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Insights into the Genetics of Clubfoot

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Molecular Genetics of Pediatric Orthopaedic Disorders

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Abstract

Clubfoot, a common complex birth defect, affects 135,000 newborns each year worldwide. While tremendous strides have been made in treatment with the Ponsetti nonsurgical method, the post-treatment foot generally remains small with hypoplastic calf musculature. Even though clubfoot has been studied for more than 100 years, only a few contributing factors have been identified. Prenatal tobacco smoke exposure is the only consistently associated environmental factor and confers an increased risk in a dose dependent manner. Moreover, maternal smoking and a family history of clubfoot increases the risk 20-fold confirming that genetic factors play a role. Genetic studies have shown that variation in TBX4 and PITX1 cause syndromic forms of clubfoot; however, there is no evidence that variation in these genes contribute to nonsyndromic clubfoot. Recent work suggests that variants in the regulatory regions of muscle-specific genes play a role by subtly affecting gene expression and it is hypothesized that variation in the expression of multiple genes is necessary for clubfoot development. This mechanism is consistent with the multifactorial model first proposed for clubfoot over 50 years ago. Confirmation of this work should enable identification of unique gene risk signatures that will aid in genetic counseling. Next generation approaches should speed gene identification in clubfoot.

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Acknowledgements

We thank Hilary Page (www.hilarypage.com) for the depiction of clubfeet in Fig. 6.1. Parts of the work described in this chapter were supported by grants from NIH (R01-HD043342) and Shriners Hospital for Children.

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Authors and Affiliations

  1. Department of Pediatrics, University of Texas Health Science Center—Medical School, 6431 Fannin St. MSB 3.031, 77020, Houston, TX, USA

    Katelyn S. Weymouth PhD

  2. Department of Human Genetics, University of Miami, 1501 NW 10th Ave BRB-406, 33136, Miami, FL, USA

    Susan H. Blanton PhD

  3. Department of Pediatrics, University of Texas Health Science Center—Medical School and School of Dentistry, 6431 Fannin St, Ste 3.136, 77020, Houston, TX, USA

    Jacqueline T. Hecht PhD

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  1. Katelyn S. Weymouth PhD
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  2. Susan H. Blanton PhD
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  3. Jacqueline T. Hecht PhD
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Correspondence to Katelyn S. Weymouth PhD .

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Editors and Affiliations

  1. Molecular Genetics, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA

    Carol A. Wise

  2. Texas Scottish Rite Hospital for Children, Dallas, Texas, USA

    Jonathan J. Rios

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Weymouth, K., Blanton, S., Hecht, J. (2015). Insights into the Genetics of Clubfoot. In: Wise, C., Rios, J. (eds) Molecular Genetics of Pediatric Orthopaedic Disorders. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2169-0_6

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