Abstract
Background
Primary vesicoureteral reflux (VUR) is a common congenital anomaly of the kidney and urinary tract (CAKUT) in childhood. The present study identified the possible genetic contributions to primary VUR in children.
Methods
Patients with primary VUR were enrolled and analysed based on a national multi-center registration network (Chinese Children Genetic Kidney Disease Database, CCGKDD) that covered 23 different provinces/regions in China from 2014 to 2019. Genetic causes were sought using whole-exome sequencing (WES) or targeted-exome sequencing.
Results
A total of 379 unrelated patients (male: female 219:160) with primary VUR were recruited. Sixty-four (16.9%) children had extrarenal manifestations, and 165 (43.5%) patients showed the coexistence of other CAKUT phenotypes. Eighty-eight patient (23.2%) exhibited impaired renal function at their last visit, and 18 of them (20.5%) developed ESRD at the median age of 7.0 (IQR 0.9–11.4) years. A monogenic cause was identified in 28 patients (7.39%). These genes included PAX2 (n = 4), TNXB (n = 3), GATA3 (n = 3), SLIT2 (n = 3), ROBO2 (n = 2), TBX18 (n = 2), and the other 11 genes (one gene for each patient). There was a significant difference in the rate of gene mutations between patients with or without extrarenal complications (14.1% vs. 6%, P = 0.035). The frequency of genetic abnormality was not statistically significant based on the coexistence of another CAKUT (9.6% vs. 5.6%, P = 0.139, Chi-square test) and the grade of reflux (9.4% vs. 6.7%, P = 0.429). Kaplan–Meier survival curve showed that the presence of genetic mutations did affect renal survival (Log-rank test, P = 0.01). PAX2 mutation carriers (HR 5.1, 95% CI 1.3–20.0; P = 0.02) and TNXB mutation carriers (HR 20.3, 95% CI 2.4–168.7; P = 0.01) were associated with increased risk of progression to ESRD.
Conclusions
PAX2, TNXB, GATA3 and SLIT2 were the main underlying monogenic causes and accounted for up to 46.4% of monogenic VUR. Extrarenal complications and renal function were significantly related to the findings of genetic factors in children with primary VUR. Like other types of CAKUT, several genes may be responsible for isolated VUR.
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Acknowledgements
We thank all participating patients and their families. Also, we thank our coordinators from Chigene (Beijing), Translational Medical Research Center Co. Ltd., WuXi NextCODE's Shanghai, Beijing MyGenostics Co. Ltd., for sequencing technology support.
Funding
This work was supported by the Grant NSFC-81800602 from National Natural Science Foundation of China (Dr. Jia-Lu Liu); the Grant 20184Y0176 from Shanghai Municipal Commission of Health and Family Planning Youth Research Program (Dr. Jia-Lu Liu); the Grant SHDC12016107 from Shanghai Shenkang Hospital Developmental Center (Dr. Hong Xu); the Grant NSFC-81670609 from National Natural Science Foundation of China (Dr. Hong Xu); the Grant 2018YFA0801102 from National Key Research and Development Project (Dr. Hong Xu).
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JLL, QS, MYW, GHZ, YFL are joint first authors. The roles of JLL, QS, MYW, GHZ and YFL are data curation, formal analysis, investigation, methodology, validation, visualization, writing—original draft, writing—review and editing. The roles of XWW, XST, YLB, YNG, JC, XYF, YHZ, GML, YBS, XJG, CHL, XYJ, SH, YLK, YLG, LPR, DL and SW are investigation and data curation. The role of BBW, DM, JR, QS and HX are writing—review and editing. The role of JLL and HX is funding acquisition. The roles of QS and HX are conceptualization, resources, supervision and project administration. All authors have seen and approved the final version of the manuscript.
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The study was approved by the Children’s Hospital of Fudan University’ Ethical Committee (no. 2017-56), and informed consent was obtained for all research individuals.
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Author Hong Xu is a member of the Editorial Board for World Journal of Pediatrics. The paper was handled by the other Editor and has undergone rigorous peer review process. Author Hong Xu was not involved in the journal's review of, or decisions related to, this manuscript. All the other authors have no conflicts of interest to disclose.
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Liu, JL., Shen, Q., Wu, MY. et al. Responsible genes in children with primary vesicoureteral reflux: findings from the Chinese Children Genetic Kidney Disease Database. World J Pediatr 17, 409–418 (2021). https://doi.org/10.1007/s12519-021-00428-x
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DOI: https://doi.org/10.1007/s12519-021-00428-x