Abstract Context X-linked hypophosphatemia (XLH) is the most common form of inherited hypophosphatemic rickets (HR), caused by pathogenic variants in the PHEX gene. Genetic diagnosis of XLH facilitates early treatment optimization, especially for patients suitable for burosumab, a recombinant anti-fibroblast growth factor-23 monoclonal antibody. Objective This study aimed to use whole-exome sequencing (WES) and pedigree analysis to identify patients with XLH. Methods Medical records at a single center in Saudi Arabia were screened between 2014 and 2024 to identify patients with suggested HR. Of the 800 patients identified, 27 had had suspected XLH. The genetic study comprised 100 patients drawn from these 27 families. Results Clinical manifestations were widespread and variable within families. Severe disease was reported in 55% of children and 25% of adults. At presentation, all children were receiving either conventional therapy (60%) or burosumab (40%); however, 53% of adults were not treated. WES provided a genetic diagnosis in 23 families: alterations in the PHEX gene (20 families), with homozygous ENPP1 and DMP1 variants detected in 2 and 1 families, respectively. Pathogenic/likely pathogenic variants were detected in 23 families (diagnostic yield 85%). Ten novel likely pathogenic variants were detected. Pedigree analysis provided information to support disease-specific patient management. Conclusion WES detected a diagnostic molecular abnormality in 85% of families with HR phenotypes; PHEX variants were the most common. Combined use of WES and pedigree analysis highlighted the underdiagnosis of adult XLH in this population, with most family members being diagnosed after the pedigree analysis.