Gene

Point mutation

Genetic heterogeneity

Hypophosphatemia

Biology

Multiplex ligation-dependent probe amplification

Missense mutation

Nonsense

Endocrinology

Mutation

Genetics

Rickets

PHEX

Sanger sequencing

Genotype

Vitamin D and neurology

Exon

Nonsense mutation

Phenotype

Bone

X-linked Hypophosphatemia (XLH) is caused by loss of function mutations in the PHEX gene. Given the recent availability of a new therapy for XLH, a retrospective analysis of the most recent 261 Chinese patients with XLH evaluated at Peking Union Medical College Hospital was conducted. Clinical, biochemical, radiographic studies, as well as genetic analyses, including Sanger sequencing for point mutations and Multiplex Ligation-dependent Probe Amplification (MLPA) to detect large deletions/duplications were employed. Based on the structure of Neprilysin (NEP), a member of M13 family that includes PHEX, a three-dimensional (3D) model of PHEX was constructed, missense and nonsense mutations were positioned on the predicted structure to visualize relative positions of these two types of variants. Sex differences and genotype-phenotype correlations were also undertaken. Genetic analyses identified 166 PHEX mutations in 261 XLH patients. One hundred and eleven of the 166 mutations were unreported. Four mutational 'hot-spots' were identified in this cohort (P534L, G579R, R747X, c.1645+1 G>A). Missense mutations, but not nonsense mutations, clustered in the two putative lobes of the PHEX protein, suggesting these are functionally important regions of the molecule. Circulating levels of intact FGF23 were significantly elevated (median level 101.9 pg/mL; reference range 16.1–42.2 pg/mL). No significant sex differences, as well as no phenotypic differences were identified between patients with putative truncating and non-truncating PHEX mutations. However, patients with N-terminal PHEX mutations had an earlier age of onset of disease (P = 0.015) and higher iFGF23 levels (P = 0.045) as compared to those with C-terminal mutations. These data provide a comprehensive characterization of the largest cohort of patients with XLH reported to date from China, which will help in evaluating the applicability of emerging therapies for this disease in this ethnic group.

Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia