# Project I - Human genetics of meningomyelocele and risk mitigation by folic acid

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $342,839

## Abstract

Abstract – Project I: Human genetics of meningomyelocele and risk mitigation by folic acid
This project focuses on the characterization of genomic variation in human patients with Meningomyelocele
(MM), the most common CNS birth defect, with heritability estimated at 70-75% 1,2, and a cumulative incidence
of 3.72/10,000 live US births. MM is a debilitating structural birth defect, the most common form of NTD
compatible with life, and with substantial associated morbidity and mortality. National folic acid (FA)
supplementation has reduced incidence >3-fold, but there is little understanding of the mechanism of this
Gene-Environment interaction (GXE). Here we propose to study the molecular basis of human MM through a
world-wide recruitment 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 the risk of MM, and
that FA increases the mutational burden required for phenotypic expressivity. MM shares features with other
severe childhood diseases that show strong DNM contributions such as congenital structural disorders and
autism. Our preliminary data point to a strong DNM contribution to MM, but like autism, these DNM increase
risk but likely act with other factors to determine risk. We propose to ascertain a total of 2000 carefully
phenotyped MM trios, recruited worldwide, stratified based upon national dietary FA supplementation status
at the time of conception (+FA:fortified vs -FA:nonfortified). Trios will undergo whole genome sequencing
(WGS), then analyzed for de novo and inherited mutations as risk factors, compared with control trios. Results
from Project I will be incorporated into workflow of Project II and III to model mutations, and results from
Project II and III will be used to refine WGS analysis in Project I. Project I will rely on Core B to identify
candidate FA-responsive genes from changes in epigenetic signatures, and on Core C for bioinformatic
analysis. Project I has already: 1] Founded the Spina Bifida Sequencing Consortium and enrolled a cohort of
>1500 MM trios using social media, and historic cohorts, stratified as +FA or -FA. 2] Extracted and QC’d DNA
from >700 of these trios. 3] Competed successfully for NICHDs Gabriella Miller-Kids First program access for
1000 WGS samples. 4] Performed sequencing on 600 trios, as well as optimized algorithms to achieve uniform
mutation calling. 5] Identified 12 MM candidate genes, including 3 recurrently mutated genes, and one
recurrent copy number variant (CNV). 6] Found that +FA trios but not -FA trios demonstrate a striking
accumulation of damaging DNMs compared with controls. We will test the model that de novo and inherited
mutations interact with FA to determine risk. The application proposes to complete recruitment, identify de
novo and inherited gene mutations in MM, correlate with maternal FA exposure, and uncover mechanisms of
disease within a clinical contex...

## Key facts

- **NIH application ID:** 10533744
- **Project number:** 5P01HD104436-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** JOSEPH G GLEESON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $342,839
- **Award type:** 5
- **Project period:** 2020-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10533744

## Citation

> US National Institutes of Health, RePORTER application 10533744, Project I - Human genetics of meningomyelocele and risk mitigation by folic acid (5P01HD104436-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10533744. Licensed CC0.

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