X‐linked hypophosphatemia (XLH), a dominant disorder caused by pathogenic variants in the PHEX gene, affects both sexes of all ages and results in elevated serum fibroblast growth factor 23 (FGF23) and below‐normal serum phosphate. In XLH, rickets, osteomalacia, short stature, and lower limb deformity may be present with muscle pain and/or weakness/fatigue, bone pain, joint pain/stiffness, hearing difficulty, enthesopathy, osteoarthritis, and dental abscesses. Invitae and Ultragenyx collaborated to provide a no‐charge sponsored testing program using a 13‐gene next‐generation sequencing panel to confirm clinical XLH or aid diagnosis of suspected XLH/other genetic hypophosphatemia. Individuals aged ≥6 months with clinical XLH or suspected genetic hypophosphatemia were eligible. Of 831 unrelated individuals tested between February 2019 and June 2020 in this cross‐sectional study, 519 (62.5%) individuals had a pathogenic or likely pathogenic variant in PHEX (PHEX‐positive). Among the 312 PHEX‐negative individuals, 38 received molecular diagnoses in other genes, including ALPL, CYP27B1, ENPP1, and FGF23; the remaining 274 did not have a molecular diagnosis. Among 319 patients with a provider‐reported clinical diagnosis of XLH, 88.7% (n = 283) had a reportable PHEX variant; 81.5% (n = 260) were PHEX‐positive. The most common variant among PHEX‐positive individuals was an allele with both the gain of exons 13–15 and c.*231A>G (3′UTR variant) (n = 66/519). Importantly, over 80% of copy number variants would have been missed by traditional microarray analysis. A positive molecular diagnosis in 41 probands (4.9%; 29 PHEX positive, 12 non‐PHEX positive) resulted in at least one family member receiving family testing. Additional clinical or family member information resulted in variant(s) of uncertain significance (VUS) reclassification to pathogenic/likely pathogenic (P/LP) in 48 individuals, highlighting the importance of segregation and clinical data. In one of the largest XLH genetic studies to date, 65 novel PHEX variants were identified and a high XLH diagnostic yield demonstrated broad insight into the genetic basis of XLH. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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.

The cover image is based on the Research Article Novel PHEX gene locus‐specific database: Comprehensive characterization of vast number of variants associated with X‐linked hypophosphatemia (XLH) by Yves Sabbagh et al., https://doi.org/10.1002/humu.24296.

No abstract

X-linked hypophosphatemia (XLH), a dominant disorder caused by a disease-associated variant in the PHEX gene, affects males and females of all ages. Rickets and osteomalacia may be present along with short stature, lower limb deformity, muscle pain and/or weakness/fatigue, bone pain, joint pain/stiffness, hearing difficulty, enthesopathy, osteoarthritis, and dental abscesses. Patients with XLH have below-normal serum phosphate and elevated serum FGF23. XLH is one of multiple etiologies of hypophosphatemia; depending on genetic cause, management may differ. Acquired hypophosphatemia (e.g. tumor induced osteomalacia) is non-hereditary in nature. This program provides a no-charge genetic test to confirm a clinical XLH diagnosis or to aid suspected genetic hypophosphatemia diagnosis. Patients aged >/= 6 months with either a clinical XLH diagnosis or suspicion of genetic hypophosphatemia, as evidenced by 2 or more clinical signs/ symptoms, were eligible for testing. The next generation sequencing panel includes 13 genes: ALPL, CLCN5, CYP2R1, CYP27B1, DMP1, ENPP1, FAH, FAM20C, FGF23, FGFR1, PHEX, SLC34A3 and VDR. Copy number variant detection was performed. 831 unrelated individuals were tested as of June 30, 2020. 569 (68.5%) of these subjects had a PHEX variant: 519 (91.2%) were either pathogenic or likely pathogenic (P/LP) and 50 (8.8%) were variants of uncertain significance (VUS). Of the 312 (37.5%) cases where no PHEX molecular diagnosis was found, 38 (12.2%) had molecular diagnoses associated with other genes/disorders: 4 had a variant (P/LP) in FGF23 (autosomal dominant [AD] hypophosphatemic rickets), 2 had two variants (P/LP) in CYP27B1 (autosomal recessive [AR] vitamin D dependent rickets), 1 had P/LP variants in ENPP1 (AR hypophosphatemic rickets Type 2). There were 27 cases with single P or LP variants in ALPL (AD hypophosphatasia, HPP); 4 cases carried two variants (P/LP) in ALPL (AR form). Of 237 unique P/LP PHEX variants detected: 59 were deletions, duplications or insertions; 37 were copy number variants; 52 were splice-site variants; 89 were single nucleotide variants. Additional family member testing/clinical information resulted in 48 cases having VUS reclassified to P/LP, highlighting the value of cascade family testing/clinical info to resolve VUS. RNA analyses to resolve VUS may further improve molecular diagnostic yield. Program results demonstrate a high diagnostic yield for XLH/ genetic hypophosphatemia and new insight into XLH-associated PHEX variants.