A de novo mosaic mutation of PHEX in a boy with hypophosphatemic rickets

Abstract

X-linked dominant hypophosphatemic rickets (XLHR), is characterized mainly by renal phosphate wasting with hypophosphatemia, short stature and abnormal bone mineralization. PHEX, located at Xp22.1-p22.2, is the gene causing XLHR. We aim to characterize the pathogenesis of a Chinese boy who is apparently 'heterozygous' in PHEX gene. Direct sequencing showed two peaks: one was a wild-type 'G' and the other was one base substitution to 'A', though the patient was a male. TA clone assay clearly showed each sequences and the ratios. The mutation effect was predicted via bioinformatics and validated by exon-trapping assay. Real-time PCR was applied to determine the copy number of PHEX. TA clone assay showed the frequency of normal (G) to mutant allele (A) as 19:13. Normal karyotype and real-time PCR results indicate the normal copy number of PHEX. This splice site mutation leads to 4 bp of exon 18 skipping out causing frame shift p.Gly590Glufs*28 that ends up with a loss of active site and Zn(2+)-binding site of PHEX, which probably interfere with renal phosphate reabsorption and bone mineralization. In conclusion, mutation at conserved splice acceptor site resulted in aberrant splicing, ending up with a damaged protein product. This novel mutation is de novo in mosaic pattern that may be induced during early postzygotic period. Taking mosaic somatic mutation of PHEX into consideration is strongly suggested in genetic counseling and etiology research for XLHR.

‘Isolated’ germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets

“…XLHR is a dominant disease, and the somatic mosaicism also shows clinical symptoms but mildly, which reminds us to investigate the disease-causing variant using other tissue samples. To date, four somatic mosaicism male patients with XLHR have been reported (21,27,28,29), and our in-house study also identifies two XLHR mosaic boys carrying heterozygous PHEX pathogenic variants.…”

A novel de novo mosaic mutation in PHEX in a Korean patient with hypophosphatemic rickets

“…Our patient represents the first Korean XLH case with a mosaic mutation in PHEX . Only 2 cases have reported de novo mosaic mutations in males [14,15]. One was a 4.5-year-old Chinese boy who had been suffering from gait abnormalities and bone pain since the age of 2 [14].…”

“…Only 2 cases have reported de novo mosaic mutations in males [14,15]. One was a 4.5-year-old Chinese boy who had been suffering from gait abnormalities and bone pain since the age of 2 [14]. He was diagnosed with XLH with a de novo splice-site mutation and mosaic pattern in PHEX .…”

Functional Characterization of PHEX Gene Variants in Children With X-Linked Hypophosphatemic Rickets Shows No Evidence of Genotype–Phenotype Correlation

“…A gene dosage‐effect was suggested in mosaic XLHR patients who exhibit disease severity that is dependent on the ratio of normal to mutant alleles. ( 15 ) This patient exhibited typical hypophosphatemia and elevated serum alkaline phosphatase, but no severe lower extremity bowing. He began calcitriol and Pi supplementation at age 18 months.…”