Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients with multiple congenital abnormalities and/or intellectual disability carrying de novo SVs are frequently unknown. We applied a combination of systematic experimental and bioinformatic methods to improve the molecular diagnosis of 39 patients with de novo SVs and an inconclusive diagnosis after regular genetic testing. In seven of these cases (18%) whole genome sequencing analysis detected disease-relevant complexities of the SVs missed in routine microarray-based analyses. We developed a computational tool to predict effects on genes directly affected by SVs and on genes indirectly affected due to changes in chromatin organization and impact on regulatory mechanisms. By combining these functional predictions with extensive phenotype information, candidate driver genes were identified in 16/39 (41%) patients. In eight cases evidence was found for involvement of multiple candidate drivers contributing to different parts of the phenotypes. Subsequently, we applied this computational method to a collection of 382 patients with previously detected and classified de novo SVs and identified candidate driver genes in 210 cases (54%), including 32 cases whose SVs were previously not classified as pathogenic. Pathogenic positional effects were predicted in 25% of the cases with balanced SVs and in 8% of the cases with copy number variants. These results show that driver gene prioritization based on integrative analysis of WGS data with phenotype association and chromatin organization datasets can improve the molecular diagnosis of patients with de novo SVs.

Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants