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Mobile element insertion detection in 89,874 clinical exomes
Rebecca I Torene1, Kevin Galens2, Shuxi Liu2
1GeneDx, Gaithersburg, MD, USA. rtorene@genedx.com.
Summary
A new method for detecting mobile element insertions (MEIs) using exome sequencing (ES) improves rare genetic disease diagnosis. This approach increases diagnostic yield by 0.15%, identifying variants missed by other assays.
Area of Science:
- Genomics
- Human Genetics
- Molecular Diagnostics
Background:
- Exome sequencing (ES) is vital for diagnosing rare genetic diseases.
- Pathogenic sequence variants can be missed by standard ES.
- Mobile element insertions (MEIs) are a known cause of genetic disease but are difficult to detect with current sequencing methods.
Purpose of the Study:
- To develop and apply a novel method for detecting MEIs from exome sequencing data.
- To assess the diagnostic utility of MEI detection in a clinical setting.
- To determine the impact of MEI detection on the overall diagnostic yield for rare genetic diseases.
Main Methods:
- A novel MEI detection method was developed and prospectively applied to clinical ES samples.
- Positive MEI findings were confirmed using an orthogonal method.
- The study analyzed 89,874 samples from 38,871 cases.
Main Results:
- Diagnostic MEIs were identified in 0.03% of all cases and 0.15% of cases with a molecular diagnosis.
- One diagnostic MEI represented a novel founder event.
- Most patients with pathogenic MEIs had prior genetic testing, including some with negative DNA sequencing results for the diagnostic gene.
Conclusions:
- MEI detection from ES is a valuable diagnostic tool for rare genetic diseases.
- This method identifies molecular findings that may be missed by other sequencing assays.
- MEI detection increases the diagnostic yield of exome sequencing by 0.15%.
