Identification of a Novel Pathogenic Variant in the PHEX Gene and Its Mechanistic Implications in X-Linked Hypophosphatemia

Abstract

Purpose: X-linked hypophosphatemia (XLH) arises from PHEX loss-of-function mutations driven by excess FGF23. This study aimed to characterize a novel PHEX frameshift variant in a Chinese pediatric patient, clarify its pathogenic mechanism, and report real-world conventional therapy outcomes under limited economic resources. Materials and Methods: Targeted NGS and Sanger sequencing identified the variant; ACMG criteria determined pathogenicity. Western blot, ELISA, molecular docking, and protein structural modeling assessed variant-induced functional defects. The patient received oral phosphate + calcitriol instead of burosumab for 3 months. Results: A de novo frameshift deletion chrX(GRCh37):g.22112134_22112135del (c.766_767del p.Thr256Cysfs*7) was detected, classified as pathogenic. Truncated mutant PHEX showed negligible expression, lost MEPE binding capacity, and elevated MEPE/FGF23. Conventional treatment partially improved biochemical and clinical manifestations without severe adverse events. Conclusion: This novel truncating variant expands the PHEX mutational spectrum. Complete PHEX functional inactivation disrupts the PHEX-MEPE-FGF23 axis to trigger XLH. Conventional phosphate-calcitriol therapy serves as a safe alternative for patients unable to access costly anti-FGF23 targeted agents.