Precision Nephrology in Practice: National Clinical Implementation Pilot of Genomic Testing for Kidney Diseases and Its Clinical Impact in Singapore

Résumé fourni par la source

Rationale & Objective Monogenic kidney diseases contribute substantially to chronic kidney disease (CKD), yet genomic testing remains underutilized in nephrology due to access, regulatory, and sociocultural barriers. We evaluated the diagnostic yield, clinical impact, and feasibility of a nephrologist-led genomic testing model for kidney diseases. Study Design Prospective, multicenter clinical implementation pilot. Setting & Participants Four tertiary hospitals in Singapore involving adult and pediatric nephrology services. Patients with suspected genetic glomerular disease or CKD of unknown etiology were enrolled. Predictors Age at onset, sex, family history, extrarenal manifestations, pre-test clinical diagnosis, and microscopic hematuria. Outcomes Primary outcomes were diagnostic yield and clinical impact. Secondary outcomes included genotype-phenotype spectrum and identifying predictors of a genetic diagnosis. Analytical Approach Targeted gene panels or whole exome sequencing were performed. Pre- and post-test counseling was provided by trained genetic nephrologists, with variant review by a multidisciplinary genomic board. Logistic regression identified predictors of a monogenic diagnosis. Results Among 216 probands, the overall diagnostic yield was 22%; Alport syndrome accounted for 77% of diagnosed cases. Genetic findings led to management changes in 81% of diagnosed individuals and in 37% of those with negative results. Cascade testing identified previously undiagnosed or misdiagnosed family members. Predictors of a monogenic diagnosis included younger age at onset, female sex, positive family history, extrarenal features, pre-test clinical diagnosis of Alport syndrome, and clinical suspicion of a genetic cause. Microscopic hematuria was strongly associated with Alport syndrome. Limitations Predominantly Chinese cohort enriched for glomerular phenotypes. Targeted sequencing may miss deep intronic, copy number, or structural variants. Long-term clinical outcomes are not yet available. Conclusions A nephrologist-led genomic care model supported by a multidisciplinary variant interpretation team is feasible with considerable diagnostic yield and clinical impact. Our findings provide a framework for implementing genomic care within nephrology practice in similar healthcare systems.

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