A concurrent dual analysis of genomic data augments diagnoses: Experiences of 2 clinical sites in the Undiagnosed Diseases Network

Purpose: Next-generation sequencing (NGS) has revolutionized the diagnostic process for rare/ultrarare conditions. However, diagnosis rates differ between analytical pipelines. In the National Institutes of Health-Undiagnosed Diseases Network (UDN) study, each individual's NGS data are concurrently analyzed by the UDN sequencing core laboratory and the clinical sites. We examined the outcomes of this practice.

Methods: A retrospective review was performed at 2 UDN clinical sites to compare the variants and diagnoses/candidate genes identified with the dual analyses of the NGS data.

Results: In total, 95 individuals had 100 diagnoses/candidate genes. There was 59% concordance between the UDN sequencing core laboratories and the clinical sites in identifying diagnoses/candidate genes. The core laboratory provided more diagnoses, whereas the clinical sites prioritized more research variants/candidate genes (P < .001). The clinical sites solely identified 15% of the diagnoses/candidate genes. The differences between the 2 pipelines were more often because of variant prioritization disparities than variant detection.

Conclusion: The unique dual analysis of NGS data in the UDN synergistically enhances outcomes. The core laboratory provided a clinical analysis with more diagnoses and the clinical sites prioritized more research variants/candidate genes. Implementing such concurrent dual analyses in other genomic research studies and clinical settings can improve both variant detection and prioritization.