Genome-wide association study identifies new disease loci for isolated clubfoot

Zhang, Tian Xiao; Haller, Gabe; Lin, Peng-Cheng; Alvarado, David M.; Hecht, Jacqueline; Blanton, Susan H.; Richards, B. Stephens; Rice, John P.; Dobbs, Matthew B.; Gurnett, Christina A.

doi:10.1136/jmedgenet-2014-102303

Cited by 22 publications

(17 citation statements)

References 41 publications

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“…Besides the aforementioned candidate gene studies, a genome-wide association study was conducted in 396 isolated ICTEV patients and 1000 controls of European descent to identify novel genes for ICTEV (Zhang et al 2014 ). The selected genetic variants from the genome-wide association study were further replicated with an independent cohort of 370 isolated ICTEV cases and 363 controls with the same ethnicity.…”

Section: Resultsmentioning

confidence: 99%

A systematic review of association studies of common variants associated with idiopathic congenital talipes equinovarus (ICTEV) in humans in the past 30 years

Yong¹,

Xun²,

Zhao

et al. 2016

SpringerPlus

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The genetic cause of idiopathic congenital talipes equinovarus (ICTEV) is largely unknown. We performed a systematic review to describe the findings from 21 studies that have examined the genetic variants related to ICTEV, and to evaluate the quality of reporting. We found that ICTEV was positively associated with Hox family genes, collagen family genes, GLI3, N-acetylation genes, T-box family genes, apoptotic pathway genes, and muscle contractile family genes. Negative and controversial results were also discussed, and several genes associated with ICTEV were identified. Due to the limitation of the included studies, rare coding variants should be further investigated, sample size should be enlarged, and candidate genes should be replicated in larger ICTEV populations. Epigenetic study, pathways, chromosome capture, and detailed gene-environment interaction will also allow further elucidation of factors involved in ICTEV pathogenesis and may shed light on diagnosis and timely and accurate interventions.

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Section: Resultsmentioning

confidence: 99%

A systematic review of association studies of common variants associated with idiopathic congenital talipes equinovarus (ICTEV) in humans in the past 30 years

Yong¹,

Xun²,

Zhao

et al. 2016

SpringerPlus

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“…Future improvements in the use of botulinum toxin injections to weaken overactive antagonist muscles in clubfoot also may benefit from optimized muscle selection based on examination findings or imaging [6,16]. Furthermore, tendon transfers that are commonly used to correct muscle imbalance in clubfoot [29,46,75,76] would be predicted to fail if the transferred tendon derives from a hypoplastic muscle.…”

Section: Resultsmentioning

confidence: 99%

“…We tested the common disease/common variant hypothesis of disease etiology by performing a genome-wide association study of isolated clubfoot in nearly 400 patients with clubfoot followed by confirmation with an independent cohort [76]. The strongest evidence for an association of clubfoot was found with a single nucleotide polymorphism (SNP) near the transcriptional regulators NCOR2 and ZNF664.…”

Section: Genome-wide Association Study Of Common Variants Associated mentioning

confidence: 99%

The 2017 ABJS Nicolas Andry Award: Advancing Personalized Medicine for Clubfoot Through Translational Research

Dobbs

Gurnett

2017

Clinical Orthopaedics &Amp; Related Research

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Background Clubfoot is one of the most common pediatric orthopaedic disorders. While the Ponseti method has revolutionized clubfoot treatment, it is not effective for all patients. When the Ponseti method does not correct the foot, patients are at risk for lifelong disability and may require more-extensive surgery. Questions/Purposes (1) What genetic and morphologic abnormalities contribute to the development of clubfoot? (2) How can this information be used to devise personalized treatment paradigms for patients with clubfoot? Methods Human gene sequencing, molecular genetic engineering of mouse models of clubfoot, MRI of clubfoot, and development of new treatment methods all have been used by our group to understand the biological basis and improve therapy for this group of disorders. ResultsWe gained new insight into clubfoot pathogenesis from our discovery that mutations in the PITX1-TBX4-HOXC transcriptional pathway cause familial clubfoot and vertical talus in a small number of families, with the unique lower limb expression of these genes providing an explanation for the lack of upper extremity involvement in these disorders. MRI studies revealed corresponding morphologic abnormalities, including hypomorphic muscle, bone, and vasculature, that are not only associated with these gene mutations, but also are biomarkers for treatment-resistant clubfoot. Conclusions Based on an understanding of the underlying biology, we improved treatment methods for neglected and syndromic clubfoot, developed new treatment for congenital vertical talus based on the principles of the Ponseti method, and designed a new dynamic clubfoot brace to improve strength and compliance.

