Background: Congenital scoliosis (CS) is a spinal deformity due to vertebral malformations. Although insufficiency of TBX6 dosage contributes to a substantial proportion of CS, the molecular etiology for the majority of CS remains largely unknown. TBX6-mediated genes involved in the process of somitogenesis represent promising candidates.
Methods: Individuals affected with CS and without a positive genetic finding were referred to this study. Proband-only exome sequencing (ES) were performed on the recruited individuals, followed by analysis of TBX6-mediated candidate genes, namely MEOX1, MEOX2, MESP2, MYOD1, MYF5, RIPPLY1, and RIPPLY2.
Results: A total of 584 patients with CS of unknown molecular etiology were recruited. After ES analysis, protein-truncating variants in RIPPLY1 and MYF5 were identified from two individuals, respectively. In addition, we identified five deleterious missense variants (MYOD1, n = 4; RIPPLY2, n = 1) in TBX6-mediated genes. We observed a significant mutational burden of MYOD1 in CS (p = 0.032) compared with the in-house controls (n = 1854). Moreover, a potential oligogenic disease-causing mode was proposed based on the observed mutational co-existence of MYOD1/MEOX1 and MYOD1/RIPPLY1.
Conclusion: Our study characterized the mutational spectrum of TBX6-mediated genes, prioritized core candidate genes/variants, and provided insight into a potential oligogenic disease-causing mode in CS.
Keywords: TBX6-mediated genes; congenital scoliosis; exome sequencing; mutational burden.
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.