High Occurrence of a Missense Variant (C.471C>A) in the Fgf23 Gene Related to Hyperostosis–Hyperphosphatemia Syndrome With a Possible Founder Effect Publisher



Sedghi M¹ ; Gharehdaghi EE¹ ; Ziaee V^{2, 3} ; Abbasi F^{2, 4} ; Meybodi HRA⁵ ; Smiley E⁶ ; Mehdizadeh M⁷ ; Raeeskarami SR^{2, 3} ; Aslani N² ; Shiran SN² ; Vafadar M⁸ ; Amoli MM¹ Show Affiliations
Source: Human Mutation Published:2025

Abstract

Background: The autosomal recessive metabolic disorder hyperostosis–hyperphosphatemia syndrome (HHS) is characterized by hyperphosphatemia, hyperostosis, and recurrent bone lesions. Patients may develop ectopic and vascular calcification and may present diaphyseal pain of the long bones that is misdiagnosed as osteomyelitis. Mutations in GALNT3 and FGF23 genes were detected in patients with HHS. The main manifestations of these patients are increased levels of phosphate reabsorption from kidneys and painful swelling of long bones alongside with normal levels of vitamin D and parathormone. Method: We performed whole-exome sequencing (WES) in seven Iranian patients. These patients were referred from several specialist clinics. Seven irrelevant families were examined for genetic mutations. Results: WES revealed the deleterious missense mutation c.471C>A, p. F157L in all affected members of six families. The variant c.1524+1G>A in the GALNT3 gene was found in the remaining patient which is reported previously. These variants were confirmed utilizing segregation studies in the pedigrees. Conclusion: Our data together with previous studies related to mutations in FGF23 in Iran strongly support that p. F157L mutation is abundantly prevalent in patients with Iranian origin and is likely to be a founder mutation; however, it requires further confirmative study. The result of this study suggests that p. F157L mutation should be investigated at the first step in genetic analysis of patients with HHS. This enables fast and accurate focused molecular diagnosis and would be effective for use in carrier screening as well as in prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD). Copyright © 2025 Maryam Sedghi et al. Human Mutation published by John Wiley & Sons Ltd.