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ClinVar-based reanalysis in the UDN cohort

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Genomic Medicine
  • Secondary Categories:
    • Genomic Medicine
Introduction:
The Undiagnosed Diseases Network (UDN) has been enrolling participants since 2015. A comprehensive evaluation with a UDN clinical site is provided for these participants. At the time of writing, 2,656 participants have been evaluated with 826 diagnoses. Approximately 69% of participants have no conclusive diagnosis and require periodic reanalysis of their data to ensure that updated knowledge can be brought to bear on their case.

Methods:
As part of the National Institute of Neurological Disorders and Stroke funded Phase 3 of the UDN, we made Mosaic available to UDN members, providing visual interfaces to review variants present in participants and their families as well as in the wider UDN cohort. To aid with candidate variant identification and evaluation, Exomiser was run on each participant case to provide lists of prioritized variants with a comprehensive set of annotation information. To support longitudinal analysis of all participants, we implemented a procedure that identifies variants that have been upgraded to a Pathogenic or Likely Pathogenic assertion in ClinVar. UDN clinical teams are notified when their participants are found to harbor newly-asserted pathogenic variants, but only when they have phenotypic relevance to the participant.

Results:
A total of 1,759 participant cases are available in Mosaic with between approximately 200,000 and 400,000 variants available for querying per case (approximately 66,200,000 variants in the UDN cohort at large). ClinVar updates have been occurring on a weekly basis since late 2023, with feedback from the UDN and the clinical sites informing changes in the reporting criteria and visual presentation to ensure the burden on clinical teams imposed by a weekly review of variants is minimized. The UDN clinical sites are responsible for between 51 and 455 participant cases and typically receive a handful of updates per week.

Conclusion:
We have provided the UDN members with a user friendly tool to assist in enabling a deep dive into variants present in participant cases and in the UDN cohort. We have implemented Exomiser to provide prioritized variant lists, which can be updated if participant phenotypes are updated. We have also established a ClinVar reanalysis procedure to highlight potential variants of significance as quickly as possible. We are continuing our collaboration with clinical teams to minimize the burden of reviewing new variants while maximizing the frequency at which relevant findings are identified.

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