The contribution of de novo coding mutations to meningomyelocele

• 成果类型: Article
• 署名作者: Ha, Yoo-Jin Jiny; Nisal, Ashna; Tang, Isaac; Lee, Chanjae; Jhamb, Ishani; Wallace, Cassidy; Howarth, Robyn; Schroeder, Sarah; Vong, Keng loi; Meave, Naomi; Jiwani, Fiza; Barrows, Chelsea; Lee, Sangmoon; Jiang, Nan; Patel, Arzoo; Bagga, Krisha; Banka, Niyati; Friedman, Liana; Blanco, Francisco A.; Yu, Seyoung; Rhee, Soeun; Jeong, Hui Su; Plutzer, Isaac; Major, Michael B.; Benoit, Beatrice; Pous, Christian; Heffner, Caleb; Kibar, Zoha; Bot, Gyang Markus; Northrup, Hope; Au, Kit Sing; Strain, Madison; Ashley-Koch, Allison E.; Finnell, Richard H.; Le, Joan T.; Meltzer, Hal S.; Araujo, Camila; Machado, Helio R.; Stevenson, Roger E.; Yurrita, Anna; Mumtaz, Sara; Ahmed, Awais; Khara, Mulazim Hussain; Mutchinick, Osvaldo M.; Medina-Bereciartu, Jose Ramon; Hildebrandt, Friedhelm; Melikishvili, Gia; Marwan, Ahmed I.; Capra, Valeria; Noureldeen, Mahmoud M.; Salem, Aida M. S.; Issa, Mahmoud Y.; Zaki, Maha S.; Xu, Libin; Lee, Ji Eun; Shin, Donghyuk; Alkelai, Anna; Shuldiner, Alan R.; Kingsmore, Stephen F.; Murray, Stephen A.; Gee, Heon Yung; Miller, W. Todd; Tolias, Kimberley F.; Wallingford, John B.; Kim, Sangwoo; Gleeson, Joseph G.; Spina Bifida Sequencing Consortium, Joan T.; Koch, Allison E. Ashley; Lupo, Philip J.; Magana, Tony; Kolvenbach, Caroline M.; Shril, Shirlee; Takahashi, Yukitoshi; Salimi-Dafsari, Hormos; Phillips, H. Westley; Hanak, Brian; Kara, Bulent; Gunes, Ayfer Sakarya; Gonda, David D.; Kirmani, Salman; Tkemaladze, Tinatin
• 署名单位: University of California System; University of California San Diego; Yonsei University; Yonsei University Health System; Yonsei University; Yonsei University Health System; University of Texas System; University of Texas Austin; Baylor College of Medicine; Yonsei University; Yonsei University Health System; Yonsei University; Sungkyunkwan University (SKKU); Washington University (WUSTL); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Saclay; Universite Paris Saclay; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Saint-Louis - APHP; Hopital Universitaire Antoine-Beclere - APHP; Jackson Laboratory; Universite de Montreal; University of Texas System; University of Texas Health Science Center Houston; Duke University; Baylor College of Medicine; Baylor College of Medicine; Rady Childrens Hospital San Diego; Universidade de Sao Paulo; Greenwood Genetic Center; Universidad de Concepcion; Pakistan Institute of Medical Sciences; Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran - Mexico; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; University of Missouri System; University of Missouri Columbia; University of Genoa; IRCCS Istituto Giannina Gaslini; Egyptian Knowledge Bank (EKB); Beni Suef University; Egyptian Knowledge Bank (EKB); National Research Centre (NRC); University of Washington; University of Washington Seattle; Regeneron; State University of New York (SUNY) System; Stony Brook University; Pohang University of Science & Technology (POSTECH); Baylor College of Medicine; Mekelle University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; University of Cologne; Stanford University; Childrens Hospital of Orange County; Kocaeli University; Aga Khan University; Tbilisi State Medical University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1618
• DOI: 10.1038/s41586-025-08676-x
• 发表日期: 2025-05-08
• 关键词: neural-tube closure; spina-bifida; embryonic lethality; defects; gene; variants; mechanisms; DISCOVERY; germline; region

摘要

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.