Mobile element insertion detection in 89,874 clinical exomes.

ABSTRACT:

Purpose

Exome sequencing (ES) is increasingly used for the diagnosis of rare genetic disease. However, some pathogenic sequence variants within the exome go undetected due to the technical difficulty of identifying them. Mobile element insertions (MEIs) are a known cause of genetic disease in humans but have been historically difficult to detect via ES and similar targeted sequencing methods.

Methods

We developed and applied a novel MEI detection method prospectively to samples received for clinical ES beginning in November 2017. Positive MEI findings were confirmed by an orthogonal method and reported back to the ordering provider. In this study, we examined 89,874 samples from 38,871 cases.

Results

Diagnostic MEIs were present in 0.03% (95% binomial test confidence interval: 0.02-0.06%) of all cases and account for 0.15% (95% binomial test confidence interval: 0.08-0.25%) of cases with a molecular diagnosis. One diagnostic MEI was a novel founder event. Most patients with pathogenic MEIs had prior genetic testing, three of whom had previous negative DNA sequencing analysis of the diagnostic gene.

Conclusion

MEI detection from ES is a valuable diagnostic tool, reveals molecular findings that may be undetected by other sequencing assays, and increases diagnostic yield by 0.15%.

SUBMITTER: Torene RI 

PROVIDER: S-EPMC7200591 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature