IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-62319-3.html
   My bibliography  Save this article

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

Author

Listed:
  • Hila Milo Rasouly

    (Columbia University Medical Center
    Columbia University Medical Center)

  • Sarath Babu Krishna Murthy

    (Columbia University Medical Center)

  • Natalie Vena

    (Columbia University Medical Center
    Columbia University Medical Center)

  • Gundula Povysil

    (Columbia University Medical Center
    Waypoint Bio)

  • Andrew Beenken

    (Columbia University Medical Center)

  • Miguel Verbitsky

    (Columbia University Medical Center)

  • Shirlee Shril

    (Harvard Medical School)

  • Iris Lekkerkerker

    (University Medical Center Utrecht)

  • Sandy Yang

    (Columbia University Medical Center)

  • Atlas Khan

    (Columbia University Medical Center)

  • David Fasel

    (Columbia University Medical Center)

  • Janewit Wongboonsin

    (Mahidol University
    Brigham and Women’s Hospital)

  • Jeremiah Martino

    (Columbia University Medical Center
    Pace University)

  • Juntao Ke

    (Columbia University Medical Center)

  • Naama Elefant

    (Columbia University Medical Center
    Columbia University Medical Center)

  • Nikita Tomar

    (Columbia University Medical Center)

  • Ofek Harnof

    (Columbia University Medical Center)

  • Sergey Kisselev

    (Columbia University Medical Center)

  • Shiraz Bheda

    (Columbia University Medical Center)

  • Sivan Reytan-Miron

    (Columbia University Medical Center)

  • Tze Y. Lim

    (Columbia University Medical Center
    University of Turin)

  • Anna Jamry-Dziurla

    (Poznan University of Medical Sciences)

  • Francesca Lugani

    (Istituto Giannina Gaslini)

  • Jun Y. Zhang

    (Columbia University Medical Center)

  • Maddalena Marasa

    (Columbia University Medical Center
    Clinical Research Center for Rare Diseases Aldo e Cele Daccò)

  • Victoria Kolupaeva

    (Columbia University Medical Center
    Columbia University Medical Center)

  • Emily E. Groopman

    (Columbia University Medical Center
    Children’s National Hospital)

  • Gina Jin

    (Columbia University Medical Center)

  • Iman Ghavami

    (Columbia University Medical Center)

  • Kelsey O. Stevens

    (Columbia University Medical Center)

  • Arielle C. Coughlin

    (Columbia University Medical Center
    Icahn School of Medicine at Mount Sinai)

  • Byum Hee Kil

    (Columbia University Medical Center)

  • Debanjana Chatterjee

    (Columbia University Medical Center)

  • Drew Bradbury

    (Columbia University Medical Center)

  • Jason Zheng

    (Columbia University Medical Center)

  • Karla Mehl

    (Columbia University Medical Center)

  • Maria Morban

    (Columbia University Medical Center)

  • Rachel Reingold

    (Columbia University Medical Center
    Weill Cornell Medicine)

  • Stacy Piva

    (Columbia University Medical Center)

  • Xueru Mu

    (Columbia University Medical Center)

  • Adele Mitrotti

    (Columbia University Medical Center
    University of Bari Aldo Moro)

  • Agnieszka Szmigielska

    (Medical University of Warsaw)

  • Aleksandra Gliwińska

    (Medical University of Silesia)

  • Andrea Ranghino

    (Azienda Ospedaliera Universitaria delle Marche
    Università Politecnica delle Marche)

  • Andrew S. Bomback

    (Columbia University Medical Center)

  • Andrzej Badenski

    (Medical University of Silesia)

  • Anna Latos-Bielenska

    (Poznan University of Medical Sciences)

  • Valentina Capone

    (Ospedale Maggiore Policlinico)

  • Anna Materna-Kiryluk

    (Poznan University of Medical Sciences)

  • Antonio Amoroso

    (University of Turin
    CMP3VdA)

  • Claudia Izzi

    (University of Brescia and Spedali Civili)

  • Claudio La Scola

    (IRCCS Azienda Ospedaliero-Universitaria di Bologna
    Childhood and Adolescence Rimini. AUSL of Romagna)

  • David Jonathan Cohen

    (Columbia University Medical Center)

  • Domenico Santoro

    (University of Messina)

  • Dorota Drozdz

    (Jagiellonian University Medical College)

  • Enrico Fiaccadori

    (Parma University Hospital)

  • Fangming Lin

    (Columbia University Medical Center)

  • Francesco Scolari

    (Spedali Civili and University)

  • Francesco Tondolo

    (IRCCS Azienda Ospedaliero-Universitaria di Bologna)

  • Gaetano La Manna

    (IRCCS Azienda Ospedaliero-Universitaria di Bologna
    Alma Mater Studiorum University of Bologna)

  • Gerald B. Appel

    (Columbia University Medical Center)

  • Gian Marco Ghiggeri

    (Istituto Giannina Gaslini)

