Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS)

Zhao, Sen; Zhang, Yuanqiang; Chen, Weisheng; Li, Weiyu; Wang, Shengru; Wang, Lianlei; Zhao, Yanyang; Lin, Mao; Ye, Yongyu; Lin, Jiachen; Zheng, Yu; Liu, Jiaqi; Zhao, Hengqiang; Yan, Zihui; Yang, Yongxin; Huang, Yingzhao; Lin, Guanfeng; Chen, Zefu; Zhang, Zhen; Liu, Sen; Jin, Lichao; Wang, Zhaoyang; Chen, Jingdan; Niu, Yuchen; Li, Xiaoxin; Wu, Yong; Wang, Yipeng; Du, Renqian; Gao, Na; Zhao, Hong; Yang, Ying; Liu, Ying; Tian, Ye; Li, Wenli; Zhao, Yu; Liu, Jia; Yu, Bin; Zhang, Na; Yu, Kai; Xu, Yang; Li, Shugang; Xu, Yuan; Hu, Jianhua; Liu, Zhe; Shen, Jianxiong; Zhang, Shuyang; Su, Jianzhong; Khanshour, Anas M.; Kidane, Yared H.; Ramo, Brandon; Rios, Jonathan J.; Liu, Pengfei; Sutton, V. Reid; Posey, Jennifer E.; Wu, Zhihong; Qiu, Guixing; Wise, Carol A.; Zhang, Feng; Lupski, James R.; Zhang, Jianguo; Wu, Nan

doi:10.1136/jmedgenet-2019-106823

Cited by 51 publications

(53 citation statements)

References 32 publications

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“…In counterfactual model 1 (the WES strategy), WES diagnosed a total of 73/416 (17.5%) patients, 42 of whom were diagnosed by TBX6 variations (thus TACS) and 31 of whom were diagnosed by other genes [12]. The total cost of 416 patients was $486,545.4, and the total diagnostic time was 17,224d.…”

Section: Cost-effectiveness Analysis From the Health Care Payer Perspmentioning

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

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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.

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Section: Cost-effectiveness Analysis From the Health Care Payer Perspmentioning

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

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“…Optimally, such seeding method should allow for a one-step surgical intervention [16,30] focusing As the clinical relevance of living replacement tissues is large, many groups have investigated methods to enhance cell loading for decellularized grafts. Such "repeated seeding" of autologous cells on cell-free matrix prior to the in vivo implantation, proved to prevent graft stenosis, calcification as well as valvular insufficiency and cusps thickening [31][32][33][34]. Recent findings indicate that once implanted, TEVaM undergo an inflammatory-driven process of "debris clearance" and errors in this mechanism can negatively influence their regeneration [12].…”

Section: Discussionmentioning

confidence: 99%

Puncturing of lyophilized tissue engineered vascular matrices enhances the efficiency of their recellularization

et al. 2018

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The concept of living tissue engineered, self-repairing, autologous cardiovascular replacements, was proposed alternatively to existing synthetic/xenogeneic prostheses. Recent studies in animal models demonstrate faster in vivo recellularization after grafts pre-seeding with cells prior implantation. Pre-seeded cells hold either, the ability to differentiate directionally or attract host cells, crucial for graft integration and remodeling. It is unclear, however, how efficient the pre-loading is and how well cells withstand the flow. The study presents a systematic overview of cell loading techniques of different cardiovascular constructs, tested under static and dynamic conditions. Comparison illustrates a significantly higher efficiency of cells loading in lyophilized tissues punctured before their standard seeding. This technique may beneficially accelerate remodeling of cardiovascular grafts in further in vivo studies.

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“…In-house-developed Peking Union Medical College Hospital Pipeline (PUMP) was used for variant calling and annotation. 29 , 30 …”

Section: Methodsmentioning

confidence: 99%

Deciphering the mutational signature of congenital limb malformations

Sun

Huang

Zhao

et al. 2021

Molecular Therapy - Nucleic Acids

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Congenital limb malformations (CLMs) affect 1 in 500 live births. However, the value of exome sequencing (ES) for CLM is lacking. The purpose of this study was to decipher the mutational signature of CLM on an exome level. We enrolled a cohort of 66 unrelated probands (including 47 families) with CLM requiring surgical correction. ES was performed for all patients and available parental samples. A definite molecular diagnosis was achieved in 21 out of 66 (32%) patients. We identified 19 pathogenic or likely pathogenic single-nucleotide variants and three copy number variants, of which 11 variants were novel. We identified four variants of uncertain significance. Additionally, we identified RPL9 and UBA2 as novel candidate genes for CLM. By comparing the detailed phenotypic features, we expand the phenotypic spectrum of diastrophic dysplasia and chromosome 6q terminal deletion syndrome. We also found that the diagnostic rate was significantly higher in patients with a family history of CLM (p = 0.012) or more than one limb affected (p = 0.034). Our study expands our understanding of the mutational and phenotypic spectrum of CLM and provides novel insights into the genetic basis of these syndromes.

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Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS)

Cited by 51 publications

References 32 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

Puncturing of lyophilized tissue engineered vascular matrices enhances the efficiency of their recellularization

Deciphering the mutational signature of congenital limb malformations

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