Washington, Oct 24 : Scientists at Washington University School of Medicine in St. Louis have discovered the first gene behind one of the most common birth defects in human - clubfoot.
In a study on a multi-generation family with clubfoot, the researchers closed in on a gene called PITX1, which is critical for early development of lower limbs.
The finding is the first step toward improved genetic counselling and the development of novel therapies, say the researchers.
"To our knowledge this report is the first evidence for PITX1 mutation in human disease. Once we identified the mutation, we proved that all of the individuals in this family with lower extremity malformations also have the mutation. Having large families to work with is very helpful in genetic research," said Christina Gurnett, M.D., Ph.D., assistant professor of neurology, of pediatrics and of orthopedic surgery at the School of Medicine.
During the study, the researchers examined the DNA of 35 extended family members of an infant male patient. The patients were the most severely affected in the family, had clubfoot in both feet, duplicated first toes and was missing the tibia in the right leg.
The researchers visited the family members in their community to examine their lower limbs and to take DNA samples.
They found that 13 family members were affected: Five additional family members had clubfoot, which was more severe in the right foot in three of them. Five others had lower limb abnormalities including flatfoot, an underdeveloped patella and hip dysplasia.
And after conducting the genome-wide study, the researchers found a region on chromosome 5 that was common to all family members affected.
Then they identified a mutation in a gene critical for early development of lower limbs called PITX1, which was found in all affected family members and in three carriers who showed no clinical symptoms.
Dobbs, senior author of the study, said that the finding was an exciting step in developing a better understanding of the genetic basis of clubfoot, which affects about 1 in 1,000 new births.
"Clubfoot is a complex disorder meaning that more than one gene as well as environmental factors will be discovered to play a role in its etiology. 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," said one of the senior authors of the study.
Previous studies had shown a relation between PITX1 and the development of hindlimbs in other vertebrates.
"It's our job to prove that this is going to be important for many kids with clubfoot. Until now, we didn't know whether clubfoot was a muscle, nerve, spinal cord or brain problem. Now, we have an idea that clubfoot may result from mutations of genes that are involved in early limb development," said Gurnett.
The study appears in the forthcoming issue of the American Journal of Human Genetics.