Genomic imprinting involves a DNA methylation-dependent and parent-of-origin-specific regulation of gene expression. Clinical assays for imprinting disorders are genomic locus, disorder, and molecular defect specific. We aimed to clinically validate a genome-wide approach for simultaneous testing of common imprinting disorders in a single assay. Using genome-wide DNA methylation arrays, epigenetic profiles from peripheral blood of patients with Angelman, Prader-Willi, Beckwith-Wiedemann, or Silver-Russell syndromes were compared to a reference cohort of 361 unaffected individuals. The analysis was of developmental delay and intellectual disabilities. This approach has allowed 100% sensitivity and specificity in detecting imprinting defects in all 28 patients and enabled identification of defects beyond the classically tested imprinted loci. Analysis of the cohort of patients with developmental delay and intellectual disabilities identified two patients with Prader-Willi syndrome, one with Beckwith-Wiedemann syndrome, and several other patients with DNA methylation defects in novel putative imprinting loci. These findings demonstrate clinical validation of a sensitive and specific genome-wide DNA methylation array-based approach for molecular testing of imprinting disorders to allow simultaneous assessment of genome-wide epigenetic defects in a single analytical procedure, enabling replacement of multiple locus-specific molecular tests while allowing discovery of novel clinical epigenomic associations and differential diagnosis of other epigenomic disorders.