Skip to main content
Premium Trial:

Request an Annual Quote

Exome Study Seeks New Genetic Contributors to Neural Tube Defects

CHARLOTTE, NC (GenomeWeb) – A University of Texas-led team is searching for new genetic risk factors for neural tube defects (NTD), common congenital defects such as spina bifida.

Although certain environmental contributors — most notably folic acid deficiency — have been implicated in NTD risk, there is evidence that NTDs have a strong heritable component as well, Hope Northrup, director of the medical genetics division at the University of Texas Health Science Center at Houston (UTHealth)'s McGovern Medical School, explained at the American College of Medical Genetics and Genomics annual meeting here yesterday.

Northrup, who was named this year's Samuel Pruzansky Memorial lecturer in honor of her contributions to the field, shared initial results from an exome sequencing-based analysis of NTD during a March of Dimes Clinical Genetics Conference session.

Using that approach, she and her team reasoned, it may be possible to find of new variants that might help in identifying at-risk individual and designing interventions to prevent more cases of NTD. While NTD cases decline after the introduction of folic acid-fortified cereals, she explained, cases do still occur, leaving room for improvement.

Together with colleagues from UTHealth, Duke University, the University of California, San Diego, the UTHealth School of Public Health, and University College London, Northrup sequenced protein-coding portions of the genome in 511 individuals with a severe NTD subtype called myelomeningocele (MM). That cohort included 257 individuals with European ancestry and 254 individuals with Mexican ancestry, she noted.

The team sequenced each exome to an average of 50-fold coverage, calling the variants that were supported by more than 20 reads and filtering that dataset against sequences from unaffected individuals to identify known and novel variants with potential ties to MM.

For their initial analysis, the researchers focused on new variants in more than 100 genes from pathways with plausible ties to NTD — from the folate metabolism pathway to pathways involved in glucose homeostasis, planar cell polarity, cilia structure or function, retinoic acid metabolism, and other processes.

Northrup noted that while no one pathway jumped out, some 16 percent of the exome-sequenced patients had suspicious variants in at least one of the candidate genes.

In a related poster at the conference this week, UTHealth's Craig Baker, Northrup, and co-authors are sharing additional details from the exome variant analysis, focusing on a subset of potential risk variants falling in genes radiating out from pathways that influence glucose homeostasis.

"Starting with 10 genes involved in glucose homeostasis and already associated with increased NTD development risk," authors of that study explained in the poster's abstract, "we extracted all Gene Ontology (GO) terms characterizing the range of biologic properties described for these genes."

From the resulting variants — more than 5,700 coding variants in the European patients and nearly 8,200 coding variants in affected Mexican Americans — the researchers are now focusing in on 514 non-synonymous variants not found in ClinVar, ExAc, the 1000 Genomes Project, or other large sequence datasets.

"Total variant load within genes of interest will be assessed in individual samples for evidence of cumulative effect on NTD risk," they concluded. "Individual variant association will be assessed with the goal of finding new genes of interest in maintaining glucose homeostasis to further evaluate for functional significance in NTD development in animal models."

For another related poster, UTHealth pediatrics and medical genetics researcher Paul Hillman, Baker, Northrup, and other University of Texas investigators analyzed the European- and Mexican American exomes looking for potential MM-associated variants in folate- and one-carbon metabolism-related pathways.

In her own presentation, Northrup also shared findings from a search for common, polygenic variants that may contribute to the risk of neural tube development. For that analysis, the team compared exome sequences from the European participants with ARIC exomes, while the Mexican American exomes were set against exomes from a health study centered in Starr County, Texas.

Along with separate analyses of potential NTD associations in each of the ancestry groups, the researchers are considering genes affected by NTD-associated SNPs in both the European Americans and Mexican Americans.

Northrup said the team is continuing to search for, validate, and test the function of potential NTD contributors, even as collaborators at UCSD start doing whole-genome sequencing on the NTD-affected individuals. She also highlighted the importance of gene-environment studies to tease out the complicated interactions that raise NTD risk.