Identification of Rare and Novel PHEX Variants in X-linked Hypophosphatemia

CONTEXT: X-linked hypophosphatemia (XLH) is a rare metabolic bone disease caused by inactivation mutations in the PHEX gene. Despite the extensive number of reported PHEX variants, only a few cases of chromosomal abnormalities have been documented. OBJECTIVE: We aimed to identify the pathogenic variants in 6 unrelated families with a clinical diagnosis of XLH and to propose a genetic workflow for hypophosphatemia patients suspected of having XLH. METHODS: Multiple genetic testing assays were used to analyze the 6 families' genetic profiles, including whole exome sequencing, multiplex ligation-dependent probe amplification, whole genome sequencing, reverse transcript polymerase chain reaction, Sanger sequencing, and karyotyping. RESULTS: The study identified 6 novel pathogenic variants, including 1 mosaic variant (exon 16-22 deletion), 3 chromosomal abnormalities (46, XN, inv[X][pter→p22.11::q21.31→p22.11::q21.31 →qter], 46, XN, inv[X][p22.11p22.11], and XXY), a nonclassical intron variant (NM_000444.6, c.1701_31A > G), and a deletion variant (NM_000444.6, c.64_5464-186 del5215) of PHEX. Additionally, a genetic testing workflow was proposed to aid in diagnosing patients suspected of XLH. CONCLUSION: Our research expands the mutation spectrum of PHEX and highlights the significance of using multiple genetic testing methods to diagnose XLH.