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“…So wurde gezeigt, dass insbesondere die zu Rezidiven neigenden Klumpfüße mit ausgeprägter initialer Deformität und begleitender Hüftdysplasie mit Fehlern im PITX1-TBX4-HOXC-Pfad assoziiert sind [47]. Ein weiterer Anhaltspunkt ist die gefundene genetische Assoziation von Einzelnukleotidpolymorphismen mit verschiedenen die Extremitätenentwicklung beeinflussenden Transkriptionsfaktoren bei der Klumpfußentstehung [48]. Eine präzise Analyse der verschiedenen Entstehungsursachen der Klumpfüße bietet die Möglichkeit der besseren Beratung und Behandlung, in Zukunft möglicherweise sogar einer ursächlichen, zumindest aber einer personalisierten Therapie.…”

Section: Diagnostische Fortschritteunclassified

Klumpfußtherapie nach Ponseti – aktueller Standard

Funk

Lebek

2018

Z Orthop Unfall

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ZusammenfassungIn dieser Übersicht wird die Klumpfußbehandlung unter besonderer Berücksichtigung der von Ponseti entwickelten konservativen Methode dargestellt. Im Kontext der verfügbaren Literatur werden die pathoanatomischen Grundlagen, die zu der Entwicklung der einfachen Korrekturhandgriffe führten, beschrieben. Die Auswirkungen der verschiedenen Ruhigstellungsmaterialien auf das Behandlungsergebnis werden ebenso beleuchtet wie die Probleme bei der Abduktionsschienentherapie. Weiterhin werden das Erkennen von Rezidiven und das von Ponseti entwickelte Konzept zur Rezidivbehandlung erörtert. Dass die Methode sich zum weltweiten Goldstandard entwickelt hat, belegen neben der globalen Verbreitung auch in Ländern mit geringem Einkommen Untersuchungen, die zeigen, dass sie auch bei nicht idiopathischen, vernachlässigten und voroperierten Klumpfüßen gute initiale Ergebnisse bewirkt. In verschiedenen Untersuchungen wurde auch mit instrumenteller Bewegungsanalyse gezeigt, dass konservativ behandelte Klumpfüße deutlich besser funktionieren, weil sie weniger arthrotische Veränderungen und Schmerzen zeigen als ausgedehnt operierte. Diese Informationen sind für den Behandler nicht nur nützlich bei der pränatalen Beratung hinsichtlich der besten verfügbaren Therapie, sondern helfen auch, die Compliance der Eltern bei der mehrjährigen Abduktionsschienenbehandlung hoch zu halten. Zu diesem Zweck wird auch der Vergleich zur konservativen physiotherapeutischen bzw. französischen Methode gezogen. Abschließend wird der Forschungsstand hinsichtlich der genetischen Ursachen der Klumpfußentwicklung beleuchtet.

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Genome-wide association study identifies new disease loci for isolated clubfoot

Abstract: Our study suggests a potential role for common genetic variation in several genes that have not previously been implicated in clubfoot pathogenesis.

Cited by 22 publications

References 41 publications

A systematic review of association studies of common variants associated with idiopathic congenital talipes equinovarus (ICTEV) in humans in the past 30 years

A systematic review of association studies of common variants associated with idiopathic congenital talipes equinovarus (ICTEV) in humans in the past 30 years

The 2017 ABJS Nicolas Andry Award: Advancing Personalized Medicine for Clubfoot Through Translational Research

Klumpfußtherapie nach Ponseti – aktueller Standard

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