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PgmNr 1174: Evaluating the evidence available for associating genes of unknown significance (GUS) with disease phenotypes: Review of 100 studies.

S. Tzur; N. Mizrahi; E. Feldman; R. Attali

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Affiliation: emedgene, Tel Aviv, Israel

A large portion of unresolved exome-analysis cases in rare disease research are explained by mutations in genes of unknown significance (GUS). While various types of evidence are available for most human genes (biochemical function, protein interaction, expression, animal model, pathways, and gene family), it is unclear how often these can be used as indirect supportive data for the establishment of a new gene-disease relationship.
We reviewed 100 recent publications from journals with an impact factor greater than 5 that described the discovery of new genes causing monogenic diseases. We listed the types of evidence that were available for each gene prior to the publication, and evaluated whether they could be used as indirect supporting evidence for connecting the GUS with disease phenotypes (i.e a shared pathway with another gene causing disease, or an animal knockout model resulted with similar phenotype).
We found that in 90% of the studies, biochemical function data was available for the gene under investigation. Most interestingly, in 73% of these cases the data could be used as supportive indirect evidence for the new gene-disease suggested relationship. Additional categories were also examined: Pathways (80% availability, in 76% as supportive), animal model (75% availability, in 76% as supportive), gene family (54% availability, in 50% as supportive), protein interactions (45% availability, in 70% as supportive). On average for each case, 4.3 different types of evidence were available, 2 were supportive for establishing the new gene-disease connection.
This study quantifies for the first time how prior available evidence can contribute to the identification of new gene-disease association. These data demonstrate how basic scientific evidence is highly required to establish a gene-disease relationship, and pinpoints the importance of availability of basic molecular research data as well as knockout animal projects. The implementation of these insights in rare disease research protocols would improve the ability to obtain evidence needed for a new gene-disease relationship.