Genome Medicine (Jun 2022)

Reanalysis of exome negative patients with rare disease: a pragmatic workflow for diagnostic applications

  • Gaby Schobers,
  • Jolanda H. Schieving,
  • Helger G. Yntema,
  • Maartje Pennings,
  • Rolph Pfundt,
  • Ronny Derks,
  • Tom Hofste,
  • Ilse de Wijs,
  • Nienke Wieskamp,
  • Simone van den Heuvel,
  • Jordi Corominas Galbany,
  • Christian Gilissen,
  • Marcel Nelen,
  • Han G. Brunner,
  • Tjitske Kleefstra,
  • Erik-Jan Kamsteeg,
  • Michèl A. A. P. Willemsen,
  • Lisenka E. L. M. Vissers

DOI
https://doi.org/10.1186/s13073-022-01069-z
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 10

Abstract

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Abstract Background Approximately two third of patients with a rare genetic disease remain undiagnosed after exome sequencing (ES). As part of our post-test counseling procedures, patients without a conclusive diagnosis are advised to recontact their referring clinician to discuss new diagnostic opportunities in due time. We performed a systematic study of genetically undiagnosed patients 5 years after their initial negative ES report to determine the efficiency of diverse reanalysis strategies. Methods We revisited a cohort of 150 pediatric neurology patients originally enrolled at Radboud University Medical Center, of whom 103 initially remained genetically undiagnosed. We monitored uptake of physician-initiated routine clinical and/or genetic re-evaluation (ad hoc re-evaluation) and performed systematic reanalysis, including ES-based resequencing, of all genetically undiagnosed patients (systematic re-evaluation). Results Ad hoc re-evaluation was initiated for 45 of 103 patients and yielded 18 diagnoses (including 1 non-genetic). Subsequent systematic re-evaluation identified another 14 diagnoses, increasing the diagnostic yield in our cohort from 31% (47/150) to 53% (79/150). New genetic diagnoses were established by reclassification of previously identified variants (10%, 3/31), reanalysis with enhanced bioinformatic pipelines (19%, 6/31), improved coverage after resequencing (29%, 9/31), and new disease-gene associations (42%, 13/31). Crucially, our systematic study also showed that 11 of the 14 further conclusive genetic diagnoses were made in patients without a genetic diagnosis that did not recontact their referring clinician. Conclusions We find that upon re-evaluation of undiagnosed patients, both reanalysis of existing ES data as well as resequencing strategies are needed to identify additional genetic diagnoses. Importantly, not all patients are routinely re-evaluated in clinical care, prolonging their diagnostic trajectory, unless systematic reanalysis is facilitated. We have translated our observations into considerations for systematic and ad hoc reanalysis in routine genetic care.

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