Fig. 2

Relative contribution of changes in diagnostic analysis to increase diagnostic yield. Distribution of different reasons for finding new diagnoses in a pediatric neurology cohort. A Reanalysis after an update of the diagnostic pipeline was responsible for the detection of previous unrecognized copy number and (deep) intronic single nucleotide variants (CNV and SNV) and variants with too low quality criteria parameters. For instance, including interpretation of deeper intronic variants with a possible splice effect identified a variant in FOXP1, which after follow-up analysis was reclassified to likely pathogenic. Both (B) reclassification of variants based on supporting evidence from segregation analysis or metabolic investigation and (C) reanalysis after publication of new or broadened disease-gene associations allowed for the conclusive diagnoses of variants that were previously reported as possibly pathogenic, either in this study or in the initial WES analysis. D Resequencing and subsequent reanalysis identified variants that were either not targeted or not covered in the initial analysis. For instance, resequencing identified a likely pathogenic variant in NUS1 for which the position was poorly covered in the original WES data because there was no target in the original exome capture