title: Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia.
abstract: BACKGROUND
  Hypophosphatemic rickets (HR) comprises a rare group of inherited diseases. Very recently, mutations in the dentin matrix protein 1 (DMP1) gene were identified in patients with an extremely rare autosomal recessive form of HR (ARHR). To date, very few cases of these mutations were reported.
  
  
  METHODS
  A Lebanese consanguineous family with 2 affected sisters was studied. Patients aged 45 and 47years old presented with short stature, severe genu varum, cranial hyperostosis and a very high bone density that led to a diagnosis of a familial sclerosing bone dysplasia. Molecular analysis of known genes involved in osteopetrosis showed normal results. A combination of genotyping and exome sequencing was performed in order to elucidate the genetic basis of this pathology.
  
  
  RESULTS
  Biochemical analysis was consistent with normal serum calcium and 1-25(OH)2D levels, low to normal serum phosphorus and elevated PTH values. Serum c-terminal FGF-23 was elevated in one of the two patients. A homozygous mutation disrupting the initiation codon of the DMP1 gene (OMIM 600980), NM_001079911.2: c.1A>G, p.Met1Val, was identified by exome sequencing and confirmed by Sanger sequencing.
  
  
  CONCLUSIONS
  We report here a family of ARHR secondary to a DMP1 mutation located in the first coding exon of the gene. Our cases show that some ARHR cases may develop with age an unaccountable increase in bone density and bone overgrowth.
authors.affiliation: Département d'Endocrinologie, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon. Electronic address: mhcyared@terra.net.lb.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Gannagé-Yared
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. Electronic address: Periklis.Makrythanasis@unige.ch.
authors.forename: Periklis
authors.initials: P
authors.lastname: Makrythanasis
authors.affiliation: Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon. Electronic address: eliane.chouery@usj.edu.lb.
authors.forename: Eliane
authors.initials: E
authors.lastname: Chouery
authors.affiliation: CNR/IRGB, UOS Milan Unit, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Milano, Italy. Electronic address: Cristina.Sobacchi@humanitasresearch.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sobacchi
authors.affiliation: Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon. Electronic address: Cybel.mehawej@net.usj.edu.lb.
authors.forename: Cybel
authors.initials: C
authors.lastname: Mehawej
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. Electronic address: Federico.Santoni@unige.ch.
authors.forename: Federico A
authors.initials: FA
authors.lastname: Santoni
authors.affiliation: Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. Electronic address: Michel.Guipponi@unige.ch.
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, Geneva, Switzerland. Electronic address: Stylianos.Antonarakis@unige.ch.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. Electronic address: hananhamamy@yahoo.com.
authors.forename: Hanan
authors.initials: H
authors.lastname: Hamamy
authors.affiliation: Département d'Endocrinologie, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon; Institut Jérôme Lejeune, Paris, France. Electronic address: megarbane@usj.edu.lb.
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
mesh_terms: D000328:Adult; D001483:Base Sequence; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010009:Osteochondrodysplasias / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics* / Q000652:urine; D010750:Phosphoproteins / Q000235:genetics*; D011859:Radiography
chemical_list: C513309:DMP1 protein, human; D016326:Extracellular Matrix Proteins; C000717427:FGF23 protein, human; D010750:Phosphoproteins; D000089703:Fibroblast Growth Factor-23
keywords: DMP1; Exome; Sclerosing bone dysplasia