The contribution of de novo coding mutations to meningomyelocele

Meningomyelocele (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 unexplained[1][1]. We postulated that de novo mutations (DNMs) under purifying selection contribute to MM risk[2][2]. 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 in Xenopus embryos. Our results suggest DNMs make key contributions to MM risk, and highlight critical pathways required for neural tube closure in human embryogenesis. ### Competing Interest Statement AA and ARS are full time employees of Regeneron Genetics Center. SK is cofounder of AIMA Inc., which seeks to develop techniques for early cancer diagnosis based on circulating tumor DNA. ### Clinical Protocols ### Funding Statement This work was funded by the NIH. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All subjects or their guardians provided written informed consent approved by the UCSD Institutional Review Board S99075 protocol 140028, expiration date Aug 1, 2024. Recruitment processes were conducted in accordance with the approval by review boards of the University of California San Diego, operating under Federal-wide Assurance number, FWA00004495. The above rulings cover all aspects of our study, not just recruitment and consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Exome and genome sequencing data are available in publicly accessible databases for the 1,576 subjects enrolled after inclusion of dbGaP language into the consenting process/ became standard. These data are at dbGaP (accession #phs002591.v1.p1, phs000744.v5.p2 (Yale Mendelian Sequencing Center), Kids First: Whole Genome Sequencing in Structural Defects of the Neural Tube Accession (phs002591.v1.p1). Sequencing data on the remaining 743 subjects is available upon request. [1]: #ref-1 [2]: #ref-2