Genetics of clubfoot; recent progress and future perspectives

Basit, Sulman; Khoshhal, Khalid I.

doi:10.1016/j.ejmg.2017.09.006

Cited by 53 publications

(64 citation statements)

References 96 publications

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“…Based on the progress of pathogenesis, appropriate drug treatment may improve patient compliance and ultimately improve the efficacy of the Ponseti method. In addition, familial occurrence and interand intraphenotypic variability of clubfoot is well documented (Basit & Khoshhal, 2018). Several genes were identified as susceptible genes in clubfoot, such as the HOX family, CASP family, PITX-TXB4 pathway, troponin (TN) family, GLI3, T-box and MTHFR genes (Hecht et al, 2007;Shrimpton et al, 2004;Shyy et al, 2009;Weymouth et al, 2016;Zhang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Integrated bioinformatics analysis of potential pathway biomarkers using abnormal proteins in clubfoot

Cai

Yang

Chen

et al. 2020

PeerJ

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Background As one of the most common major congenital distal skeletal abnormalities, congenital talipes equinovarus (clubfoot) affects approximately one in one thousandth newborns. Although several etiologies of clubfoot have been proposed and several genes have been identified as susceptible genes, previous studies did not further explore signaling pathways and potential upstream and downstream regulatory networks. Therefore, the aim of the present investigation is to explore abnormal pathways and their interactions in clubfoot using integrated bioinformatics analyses. Methods KEGG, gene ontology (GO), Reactome (REAC), WikiPathways (WP) or human phenotype ontology (HP) enrichment analysis were performed using WebGestalt, g:Profiler and NetworkAnalyst. Results A large number of signaling pathways were enriched e.g. signal transduction, disease, metabolism, gene expression (transcription), immune system, developmental biology, cell cycle, and ECM. Protein-protein interactions (PPIs) and gene regulatory networks (GRNs) analysis results indicated that extensive and complex interactions occur in these proteins, enrichment pathways, and TF-miRNA coregulatory networks. Transcription factors such as SOX9, CTNNB1, GLI3, FHL2, TGFBI and HOXD13, regulated these candidate proteins. Conclusion The results of the present study supported previously proposed hypotheses, such as ECM, genetic, muscle, neurological, skeletal, and vascular abnormalities. More importantly, the enrichment results also indicated cellular or immune responses to external stimuli, and abnormal molecular transport or metabolism may be new potential etiological mechanisms of clubfoot.

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Section: Introductionmentioning

confidence: 99%

Integrated bioinformatics analysis of potential pathway biomarkers using abnormal proteins in clubfoot

Cai

Yang

Chen

et al. 2020

PeerJ

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“…However, Patient 1’s mother was never exposed to poisonous or pernicious environment during pregnancy. In addition, the genetic study does not reveal mutations in known genes associated with congenital club foot . As the relationship between limb and nervous system development discussed before, patients with hereditary neuropathies may present with early or congenital foot deformities and variable delay in motor milestones due to several genes, such as FGD4 , PRX , MTMR2 , SBF2 , SH3TC2 , GDAP1 mutations, and Charcot–Marie–Tooth type 1A (CMT1A) duplication .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the genetic study does not reveal mutations in known genes associated with congenital club foot. 44 As the relationship between limb and nervous system development discussed before, 45,46 patients with hereditary neuropathies may present with early or congenital foot deformities and variable delay in motor milestones due to several genes, such as FGD4, PRX, MTMR2, SBF2, SH3TC2, GDAP1 mutations, and Charcot-Marie-Tooth type 1A (CMT1A) duplication. 47 In this study, the early-onset dHMN plus congenital foot deformity is probably related with the large fragment deletion of DCTN1 as well as lose of appropriate cytoplasmic localization.…”

Section: Discussionmentioning

confidence: 99%

New phenotype of DCTN1‐related spectrum: early‐onset dHMN plus congenital foot deformity

