Meningomyelocele is one of the most severe forms of neural tube defects
(NTDs) and the most frequent structural birth defect of the central nervous
system. We assembled the Spina Bifida Sequencing Consortium to identify
causes. Exome and genome sequencing of 715 parent-offspring trios
identified six patients with chromosomal 22q11.2 deletions, suggesting a
23-fold increased risk compared with the general population. Furthermore,
analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold
increased NTD risk of meningomyelocele. The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion
interval, was sufficient to replicate NTDs in mice, where both penetrance
and expressivity were exacerbated by maternal folate deficiency. Thus, the
common 22q11.2 deletion confers substantial meningomyelocele risk, which is
partially alleviated by folate supplementation.