Matthew B Dobbs

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (112)275.04 Total impact

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    ABSTRACT: Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis, using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was completed for three members of this multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. The HSPG2 gene was sequenced in a separate cohort of 100 unrelated individuals affected with idiopathic scoliosis, and was also examined in an independent idiopathic scoliosis population. The exome sequencing and subsequent bioinformatics filtering resulted in 16 potentially damaging and rare coding variants. One of these variants, p.Asn786Ser, is located in the HSPG2 gene. The variant p.Asn786Ser is also over-represented in a larger cohort of idiopathic scoliosis cases compared to a control population (p=0.024). Furthermore, we identified additional rare HSPG2 variants that are predicted to be damaging in two independent cohorts of individuals with idiopathic scoliosis. The HSPG2 gene encodes for a ubiquitous multifunctional protein within the extracellular matrix in which loss of function mutation are known to result in a musculoskeletal phenotype in both mouse and humans. Based on these results, we conclude that rare variants in the HSPG2 gene potentially contribute to the idiopathic scoliosis phenotype in a subset of patients with idiopathic scoliosis. Further studies must be completed to confirm the effect of the HSPG2 gene on the idiopathic scoliosis phenotype. Copyright © 2014 Author et al.
    G3 (Bethesda, Md.). 12/2014;
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    ABSTRACT: Clubfoot treatment commonly fails and often results in impaired quality of life. An understanding of the soft-tissue abnormalities associated with both treatment-responsive and treatment-resistant clubfoot is important to improving the diagnosis of clubfoot, the prognosis for patients, and treatment.
    The Journal of bone and joint surgery. American volume. 08/2014; 96(15):1249-1256.
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    ABSTRACT: Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder that causes spinal deformity in approximately 3% of the population. Candidate gene, linkage, and genome-wide association studies have sought to identify genetic variation that predisposes individuals to AIS, but the genetic basis remains unclear. Copy number variants are associated with several isolated skeletal phenotypes, but their role in AIS, to our knowledge, has not been assessed.
    Clinical Orthopaedics and Related Research 07/2014; · 2.79 Impact Factor
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    ABSTRACT: Adolescent idiopathic scoliosis (AIS) causes spinal deformity in 3% of children. Despite a strong genetic basis, few genes have been associated with AIS and the pathogenesis remains poorly understood. In a genome-wide rare variant burden analysis using exome sequence data, we identified FBN1 (fibrillin-1) as the most significantly associated gene with AIS. Based on these results, FBN1 and a related gene, FBN2 (fibrillin-2), were sequenced in a total of 852 AIS cases and 669 controls. In individuals of European ancestry, rare variants in FBN1 and FBN2 were enriched in severely affected AIS cases (7.6%) compared to in-house controls (2.4%) (OR=3.5, P=5.46×10(-4)) and Exome Sequencing Project controls (2.3%) (OR=3.5, P=1.48×10(-6)). Scoliosis severity in AIS cases was associated with FBN1 and FBN2 rare variants (P=0.0012) and replicated in an independent Han Chinese cohort (P=0.0376), suggesting that rare variants may be useful as predictors of curve progression. Clinical evaluations revealed that the majority of AIS cases with rare FBN1 variants do not meet diagnostic criteria for Marfan syndrome, though variants are associated with tall stature (P=0.0035) and upregulation of the TGF-β pathway. Overall, these results expand our definition of fibrillin-related disorders to include AIS and open up new strategies for diagnosing and treating severe AIS.
    Human Molecular Genetics 05/2014; · 7.69 Impact Factor
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    ABSTRACT: Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG). Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts. We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10-43 for rs11190870, and P=2.94×10-48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes. Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.
    Journal of Medical Genetics 04/2014; · 5.70 Impact Factor
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    ABSTRACT: Clubfoot is a common congenital birth defect with complex inheritance patterns. Currently, the genetic and morphological basis of clubfoot is poorly understood. To identify genetic risk factors associated with clubfoot, we performed a genome-wide association study of common genetic variants. The DNA of 396 isolated clubfoot patients and 1000 controls of European descent was genotyped for >600 000 single nucleotide polymorphisms (SNP) using the Affymetrix 6.0 array. Replication was performed with an independent cohort of 370 isolated clubfoot cases and 363 controls of European descent. Strongest evidence for an association of clubfoot was found with an intergenic SNP on chromosome 12q24.31 between NCOR2 and ZNF664 (rs7969148, OR=0.58, p=1.25×10(-5)) that was significant on replication (combined OR=0.63, p=1.90×10(-7)). Additional suggestive SNPs were identified near FOXN3, SORCS1 and MMP7/TMEM123 that also confirmed on replication. Our study suggests a potential role for common genetic variation in several genes that have not previously been implicated in clubfoot pathogenesis.
