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Clinical and technical assessment of MedExome vs. NGS panels in patients with suspected genetic disorders in Southwestern Ontario

Journal of Human Genetics volume 66, pages 451–464 (2021)Cite this article

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Abstract

The adaptation of a broad genomic sequencing approach in the clinical setting has been accompanied by considerations regarding the clinical utility, technical performance, and diagnostic yield compared to targeted genetic approaches. We have developed MedExome, an integrated framework for sequencing, variant calling (SNVs, Indels, and CNVs), and clinical assessment of ~4600 medically relevant genes. We compared the technical performance of MedExome with the whole-exome and targeted gene-panel sequencing, assessed the reasons for discordance, and evaluated the added clinical yield of MedExome in a cohort of unresolved subjects suspected of genetic disease. Our analysis showed that despite a higher average read depth in panels (3058 vs. 855), MedExome yielded full coverage of the enriched regions (>20X) and 99% variant concordance rate with panels. The discordance rate was associated with low-complexity regions, high-GC content, and low allele fractions, observed in both platforms. MedExome yielded full sensitivity in detecting clinically actionable variants, and the assessment of 138 patients with suspected genetic conditions resulted in 76 clinical reports (31 full [22.1%], 3 partial, and 42 uncertain/possible molecular diagnoses). MedExome sequencing has comparable performance in variant detection to gene panels. Added diagnostic yield justifies expanded implementation of broad genomic approaches in unresolved patients; however, cost-benefit and health systems impact warrants assessment.

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Acknowledgements

The authors would like to thank the staff and physicians at the medical genetics clinic at London Health Science Centre, ON, Canada for recruiting the patients into the study, as well as the patients and their families for their support.

Funding

This study was supported by the London Health Sciences Centre Pathology and Laboratory Medicine Research and Innovation Fund.

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Authors and Affiliations

  1. Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada

    Erfan Aref-Eshghi, Jennifer Kerkhof, Deana Alexis Carere, Michael Volodarsky, Pratibha Bhai, Hanxin Lin & Bekim Sadikovic

  2. Medical Genetics Program of Southwestern Ontario, Victoria Hospital, London Health Sciences Centre, London, ON, Canada

    Samantha Colaiacovo, Maha Saleh, Michelle Caudle, Natalya Karp, Chitra Prasad, Tugce Balci & Victoria Mok Siu

  3. Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada

    Hanxin Lin & Bekim Sadikovic

  4. Department of Pediatric Neurology, Children’s Hospital, London Health Science Centre, London, ON, Canada

    Craig Campbell

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  1. Erfan Aref-Eshghi
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Contributions

EA-E: bioinformatics, variant assessment, and manuscript writing; JK: Sample processing and sequencing; DAC, MV, HL, and TB: variant assessment; PB: manuscript writing; SC, MS, MC, NK, CP, TB, CC, and VMS: patient recruitment and clinical assessment; BS: principal investigator and supervision of the research team.

Corresponding author

Correspondence to Bekim Sadikovic.

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The authors declare that they have no conflict of interest.

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The study protocol has been approved by the Western University Research Ethics Board (REB 108261).

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Aref-Eshghi, E., Kerkhof, J., Carere, D.A. et al. Clinical and technical assessment of MedExome vs. NGS panels in patients with suspected genetic disorders in Southwestern Ontario. J Hum Genet 66, 451–464 (2021). https://doi.org/10.1038/s10038-020-00860-3

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