  • Gianluigi Zaza

    (University of Calabria)

  • Giovanni Montini

    (Ospedale Maggiore Policlinico
    University of Milan)

  • Giuseppe Masnata

    (ARNAS Brotzu Hospital)

  • Grażyna Krzemien

    (Medical University of Warsaw)

  • Isabella Pisani

    (Parma University Hospital)

  • Jai Radhakrishnan

    (Columbia University Medical Center)

  • Katarzyna Zachwieja

    (Jagiellonian University Medical College)

  • Loreto Gesualdo

    (University of Bari Aldo Moro)

  • Luigi Biancone

    (University of Torino
    AOU Città della Salute e della Scienza Hospital)

  • Davide Meneghesso

    (Hospital University of Padova)

  • Malgorzata Mizerska-Wasiak

    (Medical University of Warsaw)

  • Marcin Tkaczyk

    (Polish Mother’s Memorial Hospital Research Institute)

  • Marcin Zaniew

    (University of Zielona Góra)

  • Maria K. Borszewska-Kornacka

    (Medical University of Silesia in Katowice)

  • Maria Szczepanska

    (Medical University of Silesia)

  • Marijan Saraga

    (School of Medicine)

  • Maya K. Rao

    (Columbia University Medical Center)

  • Monica Bodria

    (Distretto Sud-Est)

  • Monika Miklaszewska

    (Jagiellonian University Medical College)

  • Natalie S. Uy

    (Weill Cornell Medicine)

  • Olga Baraldi

    (Alma Mater Studiorum University of Bologna
    AUSL Della Romagna)

  • Omar Bjanid

    (Medical University of Silesia)

  • Pasquale Esposito

    (University of Genoa
    IRCCS Ospedale Policlinico San Martino)

  • Pasquale Zamboli

    (AORN San Giuseppe Moscati)

  • Pierluigi Marzuillo

    (Università degli Studi della Campania “Luigi Vanvitelli”)

  • Pietro A. Canetta

    (Columbia University Medical Center)

  • Przemyslaw Sikora

    (Medical University of Lublin)

  • Rik Westland

    (University of Amsterdam)

  • Russell J. Crew

    (Columbia University Medical Center)

  • Shumyle Alam

    (El Paso Children Hospital)

  • Stefano Guarino

    (Università degli Studi della Campania “Luigi Vanvitelli”)

  • Susanna Negrisolo

    (University of Padova
    Pediatric Research Institute “IRP Città della Speranza”)

  • Thomas Hays

    (Columbia University Medical Center)

  • Shrikant Mane

    (Yale University School of Medicine)

  • Valeria Grandinetti

    (IRCCS Azienda Ospedaliero-Universitaria di Bologna)

  • Velibor Tasic

    (Faculty of Medicine)

  • Vladimir J. Lozanovski

    (Faculty of Medicine
    University Medical Center of the Johannes Gutenberg University)

  • Yasar Caliskan

    (Saint Louis University)

  • David Goldstein

    (Columbia University Medical Center
    Actio Biosciences)

  • Richard P. Lifton

    (Rockefeller University)

  • Iuliana Ionita-Laza

    (Columbia University
    Lund University)

  • Krzysztof Kiryluk

    (Columbia University Medical Center)

  • Albertien M. van Eerde

    (University Medical Center Utrecht)

  • Friedhelm Hildebrandt

    (Harvard Medical School)

  • Simone Sanna-Cherchi

    (Columbia University Medical Center)

  • Ali G. Gharavi

    (Columbia University Medical Center
    Columbia University Medical Center)

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.