    Journal of Medical Genetics 03/2014; · 5.70 Impact Factor
  • Clinical Orthopaedics and Related Research 11/2013; · 2.79 Impact Factor
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    Clinical Orthopaedics and Related Research 09/2013; · 2.79 Impact Factor
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    ABSTRACT: Myosin binding protein C1 (MYBPC1) is an abundant skeletal muscle protein that is expressed predominantly in slow twitch muscle fibers. Human MYBPC1 mutations are associated with distal arthrogryposis type 1 and lethal congenital contracture syndrome (LCCS4). Because MYBPC1 function is incompletely understood, the mechanism by which human mutations result in contractures is unknown. Here, we demonstrate using antisense morpholino knockdown, that mybpc1 is required for embryonic motor activity and survival in a zebrafish model of arthrogryposis. Mybpc1 morphant embryos have severe body curvature, cardiac edema, impaired motor excitation and are delayed in hatching. Myofibril organization is selectively impaired in slow skeletal muscle and sarcomere numbers are greatly reduced in mybpc1 knockdown embryos although electron microscopy reveals normal sarcomere structure. To evaluate the effects of human distal arthrogryposis mutations, mybpc1 mRNAs containing the corresponding human W236R and Y856H MYBPC1 mutations were injected into embryos. Dominant-negative effects of theses mutations were suggested by the resultant mild bent body curvature, decreased motor activity, as well as impaired overall survival compared to overexpression of wild-type RNA. These results demonstrate a critical role for mybpc1 in slow skeletal muscle development and establish zebrafish as a tractable model of human distal arthrogryposis.
    Human Molecular Genetics 07/2013; · 7.69 Impact Factor
  • Matthew B Dobbs
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    ABSTRACT: This CORR Insights™ is a commentary on the article ''Can a Triple Pelvic Osteotomy for Adult Symptomatic Hip Dysplasia Provide Relief of Symptoms for 25 Years?" By van Stralen and colleagues available at DOI 10.1007/s11999-012-2701-0 .
    Clinical Orthopaedics and Related Research 12/2012; · 2.79 Impact Factor
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    ABSTRACT: Talipes equinovarus is one of the most common congenital musculoskeletal anomalies and has a worldwide incidence of 1 in 1000 births. A genetic predisposition to talipes equinovarus is evidenced by the high concordance rate in twin studies and the increased risk to first-degree relatives. Despite the frequency of isolated talipes equinovarus and the strong evidence of a genetic basis for the disorder, few causative genes have been identified. To identify rare and/or recurrent copy number variants, we performed a genome-wide screen for deletions and duplications in 413 isolated talipes equinovarus patients using the Affymetrix 6.0 array. Segregation analysis within families and gene expression in mouse E12.5 limb buds were used to determine the significance of copy number variants. We identified 74 rare, gene-containing copy number variants that were present in talipes equinovarus probands and not present in 759 controls or in the Database of Genomic Variants. The overall frequency of copy number variants was similar between talipes equinovarus patients compared with controls. Twelve rare copy number variants segregate with talipes equinovarus in multiplex pedigrees, and contain the developmentally expressed transcription factors and transcriptional regulators PITX1, TBX4, HOXC13, UTX, CHD (chromodomain protein)1, and RIPPLY2. Although our results do not support a major role for recurrent copy number variations in the etiology of isolated talipes equinovarus, they do suggest a role for genes involved in early embryonic patterning in some families that can now be tested with large-scale sequencing methods.European Journal of Human Genetics advance online publication, 15 August 2012; doi:10.1038/ejhg.2012.177.
