Genetic and clinical profile of patients with hypophosphatemic rickets

Eur J Med Genet. 2022 Aug;65(8):104540. doi: 10.1016/j.ejmg.2022.104540.

PMID: 35738466

Binata Marik, Arvind Bagga, Aditi Sinha

Highlights: This study proposes a customized gene panel for targeted exome sequencing, which will be useful for confirming the diagnosis in most patients with hypophosphatemic rickets.

Abstract

Background: The most frequent cause of rickets is nutritional vitamin D insufficiency, which is followed by genetic factors such classic hypophosphatemic rickets (associated to FGF23), Dent disease, Fanconi syndrome, renal tubular acidosis, and vitamin D-dependent rickets. All of these types have the trait of hypophosphatemia. Genetic testing is needed to confirm the diagnosis, which is based on a combination of clinical, biochemical, and radiological characteristics.

Objective and methods: Between May 2015 and July 2019, whole exome sequencing (WES) was used to evaluate 66 patients with hypophosphatemic rickets who were referred to this facility. Their intact serum fibroblast growth factor 23 (FGF23) levels were also measured.

Results: In 63 individuals, WES identified 36 pathogenic and 28 likely pathogenic variants in 16 distinct genes (PHEX, FGF23, DMP1, ENPP1, CLCN5, CTNS, SLC2A2, GATM, SLC34A1, EHHADH, SLC4A1, ATP6V1B1, ATP6V0A4, CYP27B1, VDR and FGFR1) that helped distinguish between the various hypophosphatemic rickets types. Patients with mutations in the PHEX, FGF23, DMP1 or ENPP1 genes had significantly higher intact serum FGF23 levels. Classic hypophosphatemic rickets with high FGF23 levels, distal renal tubular acidosis, and vitamin D-dependent rickets were the main hereditary causes of rickets.

Conclusion: Based on the current findings, a specific gene panel is suggested for targeted exome sequencing, which will help most patients with hypophosphatemic rickets confirm their diagnosis.

Keywords: Fibroblast growth factor 23, Gene panel, Genetic testing, Hypophosphatemia, Whole exome sequencing