title: Mutational analysis of PHEX, FGF23 and CLCN5 in patients with hypophosphataemic rickets.
abstract: BACKGROUND
  Hypophosphataemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3.
  
  
  OBJECTIVE
  To investigate underlying genetic defects in patients with hypophosphataemic rickets.
  
  
  METHODS
  We analysed genomic DNA from nine unrelated families for mutations in the entire coding region of PHEX, FGF23, DMP1, ENPP1, CLCN5 or SLC34A3 by PCR sequencing and copy number analysis.
  
  
  RESULTS
  A total of 14 patients were studied. PHEX mutations were identified in 12 patients from seven families. Five of them were novel mutations present in eight patients: c.154G>T (p.E52*), c.401_402insGCCAAA (p.Q134_K135insPK), c.1600C>T (p.P534S), g.22016715_22056805del (40-kb deletion including promoter and exons 1-3) and c.2242_2243delCT (p.L748 fs*48). Four patients had previously reported mutations: c.1768+1G>A and c.1807G>A (p.W602*). Novel CLCN5 (c.1205G>A, p.W402*) and FGF23 (c.526C>G, p.R176G) mutations were found in two patients from the remaining two families. Many of the mutations were de novo: c.154G>T and c.2242_2243delCT in PHEX and c.526C>G in FGF23. Furthermore, we characterized the breakpoint of the novel PHEX g.22016715_22056805del and the c.2242_2243delCT, which is 6 bp from the stop codon, resulting in a frameshift and extension of the reading frame by 42 amino acids.
  
  
  CONCLUSIONS
  Novel and de novo mutations are frequent and PHEX mutations are still the most common genetic defects in the Turkish population. Gene copy number analysis should be considered in patients with negative results by conventional PCR-based sequencing analysis. The current study further expands the mutation spectrum underlying HR.
authors.affiliation: Department of Pediatric, Amasya University Medical Faculty, Amasya, Turkey.|Pediatric Endocrinology Clinic, Goztepe Educational and Research Hospital, Istanbul, Turkey.
authors.forename: Ayla
authors.initials: A
authors.lastname: Guven
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Roua A
authors.initials: RA
authors.lastname: Al-Rijjal
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Huda A
authors.initials: HA
authors.lastname: BinEssa
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, Uludag University Faculty of Medicine, Bursa, Turkey.
authors.forename: Durmuş
authors.initials: D
authors.lastname: Dogan
authors.affiliation: Pediatric Endocrinology Division, Adana Numune Training and Research Hospital, Adana, Turkey.
authors.forename: Yılmaz
authors.initials: Y
authors.lastname: Kor
authors.affiliation: Pediatric Endocrinology Clinic, Goztepe Educational and Research Hospital, Istanbul, Turkey.
authors.forename: Minjing
authors.initials: M
authors.lastname: Zou
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Namik
authors.initials: N
authors.lastname: Kaya
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Anwar F
authors.initials: AF
authors.lastname: Alenezi
authors.affiliation: Department of Pediatric, Amasya University Medical Faculty, Amasya, Turkey.|Pediatric Endocrinology Clinic, Goztepe Educational and Research Hospital, Istanbul, Turkey.
authors.forename: Suna
authors.initials: S
authors.lastname: Hancili
authors.affiliation: Department of Pediatrics, Division of Pediatric Endocrinology, Uludag University Faculty of Medicine, Bursa, Turkey.
authors.forename: Ömer
authors.initials: Ö
authors.lastname: Tarım
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Essa Y
authors.initials: EY
authors.lastname: Baitei
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Walaa E
authors.initials: WE
authors.lastname: Kattan
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Meyer
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Yufei
authors.identifier: http://orcid.org/0000-0002-6999-0191
authors.initials: Y
authors.lastname: Shi
mesh_terms: D018118:Chloride Channels / Q000235:genetics*; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics*; D018628:Gene Dosage; D006801:Humans; D008297:Male; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics*; D010375:Pedigree; D063730:Rickets, Hypophosphatemic / Q000235:genetics*; D014421:Turkey
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels; C000717427:FGF23 protein, human; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase
keywords: 
  CLCN5
  ; 
  FGF23
  ; 
  PHEX
  ; hypophosphataemia; rickets