title: Genetic diagnosis of X-linked dominant Hypophosphatemic Rickets in a cohort study: tubular reabsorption of phosphate and 1,25(OH)2D serum levels are associated with PHEX mutation type.
abstract: BACKGROUND
  Genetic Hypophosphatemic Rickets (HR) is a group of diseases characterized by renal phosphate wasting with inappropriately low or normal 1,25-dihydroxyvitamin D3 (1,25(OH)2D) serum levels. The most common form of HR is X-linked dominant HR (XLHR) which is caused by inactivating mutations in the PHEX gene. The purpose of this study was to perform genetic diagnosis in a cohort of patients with clinical diagnosis of HR, to perform genotype-phenotype correlations of those patients and to compare our data with other HR cohort studies.
  
  
  METHODS
  Forty three affected individuals from 36 non related families were analyzed. For the genetic analysis, the PHEX gene was sequenced in all of the patients and in 13 cases the study was complemented by mRNA sequencing and Multiple Ligation Probe Assay. For the genotype-phenotype correlation study, the clinical and biochemical phenotype of the patients was compared with the type of mutation, which was grouped into clearly deleterious or likely causative, using the Mann-Whitney and Fisher's exact test.
  
  
  RESULTS
  Mutations in the PHEX gene were identified in all the patients thus confirming an XLHR. Thirty four different mutations were found distributed throughout the gene with higher density at the 3' end. The majority of the mutations were novel (69.4%), most of them resulted in a truncated PHEX protein (83.3%) and were family specific (88.9%). Tubular reabsorption of phosphate (TRP) and 1,25(OH)2D serum levels were significantly lower in patients carrying clearly deleterious mutations than in patients carrying likely causative ones (61.39 ± 19.76 vs. 80.14 ± 8.80%, p = 0.028 and 40.93 ± 30.73 vs. 78.46 ± 36.27 pg/ml, p = 0.013).
  
  
  CONCLUSIONS
  PHEX gene mutations were found in all the HR cases analyzed, which was in contrast with other cohort studies. Patients with clearly deleterious PHEX mutations had lower TRP and 1,25(OH)2D levels suggesting that the PHEX type of mutation might predict the XLHR phenotype severity.
authors: Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
authors: Marcos
authors: M
authors: Morey
authors: Lidia
authors: L
authors: Castro-Feijóo
authors: Jesús
authors: J
authors: Barreiro
authors: Paloma
authors: P
authors: Cabanas
authors: Manuel
authors: M
authors: Pombo
authors: Marta
authors: M
authors: Gil
authors: Ignacio
authors: I
authors: Bernabeu
authors: José M
authors: JM
authors: Díaz-Grande
authors: Lourdes
authors: L
authors: Rey-Cordo
authors: Gema
authors: G
authors: Ariceta
authors: Itxaso
authors: I
authors: Rica
authors: José
authors: J
authors: Nieto
authors: Ramón
authors: R
authors: Vilalta
authors: Loreto
authors: L
authors: Martorell
authors: Jaime
authors: J
authors: Vila-Cots
authors: Fernando
authors: F
authors: Aleixandre
authors: Ana
authors: A
authors: Fontalba
authors: Leandro
authors: L
authors: Soriano-Guillén
authors: José M
authors: JM
authors: García-Sagredo
authors: Sixto
authors: S
authors: García-Miñaur
authors: Berta
authors: B
authors: Rodríguez
authors: Saioa
authors: S
authors: Juaristi
authors: Carmen
authors: C
authors: García-Pardos
authors: Antonio
authors: A
authors: Martínez-Peinado
authors: José M
authors: JM
authors: Millán
authors: Ana
authors: A
authors: Medeira
authors: Oana
authors: O
authors: Moldovan
authors: Angeles
authors: A
authors: Fernandez
authors: Lourdes
authors: L
authors: Loidi
mesh_terms: D000293:Adolescent; D002117:Calcitriol / Q000097:blood* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D053098:Familial Hypophosphatemic Rickets / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D040181:Genetic Diseases, X-Linked; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D009154:Mutation; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics*; D010641:Phenotype; D010710:Phosphates / Q000097:blood* / Q000737:chemistry; D012279:Rickets / Q000235:genetics*
chemical_list: D010710:Phosphates; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human; D002117:Calcitriol