The contribution of de novo coding mutations to meningomyelocele

Yoo-Jin Jiny Ha, Ashna Nisal, Isaac Tang, Chanjae Lee, Ishani Jhamb, Cassidy Wallace, Robyn Howarth, Sarah Schroeder, Keng Ioi Vong, Naomi Meave, Fiza Jiwani, Chelsea Barrows, Sangmoon Lee, Nan Jiang, Arzoo Patel, Krisha Bagga, Niyati Banka, Liana Friedman, Francisco A. Blanco, Seyoung Yu, Soeun Rhee, Hui Su Jeong, Isaac Plutzer, Michael B. Major, Béatrice Benoit, Christian Poüs, Caleb Heffner, Zoha Kibar, Gyang Markus Bot, Hope Northrup, Kit Sing Au, Madison Strain, Allison E. Ashley-Koch, Richard H. Finnell, Joan T. Le, Hal S. Meltzer, Camila Araujo, Helio R. Machado, Roger E. Stevenson, Anna Yurrita, Sara Mumtaz, Awais Ahmed, Mulazim Hussain Khara, Osvaldo M. Mutchinick, José Ramón Medina-Bereciartu, Friedhelm Hildebrandt, Gia Melikishvili, Ahmed I. Marwan, Valeria Capra, Mahmoud M. Noureldeen, Aida M. S. Salem, Mahmoud Y. Issa, Maha S. Zaki, Libin Xu, Ji Eun Lee, Donghyuk Shin, Anna Alkelai, Alan R. Shuldiner, Stephen F. Kingsmore, Stephen A. Murray, Heon Yung Gee, W. Todd Miller, Kimberley F. Tolias, John B. Wallingford, Sangwoo Kim () and Joseph G. Gleeson ()
Additional contact information
Yoo-Jin Jiny Ha: Rady Children’s Institute for Genomic Medicine
Ashna Nisal: Rady Children’s Institute for Genomic Medicine
Isaac Tang: Rady Children’s Institute for Genomic Medicine
Chanjae Lee: University of Texas at Austin
Ishani Jhamb: Rady Children’s Institute for Genomic Medicine
Cassidy Wallace: Rady Children’s Institute for Genomic Medicine
Robyn Howarth: Rady Children’s Institute for Genomic Medicine
Sarah Schroeder: Rady Children’s Institute for Genomic Medicine
Keng Ioi Vong: Rady Children’s Institute for Genomic Medicine
Naomi Meave: Rady Children’s Institute for Genomic Medicine
Fiza Jiwani: Rady Children’s Institute for Genomic Medicine
Chelsea Barrows: Rady Children’s Institute for Genomic Medicine
Sangmoon Lee: Rady Children’s Institute for Genomic Medicine
Nan Jiang: Rady Children’s Institute for Genomic Medicine
Arzoo Patel: Rady Children’s Institute for Genomic Medicine
Krisha Bagga: Rady Children’s Institute for Genomic Medicine
Niyati Banka: Rady Children’s Institute for Genomic Medicine
Liana Friedman: Rady Children’s Institute for Genomic Medicine
Francisco A. Blanco: Baylor College of Medicine
Seyoung Yu: Yonsei University College of Medicine
Soeun Rhee: Yonsei University
Hui Su Jeong: Rady Children’s Institute for Genomic Medicine
Isaac Plutzer: Washington University in St Louis
Michael B. Major: Washington University in St Louis
Béatrice Benoit: University Paris-Saclay
Christian Poüs: University Paris-Saclay
Caleb Heffner: The Jackson Laboratory
Zoha Kibar: University of Montreal
Gyang Markus Bot: Jos University Teaching Hospital
Hope Northrup: University of Texas Health Science Center at Houston and Children’s Memorial Hermann Hospital
Kit Sing Au: University of Texas Health Science Center at Houston and Children’s Memorial Hermann Hospital
Madison Strain: Duke University Medical Center
Allison E. Ashley-Koch: Duke University Medical Center
Richard H. Finnell: Baylor College of Medicine
Joan T. Le: Rady Children’s Hospital
Hal S. Meltzer: Rady Children’s Hospital
Camila Araujo: University of São Paulo
Helio R. Machado: University of São Paulo
Roger E. Stevenson: Greenwood Genetic Center
Anna Yurrita: Universidad Francisco Marroquín
Sara Mumtaz: National University of Medical Sciences
Awais Ahmed: University of Concepcion
Mulazim Hussain Khara: Children’s Hospital, Pakistan Institute of Medical Sciences
Osvaldo M. Mutchinick: Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
José Ramón Medina-Bereciartu: Clínica Santa Sofia
Friedhelm Hildebrandt: Boston Children’s Hospital
Gia Melikishvili: MediClubGeorgia Medical Center
Ahmed I. Marwan: University of Missouri School of Medicine
Valeria Capra: IRCCS Istituto Giannina Gaslini
Mahmoud M. Noureldeen: Beni-Suef University
Aida M. S. Salem: Beni-Suef University
Mahmoud Y. Issa: National Research Centre
Maha S. Zaki: National Research Centre
Libin Xu: University of Washington
Ji Eun Lee: Sungkyunkwan University
Donghyuk Shin: Yonsei University
Anna Alkelai: Regeneron Genetics Center
Alan R. Shuldiner: Regeneron Genetics Center
Stephen F. Kingsmore: Rady Children’s Institute for Genomic Medicine
Stephen A. Murray: The Jackson Laboratory
Heon Yung Gee: Yonsei University College of Medicine
W. Todd Miller: Stony Brook University
Kimberley F. Tolias: Baylor College of Medicine
John B. Wallingford: University of Texas at Austin
Sangwoo Kim: Yonsei University College of Medicine
Joseph G. Gleeson: Rady Children’s Institute for Genomic Medicine

Nature, 2025, vol. 641, issue 8062, 419-426

Abstract: Abstract Meningomyelocele (also known as spina bifida) is considered to be a genetically complex disease resulting from a failure of the neural tube to close. Individuals with meningomyelocele display neuromotor disability and frequent hydrocephalus, requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but beyond that it remains unexplained1. We postulated that de novo mutations under purifying selection contribute to the risk of developing meningomyelocele2. Here we recruited a cohort of 851 meningomyelocele trios who required shunting at birth and 732 control trios, and found that de novo likely gene disruption or damaging missense mutations occurred in approximately 22.3% of subjects, with 28% of such variants estimated to contribute to disease risk. The 187 genes with damaging de novo mutations collectively define networks including actin cytoskeleton and microtubule-based processes, Netrin-1 signalling and chromatin-modifying enzymes. Gene validation demonstrated partial or complete loss of function, impaired signalling and defective closure of the neural tube in Xenopus embryos. Our results indicate that de novo mutations make key contributions to meningomyelocele risk, and highlight critical pathways required for neural tube closure in human embryogenesis.

Date: 2025
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DOI: 10.1038/s41586-025-08676-x

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