Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one-carbon metabolism networks

Paul Hillman, Craig Baker, Luke Hebert, Michael Brown, James Hixson, Allison Ashley-Koch, Alanna C. Morrison, Hope Northrup, Kit Sing Au

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Background: Neural tube defects (NTDs) are the second most common complex birth defect, yet, our understanding of the genetic contribution to their development remains incomplete. Two environmental factors associated with NTDs are Folate and One Carbon Metabolism (FOCM) and Glucose Homeostasis and Oxidative Stress (GHOS). Utilizing next-generation sequencing of a large patient cohort, we identify novel candidate genes in these two networks to provide insights into NTD mechanisms. Methods: Exome sequencing (ES) was performed in 511 patients, born with myelomeningocele, divided between European American and Mexican American ethnicities. Healthy control data from the Genome Aggregation database were ethnically matched and used as controls. Rare, high fidelity, nonsynonymous predicted damaging missense, nonsense, or canonical splice site variants in independently generated candidate gene lists for FOCM and GHOS were identified. We used a gene-based collapsing approach to quantify mutational burden in case and controls, with the control cohort estimated using cumulative allele frequencies assuming Hardy–Weinberg equilibrium. Results: We identified 45 of 837 genes in the FOCM network and 22 of 568 genes in the GHOS network as possible NTD risk genes with p < 0.05. No nominally significant risk genes were shared between ethnicities. Using a novel approach to mutational burden we identify 55 novel NTD risk associations. Conclusions: We provide a means of utilizing large publicly available sequencing datasets as controls for sequencing projects examining rare disease. This approach confirmed existing risk genes for myelomeningocele and identified possible novel risk genes. Lastly, it suggests possible distinct genetic etiologies for this malformation between different ethnicities.

Original languageEnglish (US)
Article numbere1495
JournalMolecular Genetics and Genomic Medicine
Issue number11
StatePublished - Nov 2020
Externally publishedYes


  • Myelomeningocele
  • exome sequencing
  • folate
  • glucose
  • mutation burden

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Identification of novel candidate risk genes for myelomeningocele within the glucose homeostasis/oxidative stress and folate/one-carbon metabolism networks'. Together they form a unique fingerprint.

Cite this