Identification of six novel variants from nine Chinese families with hypophosphatemic rickets

BMC Med Genomics. 2022 Jul 16;15(1):161. doi: 10.1186/s12920-022-01305-w.

PMID: 35842615

Yixuan Cao, Yi You, Qiong Wang

Highlights: This study highlights the dominant role of PHEX in hypophosphatemic rickets (HR) and expand the genotypic and phenotypic spectra of this disorder.

Abstract

Background: A rare genetic condition known as hypophosphatemic rickets (HR) that causes bone abnormalities and is characterized by renal phosphate wasting. The majority of cases of HR are caused by inactivating mutations in the phosphate regulating endopeptidase homolog X-linked gene (PHEX). This study sought to assess the possible pathogenicity of the discovered variants and to find the causal variations in nine unrelated Chinese families associated with HR.

Methods: Genomic DNA was extracted from the peripheral blood of HR patients and their unaffected relatives, and it was then subjected to Sanger or next-generation sequencing. To evaluate the effects of the variants, in silico prediction along with conservation analysis was undertaken, and 3D protein modeling was done to forecast the functional effects on the encoded protein.

Results: All of the HR patients included in this study had tooth agenesis, bone deformities, low serum phosphate levels, and high urine phosphate levels. Nine PHEX variants, including four unique variants (c.1661_1726del, c.980A > G, c.1078A > T, and c.1017_1051dup), were found in eight families. 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. There was also one family that contained the novel SLC34A3 variants c.1336G > A and c.1364 T > C. Conservation analysis showed that all the amino acids corresponding to the missense variants were highly conserved. The pathogenicity of these variants was validated by in silico analysis and 3D protein structure modeling.

Conclusions: In a Chinese population with HR, this investigation found two novel SLC34A3 variants and four novel PHEX variants. These findings broaden the genotypic and phenotypic range of HR and underscore the major involvement of PHEX in this disorder.

Keywords: Genetic diagnosis, Hypophosphatemic rickets, PHEX, SLC34A3, Variant