Although clubfoot is one of the most common congenital birth defects, few genetic causes have been found. Now, researchers at Washington University School of Medicine in St. Louis have found what they believe to be the most common cause of inherited clubfoot yet discovered.
By performing a routine genetic screening on 66 patients with an inherited form of clubfoot, Christina Gurnett, MD, PhD, a Washington University pediatric geneticist and neurologist at St. Louis Children's Hospital, and her colleagues found abnormalities in a region of chromosome 17 in four patients. Three of the patients had small recurrent DNA duplications, and one had a small recurrent DNA deletion on chromosome 17.
"What we're learning about birth defects is that for some genes involved in very early fetal development, if you have either too much or too little of them, you may develop the same condition," Gurnett says. "This appears to be the case for clubfoot."
The results will be published in the July 9 issue of the American Journal of Human Genetics.
The researchers ran a test commonly used to evaluate children for neurodevelopmental disorders such as autism called a chromosomal microarray. Gurnett, assistant professor of neurology, of pediatrics and of orthopaedic surgery, said this is the first time researchers have used this kind of test specifically for isolated clubfoot.
"Since few genes have previously been implicated in clubfoot, this discovery represents the most common cause of isolated clubfoot found to date," Gurnett says. "This technology can be used immediately for genetic testing."
Nearly one in 1,000 babies is born with clubfoot and one-fourth of them have a family history of the birth defect, which causes the bones and joints of the foot to be aligned incorrectly. The condition occurs in boys twice as often as in girls. If untreated, those affected walk on the outside of their feet, which can lead to long-term pain and disability. Standard treatment for milder forms of clubfoot involves gentle manipulation and casting of the feet over several weeks then wearing a brace for several years. Treatment for more severe forms requires surgery.
Initially, Gurnett and her research team, including Matthew B. Dobbs, MD, associate professor of orthopedic surgery at the School of Medicine, screened the DNA of 40 patients with inherited clubfoot. Two were found to have nearly identical DNA duplications on chromosome 17 in a region previously linked to limb abnormalities, developmental delays and heart defects. That DNA duplication was not found in the DNA of 700 control subjects without clubfoot.
They then screened 26 additional patients and found another clubfoot patient with a duplication in chromosome 17 and one more with a deletion, resulting in four patients of 66 screened with defects on chromosome 17.
To determine that the chromosomal duplications were inherited, the team ran the same tests on 10 family members of the three patients with the duplications. All of the family members who had clubfoot and the duplication were male. One female family member with the duplication had hip dysplasia but not clubfoot.
Dobbs says the findings may prompt orthopedic surgeons to consider this readily available genetic screening test for children who have inherited clubfoot and may be at risk of hip abnormalities.