Continuous and Segmental Cervical Ossification of the Posterior Longitudinal Ligament Have Distinct Genomic Architectures: Inflammatory Versus Bone Metabolic Phenotypes on Whole-Exome Sequencing

BACKGROUND AND OBJECTIVES: Cervical ossification of the posterior longitudinal ligament (OPLL) may represent 2 convergent entities-a genetically driven continuous phenotype and an idiopathic segmental phenotype-with a wide clinical prognosis ranging from asymptomatic to life-threatening quadriplegia. However, previous studies evaluated OPLL as a single homogeneous entity, leaving subtype-specific mechanisms unresolved. We sought to delineate the genomic, biomarker, and clinical determinants distinguishing continuous from segmental OPLL. METHODS: Patients diagnosed with cervical OPLL and healthy controls were consecutively enrolled between March 2021 and February 2024. All participants underwent whole-exome sequencing, radiological examinations, and blood biomarker measurements (C-reactive protein [CRP], white blood cell, erythrocyte sedimentation rate, alkaline phosphatase, and osteocalcin). To maximize phenotypic homogeneity, subgroups were defined by K-means clustering (occupying ratio and progression rate). Single-variant and gene-wise variant burden analyses were performed. RESULTS: In total, 176 participants were enrolled: 52 with continuous/mixed OPLL (Group C), 58 with segmental/localized OPLL (Group S), and 66 OPLL-free controls (Group N). Clustering identified a severe continuous subgroup (n = 31) and a mild segmental subgroup (n = 45). Group C was significantly younger and exhibited greater ossification depth, length, and occupying ratio; faster progression; and higher white blood cell count and CRP level than Group S; the annual progression rate correlated positively with CRP (r = 0.208, P = .035). Gene-wise analysis associated the severe subgroup C with immune- and oxidative stress-related genes (KIR2DL3, OGG1), OR2T6, and ZAR1 relative to controls, whereas CCDC154, a bone metabolism gene, uniquely distinguished the segmental phenotype and displayed a graded burden that increased sequentially from the severe continuous to the milder segmental subgroups. CONCLUSION: Continuous and segmental OPLL exhibit distinct genomic architectures-an inflammatory phenotype (KIR2DL3, OGG1) vs a bone metabolic phenotype (CCDC154). This multimodal subtyping may support a mechanism-based reclassification of OPLL and guide patient-specific prognostication.