The contribution of de novo coding mutations to meningomyelocele
Author:
Ha Yoo-JinORCID, Tang Isaac, Nisal Ashna, Jhamb Ishani, Wallace Cassidy, Schroeder Sarah, Lee Chanjae, Vong Keng loi, Meave Naomi, Jiwani Fiza, Barrows Chelsea, Lee Sangmoon, Jiang Nan, Patel Arzoo, Blanco Francisco A., Yu Seyoung, Jeong Hui Su, Plutzer Isaac, Major Michael B., Benoit Béatrice, Poüs Christian, Heffner Caleb, Kibar Zoha, Bot Gyang Markus, Northrup Hope, Au Kit Sing, Strain Madison, Ashley-Koch Allison, Finnell Richard H., Le Joan T., Meltzer Hal, Araujo Camila, Machado Helio R., Stevenson Roger E., Yurrita Anna, Mumtaz Sara, Mutchinick Osvaldo M., Medina-Bereciartu José Ramón, Hildebrandt Friedhelm, Melikishvili Gia, Marwan Rony, Capra Valeria, Noureldeen Mahmoud M., Salem Aida M.S., Issa Mahmoud Y., Zaki Maha S., Lee Ji Eun, 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.ORCID
Abstract
AbstractMeningomyelocele (MM) is considered a genetically complex disease resulting from failure of neural tube closure (NTD). Patients display neuromotor disability and frequent hydrocephalus requiring ventricular shunting. A few proposed genes contribute to disease susceptibility, but most risk remains unexplained1. We postulated that de novo mutations (DNMs) under purifying selection contribute to MM risk2. Here we recruited a cohort of 851 MM trios requiring shunting at birth, compared with 732 control trios, and found that de novo likely gene disrupting or damaging missense mutations occur in approximately 22.3% of subjects, 28% of which are estimated to contribute to disease risk. The 187 genes with damaging DNMs collectively define networks including actin cytoskeleton and microtubule-based processes, axon guidance, and histone modification. Gene validation demonstrates partial or complete loss of function, impaired signaling and defective neural tube closure inXenopusembryos. Our results suggest DNMs make key contributions to MM risk, and highlight critical pathways required for neural tube closure in human embryogenesis.
Publisher
Cold Spring Harbor Laboratory
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