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Open Access Highly Accessed Research article

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

Marcos Morey1, Lidia Castro-Feijóo2, Jesús Barreiro2, Paloma Cabanas2, Manuel Pombo2, Marta Gil3, Ignacio Bernabeu4, José M Díaz-Grande5, Lourdes Rey-Cordo6, Gema Ariceta7, Itxaso Rica7, José Nieto8, Ramón Vilalta8, Loreto Martorell9, Jaime Vila-Cots10, Fernando Aleixandre11, Ana Fontalba12, Leandro Soriano-Guillén13, José M García-Sagredo14, Sixto García-Miñaur15, Berta Rodríguez16, Saioa Juaristi17, Carmen García-Pardos18, Antonio Martínez-Peinado19, José M Millán20, Ana Medeira21, Oana Moldovan21, Angeles Fernandez22 and Lourdes Loidi1*

Author Affiliations

1 Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain

2 Unidad de Endocrinología Pediátrica, Crecimiento y Adolescencia. Pediatría, Hospital Clínico Universitario y Universidad de Santiago de Compostela, Spain

3 Pediatría. Hospital Clínico Universitario, Santiago de Compostela, Spain

4 Endocrinología, Hospital Clínico Universitario, Santiago de Compostela, Spain

5 Pediatría, Complejo Hospitalario de Pontevedra, Spain

6 Pediatría, Complejo Hospitalario de Vigo, Spain

7 Pediatría, Hospital de Cruces, Barakaldo, Spain

8 Nefrología Pediátrica, Hospital Vall d'Hebrón, Barcelona, Spain

9 Genética, Hospital San Joan de Deu, Espluges-Barcelona, Spain

10 Nefrología, Hospital San Joan de Deu, Espluges-Barcelona, Spain

11 Pediatría, Hospital Virgen de la Salud, Elda, Spain

12 Genética, Hospital Universitario Marqués de Valdecilla, Santander, Spain

13 Pediatría, Fundación Jiménez Díaz, Madrid, Spain

14 Genética, Hospital Ramón y Cajal, Madrid, Spain

15 Genética, Hospital Universitario La Paz, Madrid, Spain

16 Genética, Complejo Hospitalario A Coruña, Spain

17 Genética, Hospital Donostia, San Sebastián, Spain

18 Pediatría, Hospital Donostia, San Sebastián, Spain

19 Genética, Hospital Reina Sofía, Córdoba, Spain

20 Genética, Hospital La Fé and CIBERER, Valencia, Spain

21 Genética, Hospital Santa María, Lisboa, Portugal

22 Pediatría, Complejo Hospitalario de Toledo. Spain

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BMC Medical Genetics 2011, 12:116  doi:10.1186/1471-2350-12-116

Published: 8 September 2011



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.


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.


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).


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.