ABSTRACT
Introduction: Genetic testing is increasingly utilized in nephrology practice, but limited real-world data exist on variant reclassification following renal genetics testing. Methods: A cohort of patients at the Cleveland Clinic Renal Genetics Clinic who underwent genetic testing through clinical laboratories was assessed with their clinical and laboratory data analyzed. Results: Between January 2019 and June 2023, 425 new patients with variable kidney disorders from 413 pedigrees completed genetic testing through 10 clinical laboratories, including 255 (60%) females with median (25th, 75th percentiles) age of 36 (22-54) years. Multigene panel was the most frequently used modality followed by single-gene testing, exome sequencing (ES), chromosomal microarray (CMA), and genome sequencing (GS). At initial report, 52% of patients had ≥1 variants 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. Of the reclassified variants, 79% were initially reported as VUS. The median time-to-amendments from initial reports was 8.4 (4-27) months. Following the variant reclassifications, 60% of the patients received a new diagnosis or a change in diagnosis. Among these, 67% of patients received significant changes in clinical management. Conclusion: Variant reclassification following genetic testing is infrequent but important for diagnosis and management of patients with suspected genetic kidney disease. The majority of variant reclassifications involve VUS and are upgrades in clinically issued amended reports. Further studies are needed to investigate the predictors of such events.
ABSTRACT
Introduction: Genetic testing is increasingly accessible to patients with kidney diseases. Racial disparities in renal genetics evaluations have not been investigated. Methods: A cohort of patients evaluated by the Cleveland Clinic Renal Genetics Clinic (RGC) from January 2019 to March 2022 was analyzed. Results: Forty-eight Black patients, including 27 (56.3%) males, median age 34 (22-49) years and 232 White patients, including 76 (32.8%) males, median age 35 (21-53) years, were evaluated. Black patients were more likely to have end-stage kidney disease (ESKD) at the time of referral compared with White patients (23% vs. 7.3%, P = 0.004), more likely to be covered by Medicaid (46% vs. 15%, P < 0.001), and less likely to be covered by private insurance (35% vs. 66%, P < 0.001). Black patients were more likely to "no show" to scheduled appointment(s) or not submit specimens for genetic testing compared with White patients (24.1% vs. 6.7%, P = 0.0005). Genetic testing was completed in 35 Black patients. Of these, 37% had a positive result with 9 unique monogenic disorders and 1 chromosomal disorder diagnosed. Sixty-nine percent of Black patients with positive results received a new diagnosis or a change in diagnosis. Of these, 44% received a significant change in disease management. No differences in diagnostic yield and implications of management were noted between Black and White patients. Conclusion: Black patients equally benefit from renal genetics evaluation, but barriers to access exist. Steps must be taken to ensure equitable and early access for all patients. Further studies investigating specific interventions to improve access are needed.
ABSTRACT
Rationale & Objective: There has been an increasing demand for the expertise provided by a renal genetics clinic. Such programs are limited in the United States and typically operate in a genomics research setting. Here we report a 3-year, real-world, single-center renal genetics clinic experience. Study Design: Retrospective cohort. Setting & Participants: Outpatient cases referred to the renal genetics clinic of the Cleveland Clinic between January 2019 and March 2022 were reviewed. Analytical Approach: Clinical and laboratory characteristics were analyzed. All genetic testing was performed in clinical labs. Results: 309 new patients referred from 15 specialties were evaluated, including 118 males and 191 females aged 35.1 ± 20.3 years. Glomerular diseases were the leading presentation followed by cystic kidney diseases, electrolyte disorders, congenital anomalies of kidneys and urinary tract, nephrolithiasis, and tubulointerstitial kidney diseases. Dysmorphic features were noted in 27 (8.7%) patients. Genetic testing was recommended in 292 (94.5%) patients including chromosomal microarray (8.9%), single-gene tests (19.5%), multigene panels (77.3%), and exome sequencing (17.5%). 80.5% of patients received insurance coverage for genetic testing. 45% (115/256) of patients had positive results, 25% (64/256) had variants of unknown significance, and 22.3% (57/256) had negative results. 43 distinct monogenic disorders were diagnosed. Family history of kidney disease was present in 52.8% of patients and associated with positive genetic findings (OR, 2.28; 95% CI, 1.40-3.74). 69% of patients with positive results received a new diagnosis and/or a change in the diagnosis. Among these, 39.7% (31/78) of patients received a significant change in disease management. Limitations: Retrospective and single-center study. Conclusions: The renal genetics clinic plays important roles in the diagnosis and management of patients with genetic kidney diseases. Multigene panels are the most frequently used testing modality with a high diagnostic yield. Family history of kidney disease is a strong indication for renal genetics clinic referral.
