SGK3 promoter deletion in late-onset hypophosphatemic rickets, a possible genetic cause of the disease.

backgroundHypophosphataemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in the PHEX, FGF23, DMP1, ENPP1, CLCN5, SGK3, SLC9A3R1, SLC34A1 or SLC34A3.

objectiveTo identify the genetic defects in a patient with late-onset hypophosphatemia. SUBJECTS: A 15-year old boy with hypophosphatemic rickets, his unaffected parents and 7 siblings.

designPatients and their family members were initially analyzed for PHEX and FGF23 mutations by PCR-sequencing analysis. Exome and whole-genome sequencing were subsequently performed to identify causative genetic defects.

resultsThe patient was normal until the age of 11 years old. He presented with severe rickets, hypophosphatemia with increased renal phosphate wasting, normal serum calcium, 1,25(OH)2D and parathyroid hormone (PTH), and mild elevation of serum FGF23. No mutation was detected in the genes known to cause HR such as PHEX, FGF23, DMP1, ENPP1, CLCN5, SGK3, FAM20C, SLC9A3R1, SLC34A1 or SLC34A3 by exome sequencing. A heterozygous variant c.448 C>T (p.Arg150Cys) in the PTH1R gene was found in the patient, his unaffected father and 5 siblings. The same heterozygous variant was previously reported in human enchondromatosis and caused enchondroma-like lesions in transgenic mice. A large heterozygous deletion of more than 7 Kb in the SGK3 distal promoter was identified in the patient by whole genome sequencing.

conclusionsSGK3 distal promoter deletion is likely the candidate gene causing the disease. PTH1R Arg150Cys variant may contribute to the disease phenotype. SGK3 promoter deletion should be considered in patients with late-onset genetic hypophosphatemic rickets.