A recurrent pathogenic variant in <scp><i>TPM2</i></scp> reveals further phenotypic and genetic heterogeneity in multiple pterygium syndrome‐related disorders

Vogt, Julie; Alsaedi, Atif Saud; Willis, Tracey; Male, Alison; McKie, Arthur B.; Kiely, Nigel

doi:10.1111/cge.13728

Cited by 6 publications

(7 citation statements)

References 35 publications

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“…Only three papers described mutations in the TPM2 gene associated with Escobar syndrome [ 17 , 18 , 19 ]. The variant identified in our patients was previously reported in an Algerian consanguineous family [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Other genes are related to MPS. Indeed, mutations in CHRNA1 , CHRND [ 4 , 16 ], and TPM2 have been described to be associated with Escobar syndrome [ 17 , 18 , 19 , 20 ]. This genetic heterogeneity makes genetic investigation challenging.…”

Section: Introductionmentioning

confidence: 99%

“…Some cases of patients with TPM2 mutations presented with nemaline myopathy (NM) associated with the Escobar syndrome phenotype [ 17 , 18 , 19 ]. Previous studies have shown that patients with NM have subsarcolemmal accumulations of abnormal mitochondria and nemaline rods [ 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Combining Gene Mutation with Expression of Candidate Genes to Improve Diagnosis of Escobar Syndrome

Najjar

Chikhaoui

Zarrouk‐Mahjoub

et al. 2022

Genes

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Escobar syndrome is a rare, autosomal recessive disorder that affects the musculoskeletal system and the skin. Mutations in the CHRNG and TPM2 genes are associated with this pathology. In this study, we conducted a clinical and genetic investigation of five patients and also explored via in silico and gene expression analysis their phenotypic variability. In detail, we identified a patient with a novel composite heterozygous variant of the CHRNG gene and two recurrent mutations in both CHRNG and TPM2 in the rest of the patients. As for the clinical particularities, we reported a list of modifier genes in a patient suffering from myopathy. Moreover, we identified decreased expression of IGF-1, which could be related to the short stature of Escobar patients, and increased expression of POLG1 specific to patients with TPM2 mutation. Through this study, we identified the genetic spectrum of Escobar syndrome in the Tunisian population, which will allow setting up genetic counseling and prenatal diagnosis for families at risk. In addition, we highlighted relevant biomarkers that could differentiate between patients with different genetic defects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Combining Gene Mutation with Expression of Candidate Genes to Improve Diagnosis of Escobar Syndrome

Najjar

Chikhaoui

Zarrouk‐Mahjoub

et al. 2022

Genes

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“…TPM2 variants are also causative of Escobar variant of multiple pterygium syndrome (EVMPS) (Marttila et al, 2014;Tajsharghi et al, 2012;Vogt et al, 2020). EVMPS patients show joint contractures similar to those reported for DA patients, but EVMPS is distinguished from DA by the presence of webbing (pterygia) at the neck, elbows, or knees (Morgan et al, 2006).…”

Section: Introductionmentioning

confidence: 85%

Anin vivoapproach to characterize novel variants associated with musculoskeletal disorders

McAdow

Yang

et al. 2021

Preprint

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Pathogenic variants in Tropomyosin 2 (TPM2), which encodes a skeletal muscle specific actin binding protein essential for sarcomere function, cause a spectrum of musculoskeletal disorders including Nemaline Myopathy, Cap Myopathy, congenital fiber type disproportion, and distal arthrogrypsosis (DA). TPM2-related disorders have not been modeled in vivo, so we expressed a series of dominant, pathogenic TPM2 variants in Drosophila embryos and found two variants, K49Del and E122K, disrupted muscle morphogenesis and muscle function. Transient overexpression of K49Del and E122K also disrupted muscle morphogenesis in zebrafish. We further developed a benchmarked overexpression assay in zebrafish to characterize TPM2 variants that we identified in DA patients, and found these variants caused musculoskeletal defects similar to those of the known pathogenic variants. In addition, the severity of musculoskeletal phenotypes in zebrafish expressing TPM2 variants correlated with the severity of clinical phenotypes observed in DA patients. Our study establishes transient overexpression in zebrafish as an efficient platform to characterize variants of uncertain significance in vivo, and argues our assays can predict the clinical severity of musculoskeletal associated variants.

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“…TPM2 variants are also causative of Escobar variant of multiple pterygium syndrome (EVMPS) ( 19 , 21 , 22 ). Patients with EVMPS show joint contractures similar to those reported for patients with DA, but EVMPS is differentiated from DA by the presence of webbing (pterygia) at the neck, elbows, or knees ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

A pathogenic mechanism associated with myopathies and structural birth defects involves TPM2-directed myogenesis

McAdow¹,

Yang²,

Ou³

et al. 2022

JCI Insight

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Nemaline myopathy (NM) is the most common congenital myopathy, characterized by extreme weakness of the respiratory, limb, and facial muscles. Pathogenic variants in Tropomyosin 2 ( TPM2 ), which encodes a skeletal muscle–specific actin binding protein essential for sarcomere function, cause a spectrum of musculoskeletal disorders that include NM as well as cap myopathy, congenital fiber type disproportion, and distal arthrogryposis (DA). The in vivo pathomechanisms underlying TPM2 -related disorders are unknown, so we expressed a series of dominant, pathogenic TPM2 variants in Drosophila embryos and found 4 variants significantly affected muscle development and muscle function. Transient overexpression of the 4 variants also disrupted the morphogenesis of mouse myotubes in vitro and negatively affected zebrafish muscle development in vivo. We used transient overexpression assays in zebrafish to characterize 2 potentially novel TPM2 variants and 1 recurring variant that we identified in patients with DA (V129A, E139K, A155T, respectively) and found these variants caused musculoskeletal defects similar to those of known pathogenic variants. The consistency of musculoskeletal phenotypes in our assays correlated with the severity of clinical phenotypes observed in our patients with DA, suggesting disrupted myogenesis is a potentially novel pathomechanism of TPM2 disorders and that our myogenic assays can predict the clinical severity of TPM2 variants.

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A recurrent pathogenic variant in TPM2 reveals further phenotypic and genetic heterogeneity in multiple pterygium syndrome‐related disorders

Cited by 6 publications

References 35 publications

Combining Gene Mutation with Expression of Candidate Genes to Improve Diagnosis of Escobar Syndrome

Combining Gene Mutation with Expression of Candidate Genes to Improve Diagnosis of Escobar Syndrome

Anin vivoapproach to characterize novel variants associated with musculoskeletal disorders

A pathogenic mechanism associated with myopathies and structural birth defects involves TPM2-directed myogenesis

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