Spina bifida, the most common structural disorder of the human nervous system, has causes that are not well understood. However, a recent study suggests a potential connection involving a chromosomal microdeletion. This study also emphasizes the importance of folic acid as a preventive measure.
A team of researchers at the University of California San Diego School of Medicine conducted an investigation that provides new insights into the causes of spina bifida. The group, led by Keng Ioi Vong, Ph.D., and Sangmoon Lee, M.D. Ph.D., from the laboratory The research conducted by Joseph G. Gleeson, M.D., at the UC San Diego School of Medicine Department of Neurosciences and the Rady Children’s Institute for Genomic Medicine, has uncovered the first connection between spina bifida and a common chromosomal microdeletion in humans. The study shows that individuals with this chromosomal deletion, which is present in one out of every 2,500 live births, have a risk of spina bifida more than 10 times higher than the general population.
The study also emphasizes the potential role of a common food supplement in reducing the risk of spina bifida. These findings were recently published in the journal Science.
GlRady Professor Rady Children’s Institute for Genomic Medicine, said that spina bifida, also known as meningomyelocele, affects one in every 3,000 newborns. The causes are mostly unknown and only a few mutations have been reported to explain a small fraction of the risk. To find the genetic causes of the disease, Gleeson’s UC San Diego lab partnered with colleagues from around the world to form the Spina Bifida Sequencing Consortium in 2015. The consortium started to focus on a small deletion in the cChromosome 22. A condition in which several genes in a chromosome are missing is called chromosome microdeletions. The group’s focus is on a condition known as 22q11.2del, which has been linked to various other disorders. They started searching for 22q11.2del in patients with spinal bifida.
“All patients we recruited have the most severe form of spina bifida, and all underwent best-practice comprehensive genomic sequencing,” Gleeson said. “We identified 22q11.2del in 6 out of 715 patients. This may not seem a high percentage, but this is by far the most common single genetic variation that could contribute to spina bifida.”
He also mentioned that the findings suggest a potential link between 22q11.2del and spina bifida.The team found eight more patients with spina bifida who had the same deletion from a group of around 1,500 people recruited due to having the common 22q11.2 deletion, according to Gleeson. The researchers then determined that the cause was a single gene called CRKL among the many genes in the 22q11.2 deletion. Gleeson noted that there are nine other genes in this region that could have been the cause. The team started eliminating each of the mouse genes one by one, when they got an unexpected email from Dolores Lamb from Weil Cor.The College of Medicine at Cornell University conducted a study where they found that mice missing the Crkl gene showed signs of spina bifida. Vong, one of the researchers, explained that they use capital letters to describe the gene in humans and lowercase for mice. The research group learned about the project from the Spina Bifida Association, which got them excited about the potential link between CRKL disruption and spina bifida. After removing the Crkl gene in mice, they confirmed that some of the mice developed neural tube defects, including spina bifida.2q11.2 deletion were later ruled out, he stated.
Their focus then shifted to the potential impact of folic acid on CRKL-mediated spina bifida. Vong pointed out that previous research in humans has shown that folic acid (also known as vitamin B-9) supplementation before conception can reduce the occurrence of spina bifida and other neural tube defects by 30-50 percent, but the underlying mechanisms remain unknown.
“When we removed folic acid from the diet of female mice with the Crkl mutation, their offspring had a higher rate of neural tube defects, and the severity of the defects increased significantly,” Vong said. “This indicates that folic acid intake during pregnancy could play a crucial role.”Pregnant women who take folic acid may not only lower the risk, but also the seriousness of neural tube defects in their babies.”
“We believe that our results can assist the scientific community in gaining a better understanding of the causes of neural tube defects, particularly those linked to common genetic factors such as 22q11.2 deletion,” Gleeson stated. “We also hope that our findings can contribute to promoting healthy pregnancies, improving women’s health, and enhancing outcomes for children.”
Other authors from the University of San Diego School of Medicine Department of Neurosciences, as well as from Rady Children’s Institute for Genomic Medicine, (in addition to JosephThe authors of this study (G. Gleeson Sangmoon Lee and Keng Ioi Vong) are Renee George, Bryn Gerding, Kiely N. James, Valentina Stanley, Nan Jiang, Kameron Alu, Naomi Meave, Fiza Jiwani, Isaac Tang, Ashna Nisal, Ishani Jhamb, Arzoo Patel, Aakash Patel, Jennifer McEvoy-Venneri, Chelsea Barrows, Celina Shen, Yoo-Jin Ha, and Robyn Howarth. Additional co-authors include Hal S. Meltzer from the University of California San Diego Rady Children’s Hospital Department of Neurosurgery, Anna S. Nidhiry from Rady Children’s Institute for Genomic Medicine, and the Spina Bifida Sequencing Consortium.
This research received support from the Center for Inherited Disease Research grant HHSN268.The Yale Center for Genomic Analysis, the Broad Institute, the UC Irvine Genomics Core, the UCSD Institute for Genomic Medicine, the UCSD Transgenic Core, UCSD Microscopy Core grant P30 NS047101, and Columbia Microscopy Core grant S10 OD032447- 01 provided funding for this project. Additional support came from the National Institutes of Health, including National Institute of Diabetes and Digestive and Kidney Diseases, and by support from the Howard Hughes Medical Institute and Rady’s Children Institute for Genomic Medicine to Joseph G. Gleeson.
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