Integrating Imaging and Genomics in Amelogenesis Imperfecta: A Novel Diagnostic Approach

<b>Background/Objectives:</b> Amelogenesis imperfecta (AI) represents a heterogeneous group of inherited disorders affecting the quality and quantity of dental enamel, making clinical diagnosis challenging. This study aimed to identify genetic variants in Slovenian patients with non-syndromic AI and to evaluate enamel morphology using radiographic parameters. <b>Methods:</b> Whole exome sequencing (WES) was performed on 24 AI patients and their families. Panoramic radiographs (OPTs) were analyzed using Fiji ImageJ to assess crown dimensions, enamel angle (EA), dentine angle (DA), and enamel-dentine mineralization ratio (EDMR) in lower second molar buds, compared to matched controls (<i>n</i> = 24). Two observers independently assessed measurements, and non-parametric tests compared EA, DA, and EDMR in patients with and without disease-causing variants (DCVs). Statistical models, including bootstrap-validated random forest and logistic regression, assessed variable influences. <b>Results:</b> DCVs were identified in <i>ENAM</i> (40% of families), <i>AMELX</i> (15%), and <i>MMP20</i> (10%), including four novel variants. AI patients showed significant enamel deviations with high reproducibility, particularly in hypomineralized and hypoplastic regions. DA and EDMR showed significant correlations with DCVs (<i>p</i> < 0.01). A bootstrap-validated random forest model yielded a 90% (84.0-98.0%) AUC-estimated predictive power. <b>Conclusions:</b> These findings highlight a novel and reproducible radiographic approach for detecting developmental enamel defects in AI and support its diagnostic potential.