<i>TBX6</i>
            missense variants expand the mutational spectrum in a non‐Mendelian inheritance disease

Chen, Weisheng; Lin, Jiachen; Wang, Lianlei; Li, Xiaoxin; Zhao, Sen; Liu, Jiaqi; Akdemir, Zeynep Coban; Zhao, Yanyang; Du, Renqian; Ye, Yongyu; Song, Xiaofei; Zhang, Yuanqiang; Yan, Zihui; Yang, Xinzhuang; Lin, Mao; Shen, Jianxiong; Wang, Shengru; Gao, Na; Yang, Ying; Liu, Ying; Li, Wenli; Zhang, Na; Xu, Yang; Xu, Yuan; Zhang, Jianguo; Delgado, Mauricio R.; Posey, Jennifer E.; Qiu, Guixing; Rios, Jonathan J.; Liu, Pengfei; Wise, Carol A.; Zhang, Feng; Wu, Zhihong; Lupski, James R.; Wu, Nan

doi:10.1002/humu.23907

Cited by 32 publications

(32 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We recently reported a novel clinically distinguishable subtype of CS, namely, TBX6 -associated congenital scoliosis (TACS). Briefly, TACS is caused by TBX6 loss-of-function variations compound with the common hypomorphic single nucleotide polymorphisms (defined by rs2289292-rs3809624-rs3809627), and is characterized by hemivertebrae or butterfly vertebrae in the lower half of the spine [ 6 – 9 ]. Compared with non-TACS patients, TACS patients demonstrate simpler rib anomalies and fewer intraspinal malformations.…”

Section: Introductionmentioning

confidence: 99%

Cost-effectiveness analysis of using the TBX6-associated congenital scoliosis risk score (TACScore) in genetic diagnosis of congenital scoliosis

Chen

Yan

et al. 2020

Orphanet J Rare Dis

Self Cite

View full text Add to dashboard Cite

Background We previously reported a novel clinically distinguishable subtype of congenital scoliosis (CS), namely, TBX6-associated congenital scoliosis (TACS). We further developed the TBX6-associated CS risk score (TACScore), a multivariate phenotype-based model to predict TACS according to the patient’s clinical manifestations. In this study, we aimed to evaluate whether using the TACScore as a screening method prior to performing whole-exome sequencing (WES) is more cost-effective than using WES as the first-line genetic test for CS. Methods We retrospectively collected the molecular data of 416 CS patients in the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study. A decision tree was constructed to estimate the cost and the diagnostic time required for the two alternative strategies (TACScore versus WES). Bootstrapping simulations and sensitivity analyses were performed to examine the distributions and robustness of the estimates. The economic evaluation considered both the health care payer and the personal budget perspectives. Results From the health care payer perspective, the strategy of using the TACScore as the primary screening method resulted in an average cost of $1074.2 (95%CI: $1044.8 to $1103.5) and an average diagnostic duration of 38.7d (95%CI: 37.8d to 39.6d) to obtain a molecular diagnosis for each patient. In contrast, the corresponding values were $1169.6 (95%CI: $1166.9 to $1172.2) and 41.4d (95%CI: 41.1d to 41.7d) taking WES as the first-line test (P < 0.001). From the personal budget perspective, patients who were predicted to be positive by the TACScore received a result with an average cost of $715.1 (95%CI: $594.5 to $835.7) and an average diagnostic duration of 30.4d (95%CI: 26.3d to 34.6d). Comparatively, the strategy of WES as the first-line test was estimated to have significantly longer diagnostic time with an average of 44.0d (95%CI: 43.2d to 44.9d), and more expensive with an average of $1193.4 (95%CI: $1185.5 to $1201.3) (P < 0.001). In 100% of the bootstrapping simulations, the TACScore strategy was significantly less costly and more time-saving than WES. The sensitivity analyses revealed that the TACScore strategy remained cost-effective even when the cost per WES decreased to $8.8. Conclusions This retrospective study provides clinicians with economic evidence to integrate the TACScore into clinical practice. The TACScore can be considered a cost-effective tool when it serves as a screening test prior to performing WES.

show abstract

Section: Introductionmentioning

confidence: 99%

Cost-effectiveness analysis of using the TBX6-associated congenital scoliosis risk score (TACScore) in genetic diagnosis of congenital scoliosis

Chen

Yan

et al. 2020

Orphanet J Rare Dis

Self Cite

View full text Add to dashboard Cite

show abstract

“…During this process, TBX6 is expressed in the entire pre‐somitic mesoderm, and regulates a series of genes to enable the normal somitogenesis and subsequent development of the skeletal system (Oginuma et al, 2008). As TBX6 has been revealed as a core disease gene of CS (Chen et al, 2020; Liu et al, 2019; Wu et al, 2015), we conducted this study based on a hypothesis that TBX6 ‐mediated genes may as well contribute to CS. The rationality of this hypothesis is supported by disrupted spinal development in animal models depleted of the candidate genes (Takahashi et al, 2010; Windner et al, 2015), and by several autosomal recessive syndromes resulting in spinal malformation cause by these genes (Di Gioia et al, 2018; Karaca et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Mutational burden and potential oligogenic model of TBX6‐mediated genes in congenital scoliosis

Yang

Zhao

Zhang

et al. 2020

Molec Gen & Gen Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this study, we analyzed variants in CSF1R in a cohort of congenital vertebral malformation (CVM), which has been partially attributed to genetic defects previously (Wu et al, 2015 , 2019 ; Chen et al, 2016 , 2020 ; Liu et al, 2019 ; Yang et al, 2019 , 2020 ; Lin et al, 2020 ; Ren et al, 2020 ). In vitro and in vivo functional experiments were then performed to explore the effect of these variants on protein expression and vertebral morphology.…”

Section: Introductionmentioning

confidence: 99%

Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism

Liu

Zhao

Yan

et al. 2021

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

CSF1R encodes the colony-stimulating factor 1 receptor which regulates the proliferation, differentiation, and biological activity of monocyte/macrophage lineages. Pathogenic variants in CSF1R could lead to autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia or autosomal recessive skeletal dysplasia. In this study, we identified three heterozygous deleterious rare variants in CSF1R from a congenital vertebral malformation (CVM) cohort. All of the three variants are located within the carboxy-terminal region of CSF1R protein and could lead to an increased stability of the protein. Therefore, we established a zebrafish model overexpressing CSF1R. The zebrafish model exhibits CVM phenotypes such as hemivertebral and vertebral fusion. Furthermore, overexpression of the mutated CSF1R mRNA depleted of the carboxy-terminus led to a higher proportion of zebrafish with vertebral malformations than wild-type CSF1R mRNA did (p = 0.03452), implicating a gain-of-function effect of the C-terminal variant. In conclusion, variants affecting the C-terminal of CSF1R could cause CVM though a potential gain-of-function mechanism.

show abstract

TBX6 missense variants expand the mutational spectrum in a non‐Mendelian inheritance disease

Cited by 32 publications

References 49 publications

Cost-effectiveness analysis of using the TBX6-associated congenital scoliosis risk score (TACScore) in genetic diagnosis of congenital scoliosis

Cost-effectiveness analysis of using the TBX6-associated congenital scoliosis risk score (TACScore) in genetic diagnosis of congenital scoliosis

Mutational burden and potential oligogenic model of TBX6‐mediated genes in congenital scoliosis

Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism

Contact Info

Product

Resources

About