Mutational analysis of patients with FGF23-related hypophosphatemic rickets

Abstract

X-linked hypophosphatemic rickets (XLHR) caused by mutations in the PHEX gene is considered to be the most frequent cause of fibroblast growth factor 23 (FGF23)-related congenital hypophosphatemic rickets. In previous studies, mutations in the PHEX gene were detected in 60-70% of patients with clinical diagnoses of XLHR. This leads to the question whether current screening methods for mutations in the PHEX gene are inadequate or whether there is a substantial number of patients with other genetic causes of hypophosphatemic rickets. We conducted a genetic analysis of patients with FGF23-related hypophosphatemic rickets to clarify their etiology and evaluate the prevalence of XLHR among this group. We studied 27 patients with familial and sporadic congenital hypophosphatemic rickets in whom serum FGF23 was above 30 pg/ml using an assay for the full-length protein. Exons and exon-intron junctions of genomic DNA of causative genes for FGF23-related hypophosphatemic rickets were sequenced. PHEX mRNA from peripheral blood was analyzed in some patients. Direct sequencing of genomic DNA identified 11 novel and four known mutations in the PHEX gene. Additionally, there was a large PHEX gene deletion in one case and abnormal PHEX mRNA splicing in another. In summary, 26 patients (96%) had XLHR and one patient had autosomal recessive hypophosphatemic rickets 2. XLHR is by far the most prevalent cause of FGF23-related hypophosphatemic rickets. We propose that analysis of PHEX mRNA from peripheral blood would be appropriate for the first screening step in determining the etiology of FGF23-related hypophosphatemic rickets.