Reclassification of Variants Following Renal Genetics Testing: Uncommon Yet Impactful for Diagnosis and Management

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IntroductionGenetic testing is increasingly utilized in nephrology practice while limited real-world data exist on variant reclassification following renal genetics testing. MethodsA cohort of patients at the Cleveland Clinic Renal Genetics Clinic who underwent genetic testing through clinical laboratories was assessed with clinical and laboratory data analyzed. ResultsBetween January 2019 and June 2023, 425 new patients with variable kidney disorders from 413 pedigrees completed genetic testing(s) through 10 clinical labs, including 255 (60%) females with median (25th, 75th percentiles) age of 36 (22-54) years. Multi-gene panel was the most frequently used modality followed by single-gene testing, exome sequencing, chromosomal microarray, and genome sequencing. At initial reports, 52% patients had ≥1 variant of uncertain significance (VUS) with or without concurrent pathogenic variant(s). Twenty amendments were issued across 19 pedigrees involving 19 variants in 17 genes. The overall variant reclassification rate was 5%, with 63% being upgrades and 32% downgrades. 79% of reclassified variants were initially reported as VUSs. The median time to amendments from initial reports was 8.4 (4-27) months. Following the variant reclassifications, 60% of patients received a new diagnosis or a change in diagnosis. Among these, 67% of patients received significant changes in clinical management. ConclusionVariant reclassification following genetic testing is infrequent yet important for diagnosis and management of patients with suspected genetic kidney disease. Majority of variant reclassifications involve VUSs and are upgrades in clinically issued amended reports. Further studies are needed to investigate the predictors of such events.