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Reactive curation of monogenic gene-disease associations in a rapid genome sequencing lab

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction:
Assessing the strength of a gene-disease association (GDA) is essential for accurate variant classification and reporting by diagnostic laboratories. The Clinical Genome Resource (ClinGen) established a framework for gene curation, the process of curating evidence and assessing the strength of a GDA, which has evolved since its initial dissemination in 2017. Several clinical laboratories have published on the integration of gene curation in their workflows and contributed to data harmonization efforts through the Gene Curation Coalition (GenCC) database. To-date, most literature on the topic describes the utility of gene curation for development of next-generation sequencing (NGS) panels, while examples of integration in genome sequencing (GS) settings are scarce. The untargeted nature of GS and broad range of potential findings necessitate a reactive approach, in which gene curation is prompted by the identification of a candidate variant in an active case and conducted as part of case analysis. We present Rady Children's Institute for Genomic Medicine's (RCIGM) early experience with reactive gene curation in a rapid genome sequencing laboratory.

 

Methods:
RCIGM formalized a workflow for conducting reactive gene curation for variants under reporting consideration in active cases undergoing any of our three GS test offerings- standard, rapid, or ultra-rapid whole genome sequencing (WGS, rWGS, or urWGS). This workflow included deferring to ClinGen classifications of Strong or Definitive without conducting internal curation. Internal gene curations were conducted for GDAs under reporting consideration for which there was no existing Strong or Definitive classification from ClinGen. A system of scoring evidence supporting the GDA was adapted from publicly available frameworks and was internally validated. Customizations to support clinical rWGS and urWGS reporting at RCIGM included simplified, integer-only scoring, capping maximum classification at Strong, and an emphasis on clinical evidence more than experimental evidence. We conducted a retrospective review of internal GDA curations completed between October 2023 and October 2024.

Results:
In our first year since formalizing an internal gene curation workflow, RCIGM conducted formal curation of 71 GDAs, prompted by 65 unique index cases. From these curations, 32 GDAs reached a classification of Strong (45.1%), 22 were classified as Moderate (40.0%), 16 GDAs were classified as Limited (22.5%), and 1 was classified as No GDA (1.4%). Candidate variants that prompted GDA curation were reported in 55 (84.6%) of the index cases. Reasons for not reporting variants after GDA curation included lack of evidence supporting the GDA, lack of phenotype overlap between GDA and proband’s reported clinical features, and proband variant type inconsistent with disease mechanism and/or spectrum of disease-associated variants.

Retrospective concordance analysis of internal GDA classifications with GenCC submissions allowed for further iteration of internal workflow to accept Strong and Definitive classifications from two GenCC laboratory submitters, in addition to ClinGen. Our adapted curation workflow and simplified scoring allows us to meet expected turn-around-times (TAT) for WGS, rWGS, and urWGS cases.

 

Conclusion:
Our lab's early experience with reactive gene curation demonstrates the feasibility and utility of incorporating gene curation in GS analysis. We plan to continue to iterate this workflow on a periodic basis to incorporate evolving gene-disease validity standards and the growing amount of shared GDA classification data in the GenCC. This study also emphasizes the importance of data sharing as genomics laboratories work to scale testing without sacrificing validity. Our reliance on GDA classifications from experts such as ClinGen allows us to focus on curations for emerging GDAs and continue to meet TAT expectations for patients undergoing GS on a rapid or ultra-rapid timelines.

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