Leveraging genomic biobanks to enhance genetic testing outcomes for kidney disease

Chronic kidney disease (CKD) affects 9.1% globally and is associated with significant morbidity and mortality. While up to 10% of CKD cases yield a genetic diagnosis with hundreds of implicated genes included in some genetic test panels, the results often yield many variants of uncertain significance (VUS). We sought to report genetic testing outcomes in a cohort of 228 patients who received genetic testing for kidney disease phenotypes from 2020-2023 at Geisinger, a regional health system in Pennsylvania. We report on diagnostic yield, management changes, and VUS resolution. A multidisciplinary approach was undertaken to resolve VUS. All cases were reviewed with ≥2 nephrologists and a genetic counselor. VUS with potential clinical relevance, based on known gene-disease associations, were investigated through comprehensive review of genetic databases, consultations with ClinGen variant classification expert panels and genetic testing laboratories, functional assays for Alport syndrome VUS, and case-control analyses using data from a large exome sequencing study (Geisinger MyCode DiscovEHR) linked to electronic health records. Out of 228 patients in this study, 34% had a positive (pathogenic [P] or likely pathogenic [LP]) result, 52% had a VUS result only, and 14% had a negative result. Overall, the mean number of VUS reported was 4.0 (SD 3.1) per patient. After multidisciplinary review of variants, 42 potentially relevant VUS were re-examined by our team. Utilizing MyCode biobank data with available functional analysis we were able to recommend upgrading 10 VUS to LP, which was consistent with genetic laboratories’ decisions to upgrade 5 variants over the course of the study. In addition, our data supported downgrading 10 VUS to likely benign. Genetic testing resulted in direct management changes for 69 (88.5%) positive patients and provided a better understanding of patients’ diagnoses. Genetic testing also had familial implications in 86 (37.7%) of patients. In conclusion, a multidisciplinary approach using biobank data integrating exome sequencing and electronic health records, functional testing, and collaboration with genetic testing laboratories can support the reclassification of clinically significant VUS, potentially maximizing the clinical utility of genetic testing with important diagnostic, prognostic, and management implications.