported. There are significant discrepancies in the sets of genes that laboratories consider in the interpretation process. An example is the failure to include recently reported genes in the reportable range.	The laboratories should clearly report the genes assessed in their analysis and indicate the spectrum of genetic variation assessed in the test. The sets of genes should be regularly updated. Alternatively, regularly curated and versioned virtual panels may be used (for example, the PanelApp resource).
Adherence to variant interpretation standards	Variable use and reporting of pre-defined variant interpretation standards is observed.	The laboratories should provide the information on the variant interpretation standard use. If an in-house variant classification system was used, it should be accessible upon request.
Reporting evidence to support variant pathogenicity assertion	Several laboratories do not clearly present the lines of evidence that support the final variant classification	The lines of evidence should be clearly and distinctly presented in the variant interpretation. If the ACMG guidelines are used, reporting of evidence codes and the assigned evidence strengths is strongly advised. The laboratories should include information on the specifications of the variant evidence or gene-specific classification system modifications, if they are used.
Clinical interpretation	The relevance and association of the reported finding to the clinical referral is not presented consistently	The laboratories should clearly indicate the relevance of primary findings in terms of their association with referral indication and report if a finding is consistent with the referral clinical presentation.
Clinical guidance	There is a variability in provision of clinical commentary and guidance in the reports	The necessity of genetic counselling should be consistently indicated on the reports. Indication of the mode of inheritance should be indicated for primary findings, and if possible, an assessment of recurrence risk. In case of significant limitations of NGS approaches in detecting a particular disorder (for example, when reporting a negative result for a referral primarily associated with repeat expansions), this limitation should be highlighted in among the primary conclusions of the test. If further genetic testing is needed to clarify the diagnostic relevance of the finding (for example, a segregation analysis), this should also be advised in the clinical report.
Report format	Several laboratories provide lengthy reports that require significant effort to extract the relevant information.	Despite the complexity of NGS-based genetic testing, it is recommended to state the principal outcomes and conclusions of the testing concisely on the first page of the report