Dataset Information

Screening of known disease genes in congenital scoliosis.

ABSTRACT: BACKGROUND:Congenital scoliosis (CS) is defined as a lateral curvature of the spine due to the vertebral malformations and has an incidence of 0.5-1/1,000 births. We previously examined TBX6 in Japanese CS patients and revealed that approximately 10% of CS was caused by TBX6 mutations. However, the genetic cause of remaining CS is unknown. METHODS:We recruited 78 CS patients without TBX6 mutations and major comorbidities, and investigated the genes previously reported to be associated with CS and congenital vertebral malformations by whole-exome sequencing. RESULTS:We identified the compound heterozygous missense variants in LFNG in one patient. No likely disease-causing variants were identified in other patients, however. LFNG encodes a GlcNAc-transferase. The LFNG variants showed loss of their enzyme function. CONCLUSIONS:A LFNG mutation is reported in a case of spondylocostal dysostosis (SCD), a skeletal dysplasia with severe malformations of vertebra and rib. The CS patient with LFNG mutations had multiple vertebral malformations including hemivertebrae, butterfly vertebrae, and block vertebrae, and rib malformations. LFNG mutations may cause a spectrum of phenotypes including CS and SCD. The current list of known disease genes could explain only a small fraction of genetic cause of CS.

SUBMITTER: Takeda K

PROVIDER: S-EPMC6305645 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Screening of known disease genes in congenital scoliosis.

Takeda Kazuki K Kou Ikuyo I Mizumoto Shuji S Yamada Shuhei S Kawakami Noriaki N Nakajima Masahiro M Otomo Nao N Ogura Yoji Y Miyake Noriko N Matsumoto Naomichi N Kotani Toshiaki T Sudo Hideki H Yonezawa Ikuho I Uno Koki K Taneichi Hiroshi H Watanabe Kei K Shigematsu Hideki H Sugawara Ryo R Taniguchi Yuki Y Minami Shohei S Nakamura Masaya M Matsumoto Morio M Watanabe Kota K Ikegawa Shiro S

Molecular genetics & genomic medicine 20180909 6

<h4>Background</h4>Congenital scoliosis (CS) is defined as a lateral curvature of the spine due to the vertebral malformations and has an incidence of 0.5-1/1,000 births. We previously examined TBX6 in Japanese CS patients and revealed that approximately 10% of CS was caused by TBX6 mutations. However, the genetic cause of remaining CS is unknown.<h4>Methods</h4>We recruited 78 CS patients without TBX6 mutations and major comorbidities, and investigated the genes previously reported to be associ ...[more]

PMID: 30196550

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Project description: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.

Dataset Information

Screening of known disease genes in congenital scoliosis.

Publications

Screening of known disease genes in congenital scoliosis.

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