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Kids First: Project on Congenital Clubfoot

Talipes equinovarus (clubfoot) is a common congenital structural birth defect. Clubfoot occurs in ~1 in 1,000 live births in the United States, though the incidence varies in other worldwide populations. Clubfoot affects the structural components of the foot (tarsals), muscular and connective tissues including the Achilles and tibial tendons, and ligaments of the ankle. Males are affected twice as frequently as females, and at least half of patients present with bilateral disease. Surgical correction in infants requires tendoachilles lengthening, where the Achilles tendon is severed and the foot is casted to allow healing with the foot in a proper position. Although short-term success following clubfoot treatment is positive, long-term outcomes following surgical clubfoot correction are poor; complications include arthritis, reduced range of motion, weakness, pain and persistent deformity. Importantly, the number of surgical procedures required to produce a corrected clubfoot was significantly associated with poorer long-term outcomes. The pathogenesis of clubfoot remains largely unknown, though ~12% of patients report a family history. Targeted gene sequencing studies have failed to identify genetic loci associated with clubfoot. We recently reported FSTL5 as the first GWAS-associated locus associated with clubfoot, and we showed this gene was associated with sexually-dimorphic phenotypes in mice. Together with the Gabriella Miller Kids First Initiative (GMKF), we are poised to continue advancing the field's understanding of the genetic causes of clubfoot. The GMKF provides comprehensive genome sequencing (GS) in individuals and families with congenital birth defects. However, no study of congenital limb malformations has yet been conducted as part of the GMKF; thus, our study will be the first GMKF study to investigate genetic causes of congenital limb defects.

For the past several decades, we have collected DNA samples from families with multiple relatives affected with clubfoot. Similar to our previously-awarded GMKF studies (1X01HL132375 led by Dr. Rios and DE031445 co-led by Dr. Hecht), we will utilize the power of family-based inheritance mapping to discovery genetic causes of clubfoot. Using the comprehensive GS provided by the GMKF, we will discover sequence variants and copy number variants co-segregating with clubfoot in these families. We present a systematic approach to discover these clubfoot-causing variants, including an integrated approach to investigate variants impacting potential non-coding regulatory elements, which have previously been implicated in other limb malformations. At the completion of this study, we will provide the field with the most comprehensive genomic analysis of families with clubfoot, which will provide novel hypotheses regarding the genetic etiology of this complex congenital birth defect.