We report the results of a comprehensive copy number variant (CNV) reanalysis of 9171
exome sequencing datasets from 5757 families affected by a rare disease (RD). The
data reanalysed was extremely heterogeneous, having been generated using 28 different
enrichment kits by 42 different research groups across Europe partnering in the Solve-RD
project. Each research group had previously undertaken their own analysis of the data
but failed to identify disease-causing variants. We applied three CNV calling algorithms
to maximise sensitivity, and rare CNVs overlapping genes of interest, provided by
four partner European Reference Networks, were taken forward for interpretation by
clinical experts. This reanalysis has resulted in a molecular diagnosis being provided
to 51 families in this sample, with ClinCNV performing the best of the three algorithms.
We also identified partially explanatory pathogenic CNVs in a further 34 individuals.
This work illustrates the value of reanalysing ES cold cases for CNVs.