    European journal of human genetics: EJHG 08/2012; · 3.56 Impact Factor
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    ABSTRACT: Adolescent idiopathic scoliosis occurs between two and ten times more frequently in females than in males. The exact cause of this sex discrepancy is unknown, but it may represent a difference in susceptibility to the deformity. If this difference is attributable to genetic factors, then males with adolescent idiopathic scoliosis would need to inherit a greater number of susceptibility genes compared with females to develop the deformity. Males would also be more likely to transmit the disease to their children and to have siblings with adolescent idiopathic scoliosis. Such a phenomenon is known as the Carter effect, and the presence of such an effect would support a multifactorial threshold model of inheritance. One hundred and forty multiplex families in which more than one individual was affected with adolescent idiopathic scoliosis were studied. These families contained 1616 individuals, including 474 individuals with adolescent idiopathic scoliosis and 1142 unaffected relatives. The rates of transmission from the 122 affected mothers and from the twenty-eight affected fathers were calculated, and the prevalence among siblings was determined in the nuclear families of affected individuals. The prevalence of adolescent idiopathic scoliosis in these multiplex families was lowest in sons of affected mothers (36%, thirty-eight of 105) and highest in daughters of affected fathers (85%, twenty-two of twenty-six). Affected fathers transmitted adolescent idiopathic scoliosis to 80% (thirty-seven) of forty-six children, whereas affected mothers transmitted it to 56% (133) of 239 children (p < 0.001). Siblings of affected males also had a significantly higher prevalence of adolescent idiopathic scoliosis (55%, sixty-one of 110) compared with siblings of affected females (45%, 206 of 462) (p = 0.04). This study demonstrates the presence of the Carter effect in adolescent idiopathic scoliosis. This pattern can be explained by polygenic inheritance of adolescent idiopathic scoliosis, with a greater genetic load required for males to be affected.
    The Journal of Bone and Joint Surgery 08/2012; 94(16):1485-91. · 3.23 Impact Factor
  • Ornusa Chalayon, Amelia Adams, Matthew B Dobbs
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    ABSTRACT: Traditional extensive soft-tissue release for the treatment of congenital vertical talus is associated with a myriad of complications. A minimally invasive approach has recently been introduced with good short-term results in patients with isolated vertical talus. The purpose of the present study was to evaluate the effectiveness of this approach for the treatment of rigid vertical talus associated with neuromuscular and/or genetic syndromes. Fifteen consecutive patients (twenty-five feet) with non-isolated congenital vertical talus were retrospectively reviewed at a minimum of two years following treatment with serial casting followed by limited surgery. The surgery consisted of percutaneous Achilles tenotomy in all feet and either pin fixation of the talonavicular joint through a small medial incision to ensure joint reduction and accurate pin placement (five feet) or selective capsulotomies of the talonavicular joint and the anterior aspect of the subtalar joint (twenty feet). Patients were evaluated clinically and radiographically at the time of presentation, immediately postoperatively, and at the time of the latest follow-up. Radiographic data at the time of the latest follow-up were compared with age-matched normative values. Initial correction was obtained in all cases. The mean number of casts required was five. Mean ankle dorsiflexion was 22° and mean plantar flexion was 25° at the time of the latest follow-up. Recurrence was noted in three patients (five feet), all of whom had had initial subluxation of the calcaneocuboid joint. All radiographic parameters measured at the time of the latest follow-up had improved significantly (p < 0.0001) compared with the values before treatment, and the mean values of the measured angles did not differ significantly from age-matched normal values. Serial manipulation and casting followed by limited surgery, consisting of percutaneous tenotomy of the Achilles tendon and a small medial incision to either palpate the talonavicular joint or perform capsulotomies of the talonavicular joint and the anterior aspect of the subtalar joint to ensure accurate reduction and pin fixation, result in excellent short-term correction of the deformity while preserving subtalar and ankle motion in patients with rigid congenital vertical talus associated with neuromuscular and/or genetic syndromes.
    The Journal of Bone and Joint Surgery 06/2012; 94(11):e73. · 3.23 Impact Factor
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    ABSTRACT: Over the last 40 years, anatomic reduction with plate stabilization has become the standard in adult patients with diaphyseal fractures of the radius and ulna. When operative fixation has been indicated in skeletally immature patients with these fractures, a variety of techniques have been reported, with intramedullary fixation becoming increasingly accepted. There is currently significant variability in the treatment of adolescents with forearm fractures. The purpose of this study was to investigate the clinical and radiographic outcomes in the adolescent population after intramedullary fixation of both bone forearm fractures. A retrospective review identified 32 patients 12-18 years of age who had undergone intramedullary fixation of both forearm bones in the past 20 years at our institution. Galeazzi, Monteggia, radial head, and distal metaphyseal fractures were excluded. Radiographic evaluation was performed to determine union and postoperative radial bow. Clinical follow-up was carried out for postoperative complications and range of motion of the wrist, forearm, and elbow. The mean age of the patients was 14.1 years. A total of 19 fractures were closed injuries, nine were grade 1, three were grade 2, and one fracture was a grade 3b. Of the patients, 15.6% had limited postoperative range of motion. All patients in the older age group, 15-18 years of age, had a normal range of motion. A decrease in radial bow was not associated with limitation in motion. There was a 98% union rate, and all unions occurred by 7.5 months. Only three major complications occurred, two refractures and one ulnar hardware migration, and subsequent radius nonunion occurred in the one grade 3b injury. Flexible intramedullary nailing of both bone forearm fractures provides reliable bony union and excellent postoperative clinical results in adolescents. Level of evidence, IV.
