Molecular Mechanisms of Human Meningomyelocele (Spina Bifida)

Meningomyelocele (MM, aka Spina Bifida) is the most common CNS congenital malformation, with heritability estimated at 70-75% 1,2 and a cumulative incidence of 3.72/10,000 live US births. There are more thatn 200,000 patients in the US suffering from MM. MM is a debilitating condition, the most common neural tube defect (NTD) compatible with survival, and with associated morbidity and mortality. National folic acid (FA) supplementation since 1998 has reduced incidence by approximately 30-50%, but substantial disease incidence remains, and there is little understanding of mechanism of this important Gene-Environment interaction (GXE). Here we propose to study the molecular basis of human MM through broad recruitment and analysis of trios with narrowly defined inclusion/exclusion criteria, stratified by prenatal FA exposure. We hypothesize that de novo mutations (DNMs) make a critical contribution to risk of MM, and that FA increases the mutational burden required for phenotypic expressivity. MM shares features with other severe congenital malformations such as in heart or brain that show strong DNM contributions. Our preliminary data point to a strong role for DNMs, in the form of SNPs, INDELs and SVs. To support this application, our preliminary work has: 1] Founded the Spina Bifida Sequencing Consortium (SBSC) and enrolled a cohort of 1500 MM trios to date using social media, and historic cohorts. 2] Stratified by FA exposure (+FA or -FA) based upon exposure history and detailed questionnaire. 3] Performed whole exome or whole genome sequencing on 851 previously enrolled trios, in part through the NICHD Gabriella Miller-Kids First (GMKF) program. 4] Identified a recurrent chr. 22q11.2 deletion including the CRKL gene that increases MM risk approximately 14-fold, and in animal models is influenced by FA exposure 3. 5] Identified 187 candidate MM risk genes including four recurrently mutated genes that define protein-interaction networks 6. 6] Identified a stronger DNM burden in +FA trios than -FA trios, consistent with our main hypothesis. However, these preliminary findings require confirmation and further analysis before they can be utilized in a clinical context. Here we propose: 1] To ascertain 300 carefully phenotyped new trios per year, stratified by FA supplementation status, to double the cohort size. 2] To perform complete genetic analysis for de novo and inherited variants on the entire 3000 trio cohort, compared with control trios. 3] To identify a set of high- confidence MM risk genes using a statistical framework. 4] To stratify genes based upon +FA vs -FA patient status and identify unique functional pathways. 5] To assess spatial transcriptomic differences in +FA vs -FA conditions in animals. The application proposes to build on SBSC successes, develop a multifactorial MM risk model, clarify mechanisms of FA function, and uncover high-impact disease mechanisms, that will advance the first effort towards clinical genetic testing in MM. Project Number: 1R01HD121764-01 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: JOSEPH GLEESON | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $711,432 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 MGG-R (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11343042