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      Pseudoachondroplasia and Multiple Epiphyseal Dysplasia: A 7-Year Comprehensive Analysis of the Known Disease Genes Identify Novel and Recurrent Mutations and Provides an Accurate Assessment of Their Relative Contribution

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          Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are relatively common skeletal dysplasias resulting in short-limbed dwarfism, joint pain, and stiffness. PSACH and the largest proportion of autosomal dominant MED (AD-MED) results from mutations in cartilage oligomeric matrix protein ( COMP); however, AD-MED is genetically heterogenous and can also result from mutations in matrilin-3 ( MATN3) and type IX collagen ( COL9A1, COL9A2, and COL9A3). In contrast, autosomal recessive MED (rMED) appears to result exclusively from mutations in sulphate transporter solute carrier family 26 ( SLC26A2). The diagnosis of PSACH and MED can be difficult for the nonexpert due to various complications and similarities with other related diseases and often mutation analysis is requested to either confirm or exclude the diagnosis. Since 2003, the European Skeletal Dysplasia Network (ESDN) has used an on-line review system to efficiently diagnose cases referred to the network prior to mutation analysis. In this study, we present the molecular findings in 130 patients referred to ESDN, which includes the identification of novel and recurrent mutations in over 100 patients. Furthermore, this study provides the first indication of the relative contribution of each gene and confirms that they account for the majority of PSACH and MED. Hum Mutat 33:144–157, 2012. © 2011 Wiley Periodicals, Inc.

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          Nosology and Classification of Genetic Skeletal Disorders: 2010 Revision

          Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology. © 2011 Wiley-Liss, Inc.
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            Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene.

            Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are dominantly inherited chondrodysplasias characterized by short stature and early-onset osteoarthrosis. The disease genes in families with PSACH and MED have been localized to an 800 kilobase interval on the short arm of chromosome 19. Recently the gene for cartilage oligomeric matrix protein (COMP) was localized to chromosome 19p13.1. In three patients with these diseases, we identified COMP mutations in a region of the gene that encodes a Ca++ binding motif. Our data demonstrate that PSACH and some forms of MED are allelic and suggest an essential role for Ca++ binding in COMP structure and function.
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              Nosology and classification of genetic skeletal disorders: 2006 revision.

              The objective of the paper is to provide the revision of the Nosology of Constitutional Disorders of Bone that incorporates newly recognized disorders and reflects new molecular and pathogenetic concepts. Criteria for inclusion of disorders were (1) significant skeletal involvement corresponding to the definition of skeletal dysplasias, metabolic bone disorders, dysostoses, and skeletal malformation and/or reduction syndromes, (2) publication and/or MIM listing, (3) genetic basis proven or very likely, and (4) nosologic autonomy confirmed by molecular or linkage analysis and/or distinctive diagnostic features and observation in multiple individuals or families. Three hundred seventy-two different conditions were included and placed in 37 groups defined by molecular, biochemical and/or radiographic criteria. Of these conditions, 215 were associated with one or more of 140 different genes. Nosologic status was classified as final (mutations or locus identified), probable (pedigree evidence), or bona fide (multiple observations and clear diagnostic criteria, but no pedigree or locus evidence yet). The number of recognized genetic disorders with a significant skeletal component is growing and the distinction between dysplasias, metabolic bone disorders, dysostoses, and malformation syndromes is blurring. For classification purposes, pathogenetic and molecular criteria are integrating with morphological ones but disorders are still identified by clinical features and radiographic appearance. Molecular evidence leads to confirmation of individual entities and to the constitution of new groups, but also allows for delineation of related but distinct entities and indicates a previously unexpected heterogeneity of molecular mechanisms; thus, molecular evidence does not necessarily simplify the Nosology, and a further increase in the number of entities and growing complexity is expected. By providing an updated overview of recognized entities with skeletal involvement and of the underlying gene defects, the new Nosology can provide practical diagnostic help, facilitate the recognition of new entities, and foster and direct research in skeletal biology and genetic disorders. (c) 2006 Wiley-Liss, Inc.

                Author and article information

                Hum Mutat
                Human Mutation
                Wiley Subscription Services, Inc., A Wiley Company (Hoboken )
                January 2012
                15 September 2011
                : 33
                : 1
                : 144-157
                [1 ]simpleWellcome Trust Centre for Cell Matrix Research, University of Manchester Manchester, United Kingdom
                [2 ]simpleNational Genetics Reference Laboratory Manchester, United Kingdom
                [3 ]simpleCentre Hospitalier Universitaire Vaudois Lausanne, Switzerland
                [4 ]simpleDepartment of Medical Genetics, Antwerp University Hospital Antwerp, Belgium
                [5 ]simpleInstitute for Human Genetics and Center for Paediatrics and Adolescent Medicine Freiburg, Germany
                [6 ]simpleHôpital Necker-Enfants Malades Paris, France
                [7 ]simpleGreat Ormond Street Hospital for Children London, United Kingdom
                [8 ]simpleSheffield Children's Hospital Sheffield, United Kingdom
                [9 ]simpleInstitute of Human Genetics Newcastle-upon-Tyne, United Kingdom
                [10 ]simpleMurdoch Children's Research Institute, Genetic Health Services Victoria and Department of Paediatrics, University of Melbourne Melbourne, Australia
                [11 ]simpleDepartment of Paediatric Imaging, Tokyo Metropolitan Children's Medical Centre Japan
                [12 ]simpleBone Dysplasia Research Group, University of Queensland Centre for Clinical Research, University of Queensland Brisbane, Australia
                Author notes
                *Correspondence to: Dr. Michael Briggs, Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, United Kingdom. E-mail: mike.briggs@

                Communicated by David Rimoin


                Both authors contributed equally to this work.

                Contract grant sponsors: Wellcome Trust (071161/Z/03/Z, 084353/Z/07/Z to M.D.B.); The European Commission FP5 (QLG1-CT-2001-02188) and FP6 (LSHM-CT-2007-037471); The Swiss National Science Foundation (FN 310030-132940/BONAFE Luisa); The Leenaards Foundation in Lausanne (to A.S.F.).

                © 2011 Wiley Periodicals, Inc.

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                Research Articles

                Human biology

                multiple epiphyseal dysplasia, slc26a2, pseudoachondroplasia, comp


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