Tian

Liu

Zhou

et al. 2020

Ann Clin Transl Neurol

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Objective To describe the clinical and genetic features of two patients with different phenotypes due to various Dynactin 1 (DCTN1) gene mutations and further explore the phenotype–genotype relationship. Methods Patient 1 is a 23‐year‐old man with congenital foot deformity and life‐long distal muscle weakness and atrophy. Patient 2 is a 48‐year‐old woman with adult‐onset progressive weakness, lower limbs atrophy, and pyramid bundle signs. Electrophysiology test showed normal nerve conduction velocity of both patients and neurogenic changes in needle electromyography. Open sural nerve biopsy for Patient 1 showed slight loss of myelinated nerve fibers. Both patients were performed with whole‐exome sequencing followed by functional study of identified variants. Results Two mutations in DCTN1 gene were identified in Patient 1 (c.626dupC) and Patient 2 (c.3823C>T), respectively. In vitro, the wild type mostly located in cytoplasm and colocalized with α‐tubulin. However, c.626dupC tended to be trapped into nuclear and the c.3823C>T formed cytoplasmic aggregates, both losing colocalization with α‐tubulin. Western blotting showed a truncated mutant with less molecular weight of c.626dupC was expressed. Interpretation We identify two novel DCTN1 mutations causing different phenotypes: (1) early‐onset distal hereditary motor neuropathy plus congenital foot malformation and (2) amyotrophic lateral sclerosis, respectively. We provide the initial evidence that foot developmental deficiency probably arises from subcellular localizing abnormality of Dynactin 1, revealing DCTN1‐related spectrum is still expanding.

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“…It has been related to the intra‐uterine position, environmental factors such as smoking, or abnormal muscle, soft tissue, bone and vascular malformations (Dobbs & Gurnett, 2009; Horn & Davidson, 2010). Moreover, there is definitely a genetic component regarding the development of club foot within 22q11.2DS: multiple genes (e.g., PITX1 , TBX4 ) are associated with the development of club foot and within identical twins there is 33% concordance (Basit & Khoshhal, 2018; Horn & Davidson, 2010). Interestingly, TBX1 is one of the deleted genes within the 22q11.2 region.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple (family) studies on club foot have provided (genetic) insights in the development of idiopathic club foot (Basit & Khoshhal, 2018). Despite this valuable research, the etiology of club foot is still largely unknown and therefore we propose an alternative possibility in order to gain more knowledge on the development of idiopathic club foot.…”

Section: Discussionmentioning

confidence: 99%

Club foot in association with the 22q11.2 deletion syndrome: An observational study

Homans

Crowley

Chen

et al. 2018

American J of Med Genetics Pt A

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The 22q11.2 Deletion Syndrome (22q11.2DS) occurs in ~1:3,000–6,000 individuals. Features less typically associated with 22q11.2DS, such as orthopedic manifestations, may be overlooked or may not lead to appropriate diagnostic testing. Club foot has a general population prevalence of ~1:1,000 and has been occasionally described in association with 22q11.2DS. Our hypothesis is that the prevalence of club foot is higher in patients with 22q11.2DS. We performed a retrospective review in two specialized 22q11.2DS centers to determine the prevalence of club foot. “True club foot” requires treatment (either conservative or surgical), therefore we only included those patients with proof of treatment. We investigated whether congenital heart disease (CHD) and/or cleft palate were associated with the presence of club foot within 22q11.2DS. The records of 1,466 patients were reviewed. Of these, 48 (3.3%) had confirmation of club foot (95% Confidence Interval: 2.4–4.3): 22 (46%) had a bilateral, 12 (25%) left, and 14 (29%) right club foot. Within our study, neither a CHD and/or a cleft palate were associated with a club foot. The prevalence of club foot in 22q11.2DS is 30 times higher than that observed in the general population. This suggests the diagnosis of club foot, especially in the face of other typically associated abnormalities of 22q11.2DS, should provoke consideration of 22q11.2DS as an underlying diagnosis, particularly in the neonatal setting.

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Genetics of clubfoot; recent progress and future perspectives

Cited by 53 publications

References 96 publications

Integrated bioinformatics analysis of potential pathway biomarkers using abnormal proteins in clubfoot

Integrated bioinformatics analysis of potential pathway biomarkers using abnormal proteins in clubfoot

New phenotype of DCTN1‐related spectrum: early‐onset dHMN plus congenital foot deformity

Club foot in association with the 22q11.2 deletion syndrome: An observational study

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