Two decades of spina bifida research published in Science

The culmination of over two decades of research from Hope Northrup, MD, professor, and Kit Sing Au, PhD, associate professor in the Department of Pediatrics, on the genetic factors associated with spina bifida has been published in Science.

According to the authors, spina bifida occurs when the spinal cord does not close as a baby is being formed in the womb. Since the 1960s, surgery has been available to close the defect after birth, leading to increased survival rates of babies born with spina bifida.

“We have known for many years that spina bifida occurs because of a combination of genetic and environmental factors,” Au said. “We decided to try and find some of those factors hoping that by getting a better understanding of why this happens, we could help either prevent this from happening or help affected individuals.”

For the study, the team recruited more than 1,000 families with members affected by spina bifida and collected and stored samples at McGovern Medical School. With NIH funding in 2014, the lab identified thousands of genetic variants from 511 spina bifida patients using whole exome sequencing, which examines all 20,000 genes in humans and identifies changes from normal genes.

“Our study is the largest exome sequencing study of spina bifida in humans,” Au said. “Hundreds of genetic variants were found to be associated with spina bifida, and the results were published in several important medical reports.”

Those results led to a collaboration with Joseph G. Gleeson, MD, professor in the Department of Neurosciences at the University of California, San Diego, and senior author of the paper, to join the Spina Bifida Sequencing Consortium in order to verify their results with an independent lab.

Research between the two labs showed that nearly one percent (6 out of 715) of spina bifida patients showed deletions in chromosome 22q11.2, a well-known genetic condition that affects just .015 percent (1 out of 6,000) of the population. Ten genes were found in the deleted region of all six patients. Prior knowledge of these genes  prompted the researchers to focus on the CRKL gene, which resides in the center of the LCR 22C-D region determining that CRKL is the most important gene in the 22q11 deleted region for development of spina bifida.

“The study showed that spina bifida patients have higher odds of 22q11.2 deletion involving the CRKL gene,” Au said. “Additionally, the CRKL gene has not previously been implicated in causing spina bifida in preclinical models or humans. Finding nearly one percent of spina bifida participants in a large cohort affected by the same gene is exceptionally high in a genetic study, meaning the gene is very important to spina bifida risk.”

Results of the current study focused on just 300 of the 1,168 original patients in the UTHealth Houston cohort, meaning that the lab will now shift its focus to examining the remaining. Additionally, in 2021, the lab collaborated with spina bifida experts from France, Dr. Valerie Dupe, and Dr. Marie de Tayrac, to identify and study genes that work together to cause human disease.

“Our laboratory has many national and international collaborators with the same goal: to identify genes that will cause neural tube defects in humans,” Au said.

The paper is a culmination of nearly 25 years of research, beginning prior to the year 2000. Collaborations with the lab have formed across the country, and in Canada and France, as well as locally with various departments at McGovern Medical School.

“This has been a long road,” said Northrup, the director of the Division of Medical Genetics. “Research moves slowly, takes much effort, and truly is a ‘team sport.’ Thus, there are many who contribute to significant breakthrough articles like this one.”