When Allison Grindon was born with clubfoot, doctors told her family that she would never walk. After five surgeries in 8 years and a temporary brace, the 41-year-old office manager at Washington University in St. Louis, Missouri, says she enjoys full use of the affected foot. But doctors never could explain what caused her crippling birth defect, one of the most common deformities that affects babies. Now, in a breakthrough for the field, researchers on the same campus where Grindon works have pinned one family's cases of clubfoot on a defective gene--the first time an inherited cause of clubfoot has been identified.
Clubfoot causes a newborn's toes to grow inward and point down, so it looks like the child would walk on the sides of his or her feet. It's one of the most common birth defects, affecting one in 1000 babies worldwide. The condition prevents people from walking properly and can cause painful calluses and arthritis. Despite its prevalence, doctors can explain the cause of only 25% of the cases to parents, such as when the child has a concomitant condition such as spina bifida. "A lot of people still think it's caused by cramped quarters in the womb even though it's pretty much been determined that's never the case," Grindon says.
Neurologist Christina Gurnett of the Washington University School of Medicine says the chance to test the genetic basis of clubfoot came when her husband, an orthopedic surgeon, operated on a young boy with a severe form of the condition. Because several members of his family also had a form of clubfoot, the researchers considered whether family genetics could explain the condition. They performed a genome-wide analysis on 13 family members' DNA and two carriers who did not show signs of the syndrome and were immediately drawn to a region on the long arm of chromosome 5. They then sequenced dozens of genes from that region and found a common point mutation: That single change in the DNA causes a gene called Pitx1 to produce the wrong protein. Because the Pitx1 gene turns on at the beginning of limb development, a mutation in the gene itself or pathways regulating it could warp the development of muscles, bones, and connective tissue fibers, Gurnett says. The mutation was present in all affected family members but in none of 500 control subjects without clubfoot that they later examined, the researchers report this week in The American Journal of Human Genetics.
Although the researchers could not find this specific mutation in 100 unrelated clubfoot patients, Jeff Murray, a pediatrician who studies the molecular basis of birth defects at the University of Iowa in Iowa City, says he is still excited by the discovery. "Finding a genetic connection is a major advance," he says, because it nails the link between Pitx1 and clubfoot and provides a springboard for future diagnostics and treatment. Gurnett agrees, noting that the researchers are now exploring the pathways that affect Pitx1, mutations in which could be behind clubfoot in other families.