Scientists have produced new knowledge about the genesis of the most common structural disorder of the human nervous system

A group of researchers from the University of California San Diego School of Medicine has led an investigation that provides new insights into the causes of spina bifida, the most common structural disorder of the human nervous system. This birth defect of the spine can affect physical and intellectual development for life.

Spina bifida, also known as myelomeningocele, occurs when spinal tissue fails to fuse properly in the early stages of pregnancy. The birth defect can lead to a range of cognitive, mobility, urinary and bowel disabilities throughout life.

New research reveals the first link between spina bifida and a chromosomal microdeletion (loss of a portion of a chromosome) common in humans.

The study shows that individuals carrying this chromosomal deletion – present in one in 2,500 live births – have a risk of spina bifida more than 10 times higher than the general public.

The group’s work also highlights the potential role of a common dietary supplement in reducing the risk of spina bifida.

The findings were recently published in the journal Science.

“Spina bifida, also known as meningomyelocele, affects about one in 3,000 newborns. Unfortunately, the causes are largely unknown. A few mutations have been reported, but they may explain only a small part of the risk,” Dr. Joseph G. Gleeson, of the UC San Diego School of Medicine’s Department of Neuroscience, said in a statement.

To uncover the genetic causes of the disease, Dr. Gleeson’s lab joined researchers around the world to establish the Spina Bifida Genomic Sequencing Consortium in 2015.

The consortium began focusing on a small deletion in chromosome 22. Chromosomal microdeletions refer to a condition in which multiple genes are missing from a chromosome. The group’s target condition, known as 22q11.2del, has been implicated in a number of other conditions. The team began looking for 22q11.2del in patients with spina bifida.

“All of the patients we recruited have the most severe form of spina bifida and all underwent best practice whole genome sequencing,” said Dr. Gleeson. “We identified 22q11.2del in 6 of 715 patients. It may not seem like a high percentage, but this is by far the most common single genetic variation that could contribute to spina bifida,” the doctor added.

The group identified eight other patients with spina bifida who carried this deletion from a cohort of approximately 1,500 people recruited based on the presence of the common 22q11.2 deletion.

The researchers then narrowed down the causative area among the many genes in the 22q11.2 deletion to a single gene known as CRKL.

Dr Gleeson explained that there were nine other genes in this chromosomal region that could have been the cause. He said the team knocked out each of the genes one by one in a mouse model.

The team collaborated with Dolores Lamb of Weill Cornell Medical College, who learned about the Gleeson lab’s project through the Spina Bifida Association

Lamb’s lab had noticed that some of the study specimens lacked Crkl and had spina bifida. (Researchers use all uppercase letters to describe the gene in humans and lowercase for mice).

“This finding really excited us because it meant that disrupting CRKL might be sufficient for spina bifida,” said Keng Ioi Vong, co-senior author of the study.

“We also knocked out the Crkl gene in mice and confirmed that some of the mice developed neural tube defects, including spina bifida.” Most of the other genes in the 22q11.2 deletion were later ruled out, he added.

The scientists then turned their attention to how folic acid might modulate CRKL-mediated spina bifida.

Previous human studies have shown that supplementation with folic acid (also known as vitamin B-9) before conception reduces the incidence of spina bifida and other neural tube defects by up to 30-50%, but the mechanisms are still unknown.

“When we deprived Crkl mutant females of folic acid in their diet, many more of their offspring had neural tube defects, and the severity increased dramatically,” explained Vong. “This suggests that folic acid taken by pregnant women may reduce not only the risk but also the severity of neural tube defects in their offspring.”

“We hope that our findings can help the research community better understand the causes of neural tube defects, particularly the causes attributable to common genetic findings such as the 22q11.2 deletion,” said Dr. Gleeson. “We also hope that our findings can contribute to healthy pregnancies, improve women’s health and improve outcomes for children.”