X-linked osteoporosis and fractures: an unexpected genetic cause. F. S. van Dijk1, M. C. Zillikens2, D. Micha1, M. Riessland3, C. L. M. Marcelis4, C. E. de Die-Smulders5, J. Milbradt3, A. A. M. Franken6, G. J. Harsevoort7, K. D. Lichtenbelt8, J. E. Pruijs9, M. E. Rubio-Gozalbo10,11, R. Zwertbroek12, M. Hammerschmidt13, R. Bijman1, C. M. Semeins14, A. D. Bakker14, V. Everts14, J. Klein-Nulend14, N. Campos-Obando2, A. Hofman15, A. J. M. H. Verkerk2, A. G. Uitterlinden2,15, A. Maugeri1, E. A. Sistermans1, Q. Waisfisz1, H. Meijers-Heijboer1, B. Wirth3, M. E. H. Simon16, G. Pals1 1) Clinical Gen, VU Med Ctr, Amsterdam, Netherlands; 2) Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; 3) Institute of Human Genetics, Institute of Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; 4) Department of Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 5) Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands; 6) Department of Internal Medicine, Isala Clinics Zwolle, Zwolle, the Netherlands; 7) Department of Orthopedics, Isala Clinics Zwolle, Zwolle, the Netherlands; 8) Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands; 9) Department of Pediatric Orthopaedics, University Medical Center Utrecht, Wilhelmina Childrens Hospital, Utrecht, the Netherlands; 10) Department of Pediatrics, Maastricht University Medical Center, Maastricht, the Netherlands; 11) Department of Pediatrics and Laboratory Genetic Metabolic Diseases, Maastricht University Medical Center, Maastricht, the Netherlands; 12) Department of Internal Medicine, Westfries Gasthuis, Hoorn, the Netherlands; 13) Department of Developmental Biology, University of Cologne, Cologne, Germany; 14) Department of Oral Cell Biology, ACTA, University of Amsterdam and VU University Amsterdam, MOVE Research Institute Amsterdam, Amsterdam, the Netherlands; 15) Department of Epidemiology, Erasmus MC Rotterdam, the Netherlands; 16) Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.

   Objectives: Osteoporosis with fractures as an X-linked trait, was first reported as a rare type of OI by Sillence in 1980. OI is genetically heterogeneous with an estimated 90% due to dominant mutations in the COL1A1 or COL1A2 gene and approximately 10% due to recessive mutations and other unknown causes. Our goal is to discover new genetic causes of OI and related disorders. Methods: We investigated all referred cases that had been clearly labelled as OI (all types) but where no genetic cause had been identified by sequence analysis of all known OI genes. Depending on the pedigree, specific genetic methods including exome sequencing were used to identify the causative gene. Results : In one large family with a referral diagnosis of OI type I, normal collagen type I electrophoresis and absence of COL1A1/2 mutations, X-linked inheritance appeared likely based on the pedigree. Exome sequencing of the X chromosome identified a putative pathogenic frameshift mutation in a candidate gene in affected family members. Four additional families with pathogenic mutations were discovered. In vitro and in vivo studies have been performed which support pathogenicity of the identified mutations. Furthermore, a rare variant in our candidate gene appeared upon testing in a large group of elderly subjects, associated with a twofold increased fracture risk in elderly female carriers in the normal population. Conclusions: For the first time we report a genetic cause of X-linked osteoporosis and fractures supported by in vitro and in vivo studies. Furthermore, the discovery of a rare variant, associated with a twofold increased fracture risk in elderly females, indicates genetic variation in the identified candidate gene as a novel etiological factor involved in osteoporosis.

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