The Contribution of De Novo Coding Mutations to Meningomyelocele

Meningomyelocele (MM) is considered a genetically complex disease resulting from the failure of the neural tube to close; a neural tube defect (NTD). Patients display neuromotor disability and frequent hydrocephalus requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but most risk remains unexplained. 851 MM trios were recruited and we found 187 likely gene disrupting or damaging missense de novo mutations (DNMs) that are estimated to contribute to disease risk. These 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. Data for 245 WES trios and 1 quad are available through dbGaP.]]>
Strict inclusion criteria were set for subject enrollment into the Spina Bifida Sequencing Consortium (SBSC). Participants must be affected by lumbosacral meningomyelocele (MM) with Arnold-Chiari malformation and hydrocephalus requiring surgical intervention such as ventriculoperitoneal shunt or endoscopic third ventriculostomy. We excluded subjects with closed neural tube defects, not requiring surgery at birth, with meningocele, or without hydrocephalus or not requiring surgery at birth. Enrollment required that both biological parents were available for sampling. In the case of fetal surgery to correct MM, which reduces the incidence of hydrocephalus, the requirement for inclusion of hydrocephalus at the time of enrollment was lifted. Subjects with known syndromes that would explain their conditions were excluded. Any families that did not meet the strict inclusion criteria were excluded.]]>