The mutational burden in os odontoideum patients.

backgroundOs odontoideum(OO) is a rare bone malformation at the craniovertebral junction, the presence of which can lead to potential instability of atlantoaxial joints. The cause, prevalence and treatment of OO are still controversial. There are two main theories regarding the pathogenesis of OO: congenital factors and traumatic factors. The congenital hypothesis suggests that the lesion results from segmental defects caused by incomplete fusion of the dens and the axis vertebral body during embryonic development. Our research team previously reported a case series involving three generations of a family affected by OO without a clear history of trauma, suggesting the existence of congenital pathogenic factors for this disease. Based on this, we conducted this study to further explore the pathogenesis of OO.

methodsWe consecutively recruited 25 OO patients including 15 males(60%) and 10 females(40%) from 2021 to 2023. The clinical manifestation and concomitant deformities were analyzed and whole-exome sequencing(WES) was performed. The variants in OO patients were compared with those from 79 normal population controls using a case-control association analysis of individual rare variants. The analysis results were used to prioritize disease-associated candidate genes by combining Odds Ratio(OR) values and P values. OR values measure the strength of association between genetic variations and the disease, while P values determine the statistical significance of the results. Nominally high OR values and low P values can indicate a potential association between genetic variations and the disease. By integrating these two metrics, genes with notable correlations to OO were identified.

resultsThe analysis identified four genes nominally associated with OO based on their P values and OR values. Cell Division Cycle 27(CDC27) exhibited a P value of 0.002 and an OR of 5.08, indicating a notable association with the disease. Facioscapulohumeral Muscular Dystrophy Region Gene 1 Binding Protein(FRG1BP) showed a P value of 0.004 and an OR of 5.59, further supporting its potential relevance. Tripartite Motif Containing 8(TRIM8) had a P value of 0.02 and an OR of 4.58, suggesting a potential association. Centrosomal Protein 250(CEP250) demonstrated the most notable correlation among the four genes, with a P value of 0.005 and an OR of 7.78.

conclusionOur study identifies rare variants potentially linked to OO and provides preliminary data that could inform hypotheses regarding a complex genetic basis, though larger cohorts and functional studies are needed for validation. Our findings of rare variants associated with OO, though preliminary, highlight a potential complex genetic basis for this condition. This underscores the need for further research which may ultimately aid in risk stratification and early detection in high-risk families.