Exome analysis links kidney malformations to developmental disorders and reveals causal genes
Hila Milo Rasouly, Sarath Babu Krishna Murthy, Natalie Vena, Gundula Povysil, Andrew Beenken, Miguel Verbitsky, Shirlee Shril, Iris Lekkerkerker, Sandy Yang, Atlas Khan, David Fasel, Janewit Wongboonsin, Jeremiah Martino, Juntao Ke, Naama Elefant, Nikita Tomar, Ofek Harnof, Sergey Kisselev, Shiraz Bheda, Sivan Reytan-Miron, Tze Yin Lim, Anna Jamry‐Dziurla, Francesca Lugani, Jun Y. Zhang, Maddalena Marasà, Victoria Kolupaeva, Emily Groopman, Gina Jin, Iman Ghavami, K Stevens, Arielle C. Coughlin, Byum Hee Kil, Debanjana Chatterjee, Drew Bradbury, Jason Zheng, Karla Mehl, Maria Morban, Rachel Reingold, Stacy Piva, Xueru Mu, Adele Mitrotti, Agnieszka Szmigielska, Aleksandra Gliwińska, Andrea Ranghino, Andrew S. Bomback, Andrzej Badeński, Anna Latos‐Bieleńska, Valentina Capone, Anna Materna‐Kiryluk, Antonio Amoroso, Claudia Izzi, Claudio La Scola, David J. Cohen, Domenico Santoro, Dorota Drożdż, Enrico Fiaccadori, Fangming Lin, Francesco Scolari, Francesco Tondolo, Gaetano La Manna, Gerald B. Appel, Gian Marco Ghiggeri, Gianluigi Zaza, Giovanni Montini, Giuseppe Masnata, Grażyna Krzemien, Isabella Pisani, Jai Radhakrishnan, Katarzyna Zachwieja, Loreto Gesualdo, Luigi Biancone, Davide Meneghesso, Małgorzata Mizerska-Wasiak, Marcin Tkaczyk, Marcin Zaniew, Maria Katarzyna Borszewska-Kornacka, Tomasz Szczepański, Marijan Saraga, Maya K. Rao, Monica Bodria, Monika Miklaszewska, Natalie Uy, Olga Baraldi, Omar Bjanid, Pasquale Esposito, Pasquale Zamboli, Pierluigi Marzuillo, Pietro A. Canetta, Przemysław Sikora, Rik Westland, Russell J. Crew, Shumyle Alam, Stefano Guarino, Susanna Negrisolo, Thomas Hays, Shrikant Mane, Valeria Grandinetti, Velibor Tasić, Vladimir J. Lozanovski, Yaşar Çalışkan
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. The authors analyze rare coding variants in 1990 individuals with congenital kidney anomalies, finding diagnostic variants in 14.1% of cases. They identify two new causal genes, ARID3A and NR6A1, along with 38 candidate genes, providing evidence for shared genetics with other developmental disorders.