Research Article

A Recurrent Rare SOX9 Variant (M469V) is Associated with Congenital Vertebral Malformations

Author(s): Nan Wu, Lianlei Wang, Jianhua Hu*, Sen Zhao, Bowen Liu, Yaqi Li, Huakang Du, Yuanqiang Zhang, Xiaoxin Li, Zihui Yan, Shengru Wang, Yipeng Wang, Jianguo Zhang, Zhihong Wu, DISCO (Deciphering Disorders Involving Scoliosis & Comorbidities) study group and Guixing Qiu

Volume 19, Issue 4, 2019

Page: [242 - 247] Pages: 6

DOI: 10.2174/1566523219666190924120307

open access plus


Objective: The genetic variations contributed to a substantial proportion of congenital vertebral malformations (CVM). SOX9 gene, a member of the SOX gene family, has been implicated in CVM. To study the SOX9 mutation in CVM patients is of great significance to explain the pathogenesis of scoliosis (the clinical manifestation of CVM) and to explore the pathogenesis of SOX9-related skeletal deformities.

Methods: A total of 50 singleton patients with CVM were included in this study. Exome Sequencing (ES) was performed on all the patients. The recurrent candidate variant of SOX9 gene was validated by Sanger sequencing. Luciferase assay was performed to investigate the functional changes of this variant.

Results: A recurrent rare heterozygous missense variant in SOX9 gene (NM_000346.3: c.1405A>G, p.M469V) which had not been reported previously was identified in three CVM patients who had the clinical findings of congenital scoliosis without deformities in other systems. This variant was absent from our in-house database and it was predicted to be deleterious (CADD = 24.5). The luciferase assay demonstrated that transactivation capacity of the mutated SOX9 protein was significantly lower than that of the wild-type for the two luciferase reporters (p = 0.0202, p = 0.0082, respectively).

Conclusion: This SOX9 mutation (p.M469V) may contribute to CVM without other systematic deformity, which provides important implications and better understanding of phenotypic variability in SOX9-related skeletal deformities.

Keywords: SOX9 gene, campomelic dysplasia, acampomelic campomelic dysplasia, congenital vertebral malformations, congenital scoliosis, exome sequencing.

Graphical Abstract
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