Clubfoot, one of the most common birth defects, has long been thought to have a genetic component. Now, researchers at Washington University School of Medicine in St. Louis report they have found the first gene linked to clubfoot in humans. Their research was published in the American Journal of Human Genetics.
By studying a multi-generation family with clubfoot, the scientists traced the condition to a mutation in a gene critical for early development of lower limbs called PITX1. While other genes are also likely to be linked to clubfoot, the new finding is a first step toward improved genetic counseling and the development of novel therapies.
“To our knowledge this report is the first evidence for PITX1 mutation in human disease,” Christina Gurnett, MD, PhD, assistant professor of neurology, of pediatrics and of orthopedic surgery at the School of Medicine said. “Once we identified the mutation, we proved that all of the individuals in this family with lower extremity malformations also have the mutation.”
Gurnett and her colleagues analyzed the DNA of 35 extended family members of an infant male patient of Matthew Dobbs, MD, associate professor of orthopedic surgery and a clubfoot specialist at St. Louis Children’s Hospital and St. Louis Shriners Hospital. The patient had clubfoot in both feet, duplicated first toes and was missing the tibia in the right leg.
Gurnett and Dobbs visited the family members to examine their lower limbs and to take DNA samples. They found that 13 family members were affected. Five additional family members had clubfoot. Five others had lower limb abnormalities.
Through the genome-wide study, Gurnett and her colleagues found a region on chromosome 5 that was common to all family members affected. From there, they identified the PITX1 mutation, which was found in all affected family members and in three carriers who showed no clinical symptoms.
Dobbs said the finding is an exciting step in developing a better understanding of the genetic basis of clubfoot, which affects about one in 1,000 new births.
“Identifying the genes for clubfoot will allow for improved genetic counseling and may potentially lead to new and improved treatment and preventive strategies for this disorder,” Dobbs said in a news release.