Introduction: Recent advancements in genomic technologies have significantly improved the resolution of genetic variants driving rare genodermatoses, a heterogeneous group of inherited skin disorders caused by pathogenic variants affecting skin structure and function. However, many genodermatoses remain molecularly uncharacterized, particularly in Middle Eastern populations. Objectives: This study aimed to evaluate the diagnostic accuracy and inherent challenges of utilizing (WES) for genodermatoses within a Middle Eastern context. Methods: We performed WES on three unrelated Middle Eastern pediatric patients presenting with genodermatoses. Genetic variants were prioritized and adjudicated according to ClinVar and the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: WES identified pathogenic variants in three pediatric cases presenting with genodermatoses. Findings included a GJB2 missense variant (c.148G>T; p.Asp50Asn) associated with keratitis–ichthyosis–deafness (KID) syndrome. This represents one of the first documented cases in a Middle Eastern population. Two additional patients presenting with epidermolysis bullosa harbored truncating variants in COL7A1 (c.497dup; p.Val168Glyfs12) and EXPH5 (c.5786del; p.Pro1929Leufs8), respectively; the latter also carried a KRT5 missense variant (c.1607G>A; p.Ser536Asn). Conclusions: WES is a robust diagnostic adjunct for resolving ambiguity in rare genodermatoses, though its efficacy remains contingent on the availability of regional genomic references. Within pediatric dermatology, systematic exome sequencing serves as a powerful facilitator for transitioning from clinical suspicion to definitive molecular characterization. Collectively, these findings highlight the essential role of regionally representative genomic datasets in the accurate interpretation of novel variants and the advancement of precision dermatology.