Exome analysis links kidney malformations to developmental disorders and reveals causal genes
Publication date
2025-08-07
Authors
Milo Rasouly, Hila
Krishna Murthy, Sarath Babu
Vena, Natalie
Povysil, Gundula
Beenken, Andrew
Verbitsky, Miguel
Shril, Shirlee
Lekkerkerker, Iris
Yang, Sandy
Khan, Atlas
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Article
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Abstract
Congenital anomalies of the kidneys and urinary tract (CAKUT) are developmental disorders that commonly cause pediatric chronic kidney disease and mortality. We examine here rare coding variants in 248 CAKUT trios and 1742 singleton CAKUT cases and compare them to 22,258 controls. Diagnostic and candidate diagnostic variants are detected in 14.1% of cases. We find a significant enrichment of rare damaging variants in constrained genes expressed during kidney development and in genes associated with other developmental disorders, suggesting phenotype expansion. Consistent with these data, 18% of CAKUT patients with diagnostic variants have neurodevelopmental or cardiac phenotypes. We identify 40 candidate genes, including CELSR1, SSBP2, XPO1, NR6A1, and ARID3A. Two are confirmed as CAKUT genes: ARID3A and NR6A1. This study suggests that many yet-unidentified syndromes would be discoverable with larger cohorts and cross-phenotype analysis, leading to clarification of the genetic and phenotypic spectrum of developmental disorders.
Keywords
Child, Child, Preschool, DNA-Binding Proteins/genetics, Developmental Disabilities/genetics, Exome Sequencing, Exome/genetics, Female, Genetic Predisposition to Disease, Humans, Kidney/abnormalities, Male, Phenotype, Transcription Factors/genetics, Urogenital Abnormalities/genetics, Vesico-Ureteral Reflux/genetics, Journal Article
Citation
Milo Rasouly, H, Krishna Murthy, S B, Vena, N, Povysil, G, Beenken, A, Verbitsky, M, Shril, S, Lekkerkerker, I, Yang, S, Khan, A, Fasel, D, Wongboonsin, J, Martino, J, Ke, J, Elefant, N, Tomar, N, Harnof, O, Kisselev, S, Bheda, S, Reytan-Miron, S, Lim, T Y, Jamry-Dziurla, A, Lugani, F, Zhang, J Y, Marasa, M, Kolupaeva, V, Groopman, E E, Jin, G, Ghavami, I, Stevens, K O, Coughlin, A C, Kil, B H, Chatterjee, D, Bradbury, D, Zheng, J, Mehl, K, Morban, M, Reingold, R, Piva, S, Mu, X, Mittrori, A, Szmigielska, A, Gliwińska, A, Ranghino, A, Bomback, A S, Badenski, A, Latos-Bielenska, A, Capone, V, Materna-Kiryluk, A, Amoroso, A, Izzi, C, La Scola, C, Cohen, D J, Santoro, D, Drozdz, D, Fiaccadori, E, Lin, F, Scolari, F, Tondolo, F, La Manna, G, Appel, G B, Ghiggeri, G M, Zaza, G, Montini, G, Masnata, G, Krzemien, G, Pisani, I, Radhakrishnan, J, Zachwieja, K, Gesualdo, L, Biancone, L, Meneghesso, D, Mizerska-Wasiak, M, Tkaczyk, M, Zaniew, M, Borszewska-Kornacka, M K, Szczepanska, M, Saraga, M, Rao, M K, Bodria, M, Miklaszewska, M, Uy, N S, Baraldi, O, Bjanid, O, Esposito, P, Zamboli, P, Marzuillo, P, Canetta, P A, Sikora, P, Westland, R, Crew, R J, Alam, S, Guarino, S, Negrisolo, S, Hays, T, Mane, S, Grandinetti, V, Tasic, V, Lozanovski, V J, Caliskan, Y, Goldstein, D, Lifton, R P, Ionita-Laza, I, Kiryluk, K, van Eerde, A M, Hildebrandt, F, Sanna-Cherchi, S & Gharavi, A G 2025, 'Exome analysis links kidney malformations to developmental disorders and reveals causal genes', Nature Communications, vol. 16, no. 1, 7290. https://doi.org/10.1038/s41467-025-62319-3