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

Abstract 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.