Abstract
Background
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).
Methods
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.
Results
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).
Conclusions
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.
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Data availability
Data is available upon request to the corresponding author.
References
Ward JB, Feinstein L, Pierce C, Lim J et al (2019) Pediatric urinary stone disease in the United States: the urologic diseases in America project. Urology 129:180–187. https://doi.org/10.1016/j.urology.2019.04.012
Dwyer ME, Krambeck AE, Bergstralh EJ, Milliner DS et al (2012) Temporal trends in incidence of kidney stones among children: a 25-year population based study. J Urol 188:246–252. https://doi.org/10.1016/j.juro.2012.03.021
Li Y, Bayne D, Wiener S, Ahn J et al (2002) Stone formation in patients less than 20 years of age is associated with higher rates of stone recurrence: results from the Registry for Stones of the Kidney and Ureter (ReSKU). J Pediatr Urol 16:373.E1–373.E6 https://doi.org/10.1016/j.jpurol.2020.03.014
Novak TE, Lakshmanan Y, Trock BJ, Gearhart JP et al (2009) Sex prevalence of pediatric kidney stone disease in the United States: an epidemiologic investigation. Urology 74:104–107. https://doi.org/10.1016/j.urology.2008.12.079
Zhe M, Hang Z (2017) Nephrolithiasis as a risk factor of chronic kidney disease: a meta-analysis of cohort studies with 4,770,691 participants. Urolithiasis 45:441–448. https://doi.org/10.1007/s00240-016-0938-x
Goldfarb DS, Fischer ME, Keich Y, Goldberg J (2005) A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry. Kidney Int 67:1053–1061. https://doi.org/10.1111/j.1523-1755.2005.00170.x
Goldfarb DS, Avery AR, Beara-Lasic L, Duncan GE et al (2018) A twin study of genetic influences on nephrolithiasis in women and men. Kidney Int Rep 4:535–540. https://doi.org/10.1016/j.ekir.2018.11.017
Halbritter J, Baum M, Hynes AM, Rice SJ et al (2015) Fourteen monogenic genes account for 15% of nephrolithiasis/nephrocalcinosis. J Am Soc Nephrol 26:543–551. https://doi.org/10.1681/ASN.2014040388
Braun DA, Lawson JA, Gee HY, Halbritter J et al (2016) Prevalence of monogenic causes in pediatric patients with nephrolithiasis or nephrocalcinosis. Clin J Am Soc Nephrol 11:664–672. https://doi.org/10.2215/CJN.07540715
Daga A, Majmundar AJ, Braun DA, Gee HY et al (2018) Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis. Kidney Int 93:204–213. https://doi.org/10.1016/j.kint.2017.06.025
Zhao Y, Fang X, He L, Fan Y et al (2022) A comparison of the clinical characteristics of pediatric urolithiasis patients with positive and negative molecular diagnoses. World J Urol 40:1211–1216. https://doi.org/10.1007/s00345-022-03934-3
Nykamp K, Anderson M, Powers M, Garcia J et al (2017) Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med 19:1105–1117. https://doi.org/10.1038/gim.2017.37
Scales CD Jr, Smith AC, Hanley JM, Saigal CS (2012) Prevalence of kidney stones in the United States. Eur Urol 62:160–165. https://doi.org/10.1016/j.eururo.2012.03.052
Jayasinghe K, Stark Z, Kerr PG, Gaff C et al (2021) Clinical impact of genomic testing in patients with suspected monogenic kidney disease. Genet Med 23:183–191. https://doi.org/10.1038/s41436-020-00963-4
Amlie-Wolf L, Baker L, Hiddemen O, Thomas M et al (2021) Novel genetic testing model: a collaboration between genetic counselors and nephrology. Am J Med Genet A 185:1142–1150. https://doi.org/10.1002/ajmg.a.62088
Cogal AG, Arroyo J, Shah RJ, Reese KJ et al (2021) Comprehensive genetic analysis reveals complexity of monogenic urinary stone disease. Kidney Int Rep 6:2862–2884. https://doi.org/10.1016/j.ekir.2021.08.033
Bonilla-Felix M, Villegas-Medina O, Vehaskari VM (1994) Renal acidification in children with idiopathic hypercalciuria. J Pediatr 124:529–534. https://doi.org/10.1016/s0022-3476(05)83129-4
Funding
OC is supported by grants DK126070 and DK072517 from NIH.
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Research idea and study design: AMG, CBS, and JZ. Data acquisition: AMG. Data analysis/interpretation: AMG and CBS. Statistical analysis: AMG and CBS. Supervision or mentorship: AMG, CBS, and JZ. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.
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This study protocol was reviewed and approved by the Northwell Institutional Review Board (IRB #20–0686). Written informed consent was not required from participants as the study was exempt.
Competing interests
Alnylam Pharmaceuticals sponsored the program that paid for the genetic testing of the cohort. Ashley M. Gefen has received research support from Natera, Inc. Jonathan S. Ellison is a consultant for Alnylam Pharmaceuticals and contributes to UpToDate. Christine Sethna was on an advisory board for Trevere Therapeutics. No other authors have a conflict of interest.
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Gefen, A.M., Sethna, C.B., Cil, O. et al. Genetic testing in children with nephrolithiasis and nephrocalcinosis. Pediatr Nephrol 38, 2615–2622 (2023). https://doi.org/10.1007/s00467-023-05879-0
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DOI: https://doi.org/10.1007/s00467-023-05879-0