    Journal of pediatric orthopaedics. Part B / European Paediatric Orthopaedic Society, Pediatric Orthopaedic Society of North America 03/2012; 21(5):482-8. · 0.66 Impact Factor
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    ABSTRACT: We retrospectively analyzed cases of intra-articular medial malleolar fractures in skeletally-immature patients (Salter-Harris III and IV) with suboptimal outcomes at St. Louis Children's Hospital and Shriner's Hospital for Children. Common causes of poor outcome were frac­ture malunion or malreduction and physeal damage. Malreductions of only 2 mm does not appear to be toler­ated and the concept of "remodeling" does not apply to these fracture patterns. Based on this study, we "recom­mend" fracture reduction and fixation if there is greater than 1 mm of fracture step-off..
    American journal of orthopedics (Belle Mead, N.J.) 03/2012; 41(3):113-6.
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    ABSTRACT: Circumferential casts can contribute to elevated compartment pressures in the setting of acute swelling. We have developed a novel casting method (A-frame cast) that allows cast placement while leaving the antecubital fossa free of casting material. The purpose of this study was to evaluate the safety, efficacy, and complications associated with acute placement of this definitive cast after closed reduction percutaneous pinning (CRPP) of acute supracondylar distal humerus fractures. A retrospective medical record reviewed 436 patients treated with CRPP of supracondylar fractures by 3 surgeons who routinely used an A-frame cast over a 12-year period. All complications or the need for cast modification were noted. Patients with open reduction, ipsilateral fractures, or patients lost to follow-up were excluded. There were 387 patients who met inclusion criteria, including 204 type 2 fractures and 183 type 3 fractures. Forty-three patients had preoperative nerve palsy and 1 had preoperative vascular injury. Of these 387 patients, 369 (95.3%) had an uneventful postoperative course. Nineteen patients (4.9%) required either cast splitting (15) or strict elevation (4) secondary to pain and swelling. Seven of these 19 patients had preoperative nerve palsy and 1 had preoperative vascular injury. The average time from procedure to cast splitting was 17.6 hours. No patients lost their reduction or required a second surgical procedure related to a complication from casting. An "A-frame" cast provides sturdy immobilization without increased risk of compartment syndrome after CRPP of supracondylar fractures in the pediatric population. Consideration should be given to splitting the cast prophylactically in patients with preoperative neurological or vascular deficits. IV-Case Series.
    Journal of pediatric orthopedics 01/2012; 32(1):e1-5. · 1.23 Impact Factor
  • James R Ross, Matthew B Dobbs
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    ABSTRACT: Tarsal coalitions between the navicular and the cuneiforms occur infrequently when compared with the more common talocalcaneal and calcaneonavicular coalitions. Isolated cases of navicular-medial cuneiform coalitions have only rarely been reported; however, the diagnosis is likely underrecognized. Conservative management should be pursued initially for symptomatic patients, followed by surgical options for unresponsive cases. The few reports available recommend treatment with navicular-medial cuneiform fusions, but long-term follow-up is not available to assess outcome and it remains unclear whether an isolated arthrodesis of the navicular-medial cuneiform joint will in turn lead to differing biomechanics of adjacent joints. We report a case of a patient with an isolated navicular-medial cuneiform coalition, treated with resection and free-fat interposition rather than arthrodesis. To our knowledge, this is the first case of a navicular-medial cuneiform coalition reported in a patient of North American ancestry. At 2 years postoperatively, she is pain-free with all activities and has full range of motion of her ankle and subtalar joints, and full mobility at the navicular-medial cuneiform joint. This unique method provided a successful solution to this difficult situation.
