Abstract
Background: Hypophosphatemic rickets (HR) is a rare genetic disorder associated with renal phosphate wasting and characterized by bone defects. Inactivating mutations in the phosphate regulating endopeptidase homolog X‑linked gene (PHEX) account for most cases of HR. The aim of this study was to identify causative variants in nine unrelated Chinese families associated with HR, and to determine potential pathogenicity of the identified variants. Methods: Genomic DNA was isolated from the peripheral blood of HR patients and their healthy relatives, followed by next-generation sequencing and/or Sanger sequencing. In silico prediction combined with conservation analysis was performed to assess the effects of the variants, and 3D protein modeling was conducted to predict the functional effects on the encoded protein. Results: All HR patients recruited in this study displayed bone deformities and tooth agenesis, as well as reduced serum phosphate levels and elevated urine phosphate levels. Nine PHEX variants were identified in eight families, including four novel variants (c.1661_1726del, c.980A > G, c.1078A > T, and c.1017_1051dup). Of the nine identified PHEX variants, five caused a truncated protein, two caused an altered amino acid, and the other two were the canonical splicing variants. Novel variants c.1336G > A and c.1364 T > C in SLC34A3 were also found in one family. Conservation analysis showed that all the amino acids corresponding to the missense variants were highly conserved. In silico analysis and 3D protein structure modeling confirmed the pathogenicity of these variants. Conclusions: This study identified four novel variants in PHEX and two novel variants in SLC34A3 in a Chinese cohort with HR. Our findings highlight the dominant role of PHEX in HR, and expand the genotypic and phenotypic spectra of this disorder.