Mutational burden and potential oligogenic model of TBX6‐mediated genes in congenital scoliosis

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.