Suggested Citation

  • 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 & Janewi, 2025. "Exome analysis links kidney malformations to developmental disorders and reveals causal genes," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62319-3
    DOI: 10.1038/s41467-025-62319-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-62319-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-62319-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Jovenal T. San Agustin & Nikolai Klena & Kristi Granath & Ashok Panigrahy & Eileen Stewart & William Devine & Lara Strittmatter & Julie A. Jonassen & Xiaoqin Liu & Cecilia W. Lo & Gregory J. Pazour, 2016. "Erratum: Genetic link between renal birth defects and congenital heart disease," Nature Communications, Nature, vol. 7(1), pages 1-1, September.
    2. Joanna Kaplanis & Kaitlin E. Samocha & Laurens Wiel & Zhancheng Zhang & Kevin J. Arvai & Ruth Y. Eberhardt & Giuseppe Gallone & Stefan H. Lelieveld & Hilary C. Martin & Jeremy F. McRae & Patrick J. Sh, 2020. "Evidence for 28 genetic disorders discovered by combining healthcare and research data," Nature, Nature, vol. 586(7831), pages 757-762, October.
    3. Jovenal T. San Agustin & Nikolai Klena & Kristi Granath & Ashok Panigrahy & Eileen Stewart & William Devine & Lara Strittmatter & Julie A. Jonassen & Xiaoqin Liu & Cecilia W. Lo & Gregory J. Pazour, 2016. "Genetic link between renal birth defects and congenital heart disease," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    4. Sahar Gelfman & Quanli Wang & K. Melodi McSweeney & Zhong Ren & Francesca La Carpia & Matt Halvorsen & Kelly Schoch & Fanni Ratzon & Erin L. Heinzen & Michael J. Boland & Slavé Petrovski & David B. Go, 2017. "Annotating pathogenic non-coding variants in genic regions," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    5. Xiaolin Zhu & Raghavendra Padmanabhan & Brett Copeland & Joshua Bridgers & Zhong Ren & Sitharthan Kamalakaran & Ailbhe O'Driscoll-Collins & Samuel F Berkovic & Ingrid E Scheffer & Annapurna Poduri & D, 2017. "A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations," PLOS Genetics, Public Library of Science, vol. 13(11), pages 1-12, November.
    6. Uma M. Neelathi & Ehsan Ullah & Aman George & Mara I. Maftei & Elangovan Boobalan & Daniel Sanchez-Mendoza & Chloe Adams & David McGaughey & Yuri V. Sergeev & Ranya AI Rawi & Amelia Naik & Chelsea Ben, 2025. "Variants in NR6A1 cause a novel oculo vertebral renal syndrome," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Muqing Cao & Xiaoxiao Zou & Chaoyi Li & Zaisheng Lin & Ni Wang & Zhongju Zou & Youqiong Ye & Joachim Seemann & Beth Levine & Zaiming Tang & Qing Zhong, 2023. "An actin filament branching surveillance system regulates cell cycle progression, cytokinesis and primary ciliogenesis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Emily Olfson & Luis C. Farhat & Wenzhong Liu & Lawrence A. Vitulano & Gwyneth Zai & Monicke O. Lima & Justin Parent & Guilherme V. Polanczyk & Carolina Cappi & James L. Kennedy & Thomas V. Fernandez, 2024. "Rare de novo damaging DNA variants are enriched in attention-deficit/hyperactivity disorder and implicate risk genes," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Sophie L. Chick & Peter Holmans & Darren Cameron & Detelina Grozeva & Rebecca Sims & Julie Williams & Nicholas J. Bray & Michael J. Owen & Michael C. O’Donovan & James T. R. Walters & Elliott Rees, 2025. "Whole-exome sequencing analysis identifies risk genes for schizophrenia," Nature Communications, Nature, vol. 16(1), pages 1-9, December.
    4. Ruoyu Tian & Tian Ge & Hyeokmoon Kweon & Daniel B. Rocha & Max Lam & Jimmy Z. Liu & Kritika Singh & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Ellen A. Tsai & Hailiang Huang & Christopher F., 2024. "Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Ada J. S. Chan & Worrawat Engchuan & Miriam S. Reuter & Zhuozhi Wang & Bhooma Thiruvahindrapuram & Brett Trost & Thomas Nalpathamkalam & Carol Negrijn & Sylvia Lamoureux & Giovanna Pellecchia & Rohan , 2022. "Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Stephanie O. Erjavec & Sahar Gelfman & Alexa R. Abdelaziz & Eunice Y. Lee & Isha Monga & Anna Alkelai & Iuliana Ionita-Laza & Lynn Petukhova & Angela M. Christiano, 2022. "Whole exome sequencing in Alopecia Areata identifies rare variants in KRT82," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Christian M. Boßelmann & Costin Leu & Tobias Brünger & Lucas Hoffmann & Sara Baldassari & Mathilde Chipaux & Roland Coras & Katja Kobow & Hajo Hamer & Daniel Delev & Karl Rössler & Christian G. Bien &, 2024. "Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    8. Elsa Leitão & Christopher Schröder & Ilaria Parenti & Carine Dalle & Agnès Rastetter & Theresa Kühnel & Alma Kuechler & Sabine Kaya & Bénédicte Gérard & Elise Schaefer & Caroline Nava & Nathalie Drouo, 2022. "Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    9. Shilpa Nadimpalli Kobren & Mikhail A. Moldovan & Rebecca Reimers & Daniel Traviglia & Xinyun Li & Danielle Barnum & Alexander Veit & Rosario I. Corona & George de V. Carvalho Neto & Julian Willett & M, 2025. "Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    10. Mihaly Badonyi & Joseph A. Marsh, 2025. "Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    11. Alan R. F. Godwin & Mark H. Becker & Rana Dajani & Matthew Snee & Alan M. Roseman & Clair Baldock, 2025. "Collagen VI microfibril structure reveals mechanism for molecular assembly and clustering of inherited pathogenic mutations," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    12. Elizabeth J. Radford & Hong-Kee Tan & Malin H. L. Andersson & James D. Stephenson & Eugene J. Gardner & Holly Ironfield & Andrew J. Waters & Daniel Gitterman & Sarah Lindsay & Federico Abascal & Iñigo, 2023. "Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62319-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.