The contribution of de novo coding mutations to meningomyelocele

Abstract 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 . We postulated that de novo mutations (DNMs) under purifying selection contribute to MM risk 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.