4.6 Article

Molecular Diagnoses of X-Linked and Other Genetic Hypophosphatemias: Results From a Sponsored Genetic Testing Program

期刊

JOURNAL OF BONE AND MINERAL RESEARCH
卷 37, 期 2, 页码 202-214

出版社

WILEY
DOI: 10.1002/jbmr.4454

关键词

CELL/TISSUE SIGNALING; PARACRINE PATHWAYS; OTHER; DISEASES AND DISORDERS OF/RELATED TO BONE; OTHER; DISORDERS OF CALCIUM/PHOSPHATE METABOLISM; OTHER; GENETIC RESEARCH; HUMAN ASSOCIATION STUDIES; THERAPEUTICS; OTHER

资金

  1. Ultragenyx Pharmaceutical Inc
  2. Kyowa Kirin International plc

向作者/读者索取更多资源

X-linked hypophosphatemia (XLH) is a dominant genetic disorder caused by pathogenic variants in the PHEX gene, leading to symptoms such as rickets, osteomalacia, short stature, and musculoskeletal issues. A free genetic sequencing test was found to help confirm clinical diagnosis of XLH, and the study identified numerous novel variants in XLH genetics research.
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 (30 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. (C) 2021 The Authors.

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