Novel PHEX gene locus-specific database: Comprehensive characterization of vast number of variants associated with X-linked hypophosphatemia (XLH)

Abstract

X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemia, is caused by disrupting variants in the PHEX gene, located on the X chromosome. XLH is inherited in an X-linked pattern with complete penetrance observed for both males and females. Patients experience lifelong symptoms resulting from chronic hypophosphatemia, including impaired bone mineralization, skeletal deformities, growth retardation, and diminished quality of life. This chronic condition requires life-long management with disease-specific therapies, which can improve patient outcomes especially when initiated early in life. To centralize and disseminate PHEX variant information, we have established a new PHEX gene locus-specific database, PHEX LSDB. As of April 30, 2021, 870 unique PHEX variants, compiled from an older database of PHEX variants, a comprehensive literature search, a sponsored genetic testing program, and XLH clinical trials, are represented in the PHEX LSDB. This resource is publicly available on an interactive, searchable website (https://www.rarediseasegenes.com/), which includes a table of variants and associated data, graphical/tabular outputs of genotype-phenotype analyses, and an online submission form for reporting new PHEX variants. The database will be updated regularly with new variants submitted on the website, identified in the published literature, or shared from genetic testing programs.

Keywords: Phosphate regulating gene with Homology to Endopeptidases that maps to the X chromosome (PHEX); X-linked hypophosphatemia (XLH); fibroblast growth factor 23 (FGF23); locus-specific database; osteomalacia; rickets.

Figure 1

PHEX and the XLH disease pathway. (a) PHEX exon (top) and protein (bottom) maps indicating the positions of UTR boundaries, intron/exon junctions, and key functional/structural elements. Nucleic acid positions are indicated above the exon map and amino acid positions below. Cys, cystine; Cyt, cytoplasmic region; TM, transmembrane domain. (b) Ribbon diagram of the human PHEX protein generated in PyMol based on structures of homologous endopeptidases (Kelley et al., 2015); labels call out the enzymatic active site and amino acids altered in the 10 most common missense variations. (c) In the XLH disease state, decreased PHEX activity leads to an increase in serum FGF23, which decreases blood phosphate levels due to increased renal phosphate wasting. FGF23 also decreases the synthesis and increases the metabolism of the active vitamin D metabolite, ultimately leading to reduced bone mineralization. PHEX, Phosphate regulating gene with Homology to Endopeptidases that maps to the X chromosome; XLH, X‐linked hypophosphatemia; UTR, untranslated region

Figure 2

Positions of 870 unique PHEX variants. (a) Variants that span multiple exons (copy number variants and complex rearrangements) are represented by lines above the exon map and intron‐specific variants are clustered by loci below. Del, deletion (grey lines); dup, duplication (blue lines). (b) Exon‐specific variants clustered by loci. Variants are indicated by affected nucleotides, affected amino acids, or affected exons, depending upon the limits of the detection techniques employed. ins, insertion; delins, combination deletion/insertion; >, substitution;  ?, nucleotide boundary as approximated by detection method. PHEX, Phosphate regulating gene with Homology to Endopeptidases that maps to the X chromosome

Figure 2

Positions of 870 unique PHEX variants. (a) Variants that span multiple exons (copy number variants and complex rearrangements) are represented by lines above the exon map and intron‐specific variants are clustered by loci below. Del, deletion (grey lines); dup, duplication (blue lines). (b) Exon‐specific variants clustered by loci. Variants are indicated by affected nucleotides, affected amino acids, or affected exons, depending upon the limits of the detection techniques employed. ins, insertion; delins, combination deletion/insertion; >, substitution;  ?, nucleotide boundary as approximated by detection method. PHEX, Phosphate regulating gene with Homology to Endopeptidases that maps to the X chromosome

Figure 3

Distribution of 870 unique PHEX variants by variant type. CNV, copy number variant (size greater than 100 nucleotides [nt]); small deletion (size smaller than 100 nt); small duplication (size smaller than 100 nt); small insertion (size smaller than 100 nt); SNV, single nucleotide variant. One allele that contains two variants (Ex13–15 dup and c.*231A>G) was counted in both the CNV and SNV categories. “Other” included 1 start codon change and 1 deep intronic variant. PHEX, Phosphate regulating gene with Homology to Endopeptidases that maps to the X chromosome

Figure 4

Screenshots from the PHEX LSDB website. (a) The main variant table provides specific information on all variants identified in the database including HSGV variant nomenclature, predicted effects, ACMG variant prediction, and all publications reporting the variant. The red arrow, above the exon and protein maps at the top of the page, indicates the position of a selected variant. (b) An interactive display of genotype‐phenotype analysis by variant and abnormal phenotype