Next generation sequencing for clinical diagnostics: Five year experience of an academic laboratory

Paige Hartman, Kenny B Beckman, Kevin A Silverstein, Sophia L Yohe, Matthew Schomaker, Christine Henzler, Getiria Onsongo, Ham Ching Lam, Sarah A Munro, Jerry Daniel, Bradley Billstein, Archana Deshpande, Adam Hauge, Pawel A Mroz, Whiwon Lee, Jennifer Holle, Katie Wiens, Kylene Karnuth, Teresa Kemmer, Michaela LearyStephen Michel, Laurie Pohlman, Venugopal Thayanithy, Andrew C Nelson, Matthew Bower, Bharat Thyagarajan

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Clinical laboratories have adopted next generation sequencing (NGS) as a gold standard for the diagnosis of hereditary disorders because of its analytic accuracy, high throughput, and potential for cost-effectiveness. We describe the implementation of a single broad-based NGS sequencing assay to meet the genetic testing needs at the University of Minnesota. A single hybrid capture library preparation was used for each test ordered, data was informatically blinded to clinically-ordered genes, and identified variants were reviewed and classified by genetic counselors and molecular pathologists. We performed 2509 sequencing tests from August 2012 till December 2017. The diagnostic yield has remained steady at 25%, but the number of variants of uncertain significance (VUS) included in a patient report decreased over time with 50% of the patient reports including at least one VUS in 2012 and only 22% of the patient reports reporting a VUS in 2017 (p =.002). Among the various clinical specialties, the diagnostic yield was highest in dermatology (60% diagnostic yield) and ophthalmology (42% diagnostic yield) while the diagnostic yield was lowest in gastrointestinal diseases and pulmonary diseases (10% detection yield in both specialties). Deletion/duplication analysis was also implemented in a subset of panels ordered, with 9% of samples having a diagnostic finding using the deletion/duplication analysis. We have demonstrated the feasibility of this broad-based NGS platform to meet the needs of our academic institution by aggregating a sufficient sample volume from many individually rare tests and providing a flexible ordering for custom, patient-specific panels.

Original languageEnglish (US)
Article number100464
JournalMolecular Genetics and Metabolism Reports
StatePublished - Jun 2019

Bibliographical note

Funding Information:
This work was supported in part by the Bob Allison Ataxia Research Center and the Institute for Translational Neuroscience at the University of Minnesota.

Funding Information:
These data represent the experience at a single institution and thus reflect the specific patient populations referred to our institution and the practice and ordering behaviors of specific clinicians and departments. While the conclusions about the diagnostic yield of specific panels may not be generalizable across other institutions and patient populations, we describe a cost effective approach for implementation of NGS based sequencing that can be adapted to meet the sequencing needs across diverse institutions. Initial clinical implementation of NGS testing was possible due the strong interest in utilizing NGS based testing from neurologists at our institution and formed the foundation for obtaining initial funding from the Institute for Translational Neuroscience (ITN) to develop clinical NGS infrastructure that could support future translational research. We utilized these funds to develop a broad based NGS assay that fully met the needs of the neurologists and ITN but also allowed us to expand our test menu beyond one clinical specialty. The ability to offer a NGS based test to a broad range of specialties was a critical step in convincing hospital administrators to invest in further development of clinical NGS infrastructure. Since a large number of send-out genetic tests could now be performed in-house hospital administrators could see tangible benefits from both reduction in costs of send-out testing and additional revenue from the genetic testing that was being performed in-house. In addition, this has provided our academic institution to provide a unique and local genetic testing service not otherwise available in our market.


  • Copy number variation
  • Diagnostic yield
  • Molecular diagnostics
  • Next generation sequencing
  • Panel testing
  • Variants of uncertain significance


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