    Journal of pediatric orthopedics 12/2011; 31(8):e85-8. · 1.23 Impact Factor
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    ABSTRACT: Isolated clubfoot is a relatively common birth defect that affects approximately 4,000 newborns in the US each year. Calf muscles in the affected leg(s) are underdeveloped and remain small even after corrective treatment. This observation suggests that variants in genes that influence muscle development are priority candidate risk factors for clubfoot. This contention is further supported by the discovery that mutations in genes that encode components of the muscle contractile complex (MYH3, TPM2, TNNT3, TNNI2, and MYH8) cause congenital contractures, including clubfoot, in distal arthrogryposis (DA) syndromes. Interrogation of 15 genes encoding proteins that control myofiber contractility in a cohort of both non-Hispanic White (NHW) and Hispanic families, identified positive associations (P < 0.05) with SNPs in 12 genes; only 1 was identified in a family-based validation dataset. Six SNPs in TNNC2 deviated from Hardy-Weinberg equilibrium in mothers in our NHW discovery dataset. Relative risk and likelihood ratio tests showed evidence for a maternal genotypic effect with TNNC2/rs383112 and an inherited/child genotypic effect with two SNPs, TNNC2/rs4629 and rs383112. Associations with multiple SNPs in TPM1 were identified in the NHW discovery (rs4075583, P = 0.01), family-based validation (rs1972041, P = 0.000074), and case-control validation (rs12148828, P = 0.04) datasets. Gene interactions were identified between multiple muscle contraction genes with many of the interactions involving at least one potential regulatory SNP. Collectively, our results suggest that variation in genes that encode contractile proteins of skeletal myofibers may play a role in the etiology of clubfoot.
    American Journal of Medical Genetics Part A 09/2011; 155A(9):2170-9. · 2.30 Impact Factor
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    Matthew B Dobbs, Christina A Gurnett
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    ABSTRACT: Modern advances in genetics have allowed investigators to identify the complex etiology of clubfoot. It has become increasingly apparent that clubfoot is a heterogeneous disorder with a polygenetic threshold model explaining its inheritance patterns. Several recent genetic studies have identified a key developmental pathway, the PITX1-TBX4 transcriptional pathway, as being important in clubfoot etiology. Both PITX1 and TBX4 are uniquely expressed in the hindlimb, which helps explain the foot phenotype seen with mutations in these transcription factors. Future studies are needed to develop animal models to determine the exact mechanisms by which these genetic abnormalities cause clubfoot and to test other hypotheses of clubfoot pathogenesis.
    Journal of pediatric orthopaedics. Part B / European Paediatric Orthopaedic Society, Pediatric Orthopaedic Society of North America 08/2011; 21(1):7-9. · 0.66 Impact Factor
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    ABSTRACT: Clubfoot affects 1 in 1000 live births, although little is known about its genetic or developmental basis. We recently identified a missense mutation in the PITX1 bicoid homeodomain transcription factor in a family with a spectrum of lower extremity abnormalities, including clubfoot. Because the E130K mutation reduced PITX1 activity, we hypothesized that PITX1 haploinsufficiency could also cause clubfoot. Using copy number analysis, we identified a 241 kb chromosome 5q31 microdeletion involving PITX1 in a patient with isolated familial clubfoot. The PITX1 deletion segregated with autosomal dominant clubfoot over three generations. To study the role of PITX1 haploinsufficiency in clubfoot pathogenesis, we began to breed Pitx1 knockout mice. Although Pitx1(+/-) mice were previously reported to be normal, clubfoot was observed in 20 of 225 Pitx1(+/-) mice, resulting in an 8.9% penetrance. Clubfoot was unilateral in 16 of the 20 affected Pitx1(+/-) mice, with the right and left limbs equally affected, in contrast to right-sided predominant hindlimb abnormalities previously noted with complete loss of Pitx1. Peroneal artery hypoplasia occurred in the clubfoot limb and corresponded spatially with small lateral muscle compartments. Tibial and fibular bone volumes were also reduced. Skeletal muscle gene expression was significantly reduced in Pitx1(-/-) E12.5 hindlimb buds compared with the wild-type, suggesting that muscle hypoplasia was due to abnormal early muscle development and not disuse atrophy. Our morphological data suggest that PITX1 haploinsufficiency may cause a developmental field defect preferentially affecting the lateral lower leg, a theory that accounts for similar findings in human clubfoot.
    Human Molecular Genetics 08/2011; 20(20):3943-52. · 7.69 Impact Factor

Publication Stats

2k Citations
275.04 Total Impact Points


  • 2002–2013
    • Washington University in St. Louis
      • Department of Orthopaedic Surgery
      San Luis, Missouri, United States
  • 2005–2011
    • University of Washington Seattle
      • Department of Neurology
      Seattle, WA, United States
  • 2002–2011
    • Shriners Hospitals for Children
      Tampa, Florida, United States
  • 2010
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2000–2009
    • University of Iowa
      • Department of Orthopaedics and Rehabilitation
      Iowa City, IA, United States
  • 2007
    • Barnes Jewish Hospital
      San Luis, Missouri, United States