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The genetics of clubfoot

By Jay D. Lenn

OREF-funded study helps to further understanding of foot disorder

Clubfoot is a common musculoskeletal disorder, but in many cases, the cause is unknown. Several lines of evidence—family history, twin studies, and varying prevalence rates among different ethnic groups—point to a genetic cause or a genetic susceptibility to the disorder, but the role played by genes is not clear.

In 2008, Matthew B. Dobbs, MD, and his research colleagues found a mutation in the PITX1 gene that caused multiple instances of clubfoot in a single family. Although it cannot explain all cases, the discovery of the role of PITX1 in one family is the first step toward clarifying the genetic etiology of clubfoot.

Christina A. Gurnett, MD, PhD, and Matthew B. Dobbs, MD, visit with a patient. Photo courtesy of Matthew B. Dobbs, MD

It runs in the family
Dr. Dobbs co-directs a musculoskeletal genetics laboratory with his wife, Christina A. Gurnett, MD, PhD. One goal of the laboratory is to accumulate a large DNA database from clinic patients who have a variety of pediatric orthopaedic conditions, including clubfoot. To date, the database contains samples from more than 2,000 patients.

Preliminary work for the current research project began with one of Dr. Dobbs’ patients who had bilateral clubfoot, right-sided tibial hemimelia, and other lower-limb abnormalities. After obtaining consent from the family, Dr. Dobbs took a road trip to southern Missouri to attend the patient’s family reunion. Within five generations, four other individuals had bilateral clubfoot, one had unilateral left clubfoot, and a number of others had less severe lower-limb abnormalities.

“I was able to examine family members’ limbs and feet, take pictures, and collect DNA,” said Dr. Dobbs. Genome-wide scans and more detailed genetic mapping of DNA samples from affected and unaffected family members, and unrelated control subjects led to the identification of a single type of mutation in the PITX1 gene that was responsible for clubfoot in this family.

PITX1, or paired-like homeodomain 1, encodes a transcription factor, a specialized protein that functions like an on-off switch for a gene. A transcription factor binds to a certain site on a stretch of DNA, which enables it—and often other transcription factors—to regulate when and how much a gene is expressed. This regulation ensures that a gene’s protein product is generated at the right time and in the right quantity.

When Dr. Dobbs’ team searched the DNA of other individuals with clubfoot—people not related to the Missouri family—they found no other carriers of the PITX1 mutation.

Newborn with bilateral clubfoot deformity. Photo courtesy of Matthew B. Dobbs, MD

A wealth of genetic questions
This discovery poses new questions: Are there PITX1 alleles or variations in nearby DNA that increase susceptibility to clubfoot? What genes regulate PITX1 expression, and can mutations in these genes lead to clubfoot? Which genes are the targets of PITX1 regulation, and do mutations in these genes cause the disorder?

Dr. Dobbs’ current project could identify PITX1 alleles that may increase the susceptibility to clubfoot. Washington University’s Musculoskeletal Disorders DNA Databank will serve as the primary resource for genetic information. This database includes diagnostic information, medical family histories, and DNA samples from about 400 clubfoot patients. DNA samples are available from the parents of about 300 of these patients. Dr. Dobbs’ group will add to the databank and get additional data from collaborators at other institutions to bring the total sample size to 1,000 patients with clubfoot and 1,000 controls. The goal is to identify small variations in DNA within or near the PITX1 gene that are more commonly found in people with clubfoot than in control subjects.

The research also aims to identify downstream transcriptional targets of PITX1 in the developing limb. Some evidence exists to indicate that PITX1 controls two genes involved in lower-limb development.

Finally, the research also could identify a different potential gene mutation causing clubfoot in another large family with a history of the disorder. Dr. Dobbs has already collected DNA from this second family, which has a clubfoot inheritance pattern suggesting that it is an autosomal recessive disorder. In this family, for clubfoot to develop, an individual would need to inherit two copies of a gene mutation. “If you can figure how this developmental pathway works best,” Dr. Dobbs explained, “then you can think of the potential for better treatment and preventive strategies.”

A 10-year old child whose full clubfoot relapse developed even after the child had been treated with extensive surgery in his native country. Photo courtesy of Matthew B. Dobbs, MD

Enhancing treatment
New treatments and prevention are a long way down the road, but Dr. Dobbs envisions an immediate benefit. Clinicians know from experience that some children with clubfoot have poor outcomes even after successful initial treatment and compliance with postcorrection brace wear. However, clinicians cannot predict which children will experience a relapse and require further treatment. Predicting response to treatment would have tremendous clinical benefits and cost savings because those predicted to be less at risk for relapse would not have to wear maintenance braces for the recommended 4 years. Classifying clubfoot by genetic factors may reveal that clubfoot associated with one gene mutation may be less prone to relapse than other types. This may help physicians predict treatment outcomes, alter their treatment strategies, and educate families.

Dr. Dobbs is an associate professor of pediatric orthopaedics at the Washington University School of Medicine in St. Louis and received a 2009 Career Development Award from the Orthopaedic Research and Education Foundation (OREF).

The award provides up to $75,000 annually for 3 years to researchers who have completed a residency in orthopaedic surgery and demonstrated both excellence in clinical training and a sustained interest in research.

Jay D. Lenn is a contributing writer for OREF and can be contacted at communications@oref.org

AAOS Now
November 2009 Issue
http://www.aaos.org/news/aaosnow/nov09/research1.asp