Genetic Mutations Linked to Severe Scoliosis

Genetic risk factors for children to develop s-shaped curves in their spines severe enough to require surgery have been pinpointed by research from Washington University School of Medicine.

Children having uncommon mutations in two genes are roughly four times more predisposed to develop severe scoliosis than children with normal versions of the genes, the study says.

“We’ve had a difficult time finding ways to predict who will develop severe scoliosis, and these newly identified mutations have the potential to be very helpful,” senior author Christina A. Gurnett, MD, PhD, said.

Potential for Scoliosis Prevention

These mutated genes, fibrillin-1 and fibrillin-2, control a major growth pathway. Drugs currently in clinical trials block that pathway. If this same pathway is implicated in scoliosis, it may be possible to use these drugs to prevent scoliosis in some children with these mutations.

Some mild curvature of the spine is present it from one to 3 percent of the general population. But in around one in 10,000 children, scoliosis will produce curvature so pronounced that it requires corrective surgery.

“These children often don’t have any curvature of the spine early in adolescence, but then they go through a growth spurt, and that’s when the curve appears,” said Gurnett. “Others have tried to predict severe disease using gender, age of onset and type of spine curve but haven’t been very successful.”

Out of 91 patients with acute scoliosis, the scientists sequenced the portions of the DNA that encode proteins.

Fibrillin-1 Mutation

The most consistently mutated gene in the group was fibrillin-1, which makes a protein important to the tissues that connect many components of the body. A related gene, fibrillin-2, also often was mutated.

Further genetic sequencing in 852 patients with scoliosis and 669 subjects with normal spines showed that patients with specific mutations in both fibrillin-1 and fibrillin-2 had four times the risk of severe scoliosis than people without the genetic errors.

To date, more than 600 mutations in fibrillin-1 have been identified. Among the most serious are the mutations that produce Marfan syndrome, a condition that can cause the long bones of the body to overgrow and can weaken the body’s connective tissue.

“Some variants of this important gene are associated with unusual tallness,” Gurnett said. “There appears to be a spectrum of effects caused by changes in the gene, from simple alterations in height to severe scoliosis to more life-threatening conditions such as Marfan syndrome.”

Clinical trials are currently underway in Marfan syndrome patients to see whether drugs that block TGF-beta, a growth pathway controlled by fibrillin-1, can help treat the disorder.

Gurnett and her colleagues are watching to see if the drugs affect growth of the spine. If they do, researchers may investigate using them to prevent scoliosis.

“We want to create a genetic testing panel that we can use to more accurately predict who will need treatment,” Gurnett said. “If we can develop effective treatments and apply them early enough, we might one day be able to prevent the need for surgeries.”


J. G. Buchan, D. M. Alvarado, G. E. Haller, C. Cruchaga, M. B. Harms, T. Zhang, M. C. Willing, D. K. Grange, A. C. Braverman, N. H. Miller, J. A. Morcuende, N. L.-S. Tang, T.-P. Lam, B. K.-W. Ng, J. C.-Y. Cheng, M. B. Dobbs, C. A. Gurnett.
Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis.
Human Molecular Genetics, 2014; DOI: 10.1093/hmg/ddu224