外显子组分析将肾脏畸形与发育障碍联系起来，并揭示了致病基因。

Exome analysis links kidney malformations to developmental disorders and reveals causal genes.

作者信息

Milo Rasouly Hila, Krishna Murthy Sarath Babu, Vena Natalie, Povysil Gundula, Beenken Andrew, Verbitsky Miguel, Shril Shirlee, Lekkerkerker Iris, Yang Sandy, Khan Atlas, Fasel David, Wongboonsin Janewit, Martino Jeremiah, Ke Juntao, Elefant Naama, Tomar Nikita, Harnof Ofek, Kisselev Sergey, Bheda Shiraz, Reytan-Miron Sivan, Lim Tze Y, Jamry-Dziurla Anna, Lugani Francesca, Zhang Jun Y, Marasa Maddalena, Kolupaeva Victoria, Groopman Emily E, Jin Gina, Ghavami Iman, Stevens Kelsey O, Coughlin Arielle C, Kil Byum Hee, Chatterjee Debanjana, Bradbury Drew, Zheng Jason, Mehl Karla, Morban Maria, Reingold Rachel, Piva Stacy, Mu Xueru, Mittrori Adele, Szmigielska Agnieszka, Gliwińska Aleksandra, Ranghino Andrea, Bomback Andrew S, Badenski Andrzej, Latos-Bielenska Anna, Capone Valentina, Materna-Kiryluk Anna, Amoroso Antonio, Izzi Claudia, La Scola Claudio, Cohen David Jonathan, Santoro Domenico, Drozdz Dorota, Fiaccadori Enrico, Lin Fangming, Scolari Francesco, Tondolo Francesco, La Manna Gaetano, Appel Gerald B, Ghiggeri Gian Marco, Zaza Gianluigi, Montini Giovanni, Masnata Giuseppe, Krzemien Grażyna, Pisani Isabella, Radhakrishnan Jai, Zachwieja Katarzyna, Gesualdo Loreto, Biancone Luigi, Meneghesso Davide, Mizerska-Wasiak Malgorzata, Tkaczyk Marcin, Zaniew Marcin, Borszewska-Kornacka Maria K, Szczepanska Maria, Saraga Marijan, Rao Maya K, Bodria Monica, Miklaszewska Monika, Uy Natalie S, Baraldi Olga, Bjanid Omar, Esposito Pasquale, Zamboli Pasquale, Marzuillo Pierluigi, Canetta Pietro A, Sikora Przemyslaw, Westland Rik, Crew Russell J, Alam Shumyle, Guarino Stefano, Negrisolo Susanna, Hays Thomas, Mane Shrikant, Grandinetti Valeria, Tasic Velibor, Lozanovski Vladimir J, Caliskan Yasar, Goldstein David, Lifton Richard P, Ionita-Laza Iuliana, Kiryluk Krzysztof, van Eerde Albertien M, Hildebrandt Friedhelm, Sanna-Cherchi Simone, Gharavi Ali G

机构信息

Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, NY, USA.

Center for Precision Medicine and Genomics, Department of Medicine, Columbia University Medical Center, New York, NY, USA.

出版信息

Nat Commun. 2025 Aug 7;16(1):7290. doi: 10.1038/s41467-025-62319-3.

DOI:10.1038/s41467-025-62319-3

PMID:40774958

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12332173/

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.

摘要

先天性肾脏和尿路畸形（CAKUT）是常见导致小儿慢性肾病和死亡的发育障碍。我们在此研究了248个CAKUT三联体和1742个CAKUT单病例中的罕见编码变异，并将它们与22258名对照进行比较。在14.1%的病例中检测到诊断性和候选诊断性变异。我们发现在肾脏发育过程中表达的受限基因以及与其他发育障碍相关的基因中，罕见有害变异显著富集，提示表型扩展。与这些数据一致，18%具有诊断性变异的CAKUT患者有神经发育或心脏表型。我们鉴定出40个候选基因，包括CELSR1、SSBP2、XPO1、NR6A1和ARID3A。其中两个被确认为CAKUT基因：ARID3A和NR6A1。这项研究表明，通过更大的队列和跨表型分析，许多尚未识别的综合征将可被发现，从而有助于明确发育障碍的遗传和表型谱。