Exomes or genomes: Does it matter?

Abstract

Purpose: Whole genome sequencing (WGS) can improve diagnostic rates over whole exome sequencing (WES) by accessing additional genomic variation, however the increased yield remains uncertain. We aimed to assess this diagnostic difference by undertaking WGS in families with Mendelian disorders that remained undiagnosed afterWES. Methods: WGS was performed in a cohort of 100 individuals from 38WES-negative families with various Mendelian disorders. In addition to small nuclear genomic variation, we sought structural and mitochondrial variation, complemented by homozygosity mapping to attain further diagnoses. Retrospective WES reassessment was performed to determine whether variants were diagnosable by contemporary WES or were unique to WGS analysis. Results: Overall our WGS-based pipeline identified diagnoses in over 30% of families in the cohort. Missed WES diagnoses were due to reduced coverage, older bioinformatics pipelines, inadequate literature evidence, or analyst interpretation. Preliminary retrospective investigation of WES data considering current bioinformatics pipelines and knowledge showed 20% of families could have attained a diagnosis. Thus, WGS resulted in additional diagnostic potential of 10%, which may increase with the bulk of structural and mitochondrial analysis pending. We present clinically instructive cases of unexpected diagnoses highlighting the advantage of unbiased genomic testing approaches. Conclusion: WGS increased the diagnostic yield in WES negative families; however, a majority of diagnoses could have been identified using contemporary WES reanalysis. Genomic testing remains optimal for diagnosing Mendelian disorders, particularly when there is uncertainty in clinical diagnosis and will require ongoing laboratory-clinical collaboration and periodic data reanalysis to continue to improve the yield.L6298900462019-11-22 <br />