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ClinGen Team Presents Proposed Gene-Disease Association Classification Framework

NEW YORK (GenomeWeb) – Members of a Clinical Genome Resource (ClinGen) Curation Working Group team have come up with a framework for defining authentic associations between genomic variations and disease.

"This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings," corresponding authors University of North Carolina at Chapel Hill's Jonathan Berg and Geisinger Health System's Christa Martin, and their co-authors, wrote.

As they reported in the American Journal of Human Genetics yesterday, Berg, Martin, and their colleagues established a semi-quantitative system for measuring the strength of evidence behind proposed gene-disease associations. From there, they translated support for potential associations into a more qualitative system with half a dozen classification groups ranging from "definitive" to "no reported evidence" or "conflicting evidence" based on the nature of the evidence available, if any.

The framework "classifies gene-disease relationships by the quantity and quality of the evidence supporting such a relationship," the authors explained, adding to existing association catalogs by taking a closer look at the nature and strength of the evidence for each proposed association. They noted that "[b]y including only those genes with established clinical validity, the possibility of returning ambiguous, incorrect, or uninformative results is reduced, improving the quality of interpretation of genomic data."

ClinGen collaborators established the framework through a series of meeting involving experts in clinical genetics, lab genetics, genetic counseling, and other related disciplines, the team noted. The researchers assessed nearly three-dozen gene-disease pairs with this approach, including proposed genetic contributors to bone marrow failure conditions, several types of cardiovascular disease, hereditary cancers, immune conditions, skeletal dysplasias, neuromuscular disorders, and other conditions.

In the process, the team was able to classify 31 potential gene-disease pairs. Pairs of curators independently considered these associations, reaching the same classification conclusion for all but two of the gene-disease classifications.

When classification differences did arise, the investigators went over the evidence for the associations together before bringing the evidence to clinical collaborators. The authors noted that the classification discrepancies that did occur typically placed gene-disease pairs no more than one category apart.

They noted that the newly established framework "is intentionally flexible to accommodate curation of a wide spectrum of genes and conditions by curators with varying levels of expertise."

"Within the ClinGen structure, classifications derived with this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts," the authors wrote. "Detailed guidance for utilizing this framework and access to the curation interface is available on our website."