Diagnosing genetic kidney disease has become more accessible with low-cost, rapid genetic testing. The study objectives were to determine genetic testing diagnostic yield and examine predictors of genetic diagnosis in children with nephrolithiasis/nephrocalcinosis (NL/NC).
This retrospective multicenter cross-sectional study was conducted on children ≤ 21 years old with NL/NC from pediatric nephrology/urology centers that underwent the Invitae Nephrolithiasis Panel 1/1/2019-9/30/2021. The diagnostic yield of the genetic panel was calculated. Bivariate and multiple logistic regression were performed to assess for predictors of positive genetic testing.
One hundred and thirteen children (83 NL, 30 NC) from 7 centers were included. Genetic testing was positive in 32% overall (29% NL, 40% NC) with definite diagnoses (had pathogenic variants alone) made in 11.5%, probable diagnoses (carried a combination of pathogenic variants and variants of uncertain significance (VUS) in the same gene) made in 5.4%, and possible diagnoses (had VUS alone) made in 15.0%. Variants were found in 28 genes (most commonly HOGA1 in NL, SLC34A3 in NC) and 20 different conditions were identified. Compared to NL, those with NC were younger and had a higher proportion with developmental delay, hypercalcemia, low serum bicarbonate, hypophosphatemia, and chronic kidney disease. In multivariate analysis, low serum bicarbonate was associated with increased odds of genetic diagnosis (β 2.2, OR 8.7, 95% CI 1.4-54.7, p = 0.02).
Genetic testing was high-yield with definite, probable, or possible explanatory variants found in up to one-third of children with NL/NC and shows promise to improve clinical practice. A higher resolution version of the Graphical abstract is available as Supplementary information.
Pediatric nephrology (Berlin, Germany). 2023 Jan 23 [Epub ahead of print]
Ashley M Gefen, Christine B Sethna, Onur Cil, Farzana Perwad, Megan Schoettler, Mini Michael, Joseph R Angelo, Adnan Safdar, Louise Amlie-Wolf, Tracy E Hunley, Jonathan S Ellison, Daniel Feig, Joshua Zaritsky
Division of Nephrology, Department of Pediatrics, Cohen Children's Medical Center, 269-01 76th Ave, Queens, NY, 11040, USA. ., Division of Nephrology, Department of Pediatrics, Cohen Children's Medical Center, 269-01 76th Ave, Queens, NY, 11040, USA., Division of Nephrology, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA., Division of Nephrology, Department of Pediatrics, Baylor College of Medicine/Texas Children's Hospital, Houston, TX, USA., Division of Nephrology, Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates., Precision Medicine/Genetic Testing Stewardship Program, Nemours Children's Health, Delaware Valley, Wilmington, DE, USA., Division of Nephrology, Department of Pediatrics, Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, TN, USA., Division of Pediatric Urology, Department of Urology, Medical College of Wisconsin, Milwaukee, WI, USA., Division of Nephrology, Department of Pediatrics, The University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA., Division of Nephrology, Department of Pediatrics, Phoenix Children's Hospital, Phoenix, AZ, USA.