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
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
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.