The RenaCARE Study: Updating Genetic Testing Results in Response to New Gene-Disease Association and Variant Upgrade

Background: Genetic testing enables physicians to identify underlying molecular diagnoses and tailor treatment to optimize patient care. For chronic kidney disease (CKD), positive genetic results have been shown to impact patient management in up to 89% of cases. Genetic test results may change over time due to variant reclassification or new gene-disease associations. In such cases the testing laboratory may issue an updated report to notify physicians of new findings. Methods: The Renasight Clinical Application, Review, and Evaluation (RenaCARE) study was conducted to evaluate the diagnostic and clinical utility of genetic test results in patients with CKD. 1624 patients (median: 55 years; range 18-96) were enrolled. Genetic testing was performed using a CKD-focused 385-gene panel (the Renasight™ test, Natera, Inc) on patient samples. Genetic testing results were compared at one year post-test with those at the original report date to determine the number and nature of cases with updated genetic test results. (e.g. establishment of new gene-disease associations, or upgrade of variant/s classified as a variant of uncertain significance (VUS) to likely pathogenic/ pathogenic variant. Results: 338 study patients originally had positive results in 54 genes. 18 additional cases (n=356) had a new positive result at one year; these involved five genes: COL4A3 (n=1), IFT140 (n=9), PKD1 (n=6), PKD2 (n=1), and RRM2B (n=1). Variants in IFT140 were previously only associated with an autosomal recessive ciliopathy; new evidence associating single IFT140 loss of function variants with ADPKD resulted in a result change from “carrier” to “positive” for all 9 patients. For the other 9 patients, incorporation of new data resulted in upgrades from VUS to pathogenic or likely pathogenic classification. These findings represent a 1.1% increase in positive rate and comprise 5.1% of positive study results at one year. Conclusion: This study demonstrated how new evidence in gene-disease association and variant classification can impact patients who underwent genetic testing with a broad CKD-focused panel beyond their initial result. These findings are representative of the evolving findings in CKD genetic testing and can increase the diagnostic/clinical utility of the test.