An Evidence-Tiered Developmental Framework for Congenital Vertebral Malformations: Spatiotemporal Thresholds in Genotype–Phenotype Interpretation

Congenital vertebral malformations (CVMs) encompass formation, segmentation and mixed defects, with or without scoliosis. This narrative review relates human genetic findings to paraxial mesoderm specification, somitogenesis, sclerotome differentiation and vertebral morphogenesis. An author-defined evidence hierarchy distinguishes established disease relationships, emerging susceptibility mechanisms and hypothesis-generating observations; it is not a formal ClinGen classification. Replicated TBX6 dosage mechanisms and disease-specific segmentation disorders provide stronger etiological evidence than candidate-gene burden signals, regulatory hypotheses or accessible-tissue methylation associations. Evidence is assigned to a defined gene–disease or mechanism–phenotype relationship, not to a gene or pathway universally. Building on previous developmental and gene–environment models, we outline a conceptual spatiotemporal threshold framework in which dosage, developmental stage, tissue distribution and modifiers may influence vertebral anatomy. No numerical human threshold has been established. Explicit appraisal criteria, relationship-specific evidence summaries and proposed experimental tests separate demonstrated findings from extrapolation. Standardized vertebral and rib phenotyping, associated anomalies and inheritance remain essential for genomic interpretation. Molecular diagnosis may inform counseling and syndrome-specific evaluation but does not independently establish prognosis or surgical indications.