Mutational Analysis of PHEX, FGF23 and CLCN5 in Patients with Hypophosphataemic Rickets

Abstract

Context

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

Objective

To investigate underlying genetic defects in patients with hypophosphataemic rickets.

Methods

We analyzed genomic DNA from 9 unrelated families for mutations in the entire coding region of PHEX, FGF23, DMP1, ENPP1, CLCN5, or SLC34A3 by PCR-sequencing and copy number analysis.

Results

A total of 14 patients were studied. PHEX mutations were identified in 12 patients from 7 families. Five of them were novel mutations present in 8 patients: c.154G>T (p.E52*), c.401_402insGCCAAA (p.Q134_K135insPK), c.1600C>T (p.P534S), g.22016715_22056805del (40kb deletion including promoter and exons 1-3) and c.2242_2243delCT (p.L748fs*48). Four patients had previously reported mutations: c.1768+1G>A, and c.1807G>A (p.W602*). Novel CLCN5 (c.1205G>A, p.W402*) and FGF23 (c.526C>G, p.R176G) mutations were found in two patients from the remaining 2 families. Many of the mutations were de novo: c.154G>T and c.2242_2243delCT in PHEX, and c.526C>G in FGF23. Furthermore, we characterized the breakpoint of the novel PHEX g.22016715_22056805del and the c.2242_2243delCT, which is 6 bp from the stop codon, resulting in a frameshift and extension of the reading frame by 42 amino acids.

Conclusions

Novel and de novo mutations are frequent and PHEX mutations are still the most common genetic defects in the Turkish population. Gene copy number analysis should be considered in patients with negative results by conventional PCR-based sequencing analysis. The current study further expands the mutation spectrum underlying HR.

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