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Ten novel FBN2 mutations in congenital contractural arachnodactyly: Delineation of the molecular pathogenesis and clinical phenotype
Authors:Prateek A. Gupta  Elizabeth A. Putnam  Sonya G. Carmical  Ilkka Kaitila  Beat Steinmann  Anne Child  Cesare Danesino  Kay Metcalfe  Susan A. Berry  Emily Chen  Catherine Vincent Delorme  Meow‐Keong Thong  Lesley C. Adès  Dianna M. Milewicz
Affiliation:1. Department of Internal Medicine, University of Texas‐Houston Medical School, Houston, Texas;2. Prateek A. Gupta and Elizabeth A. Putnam contributed equally to this work;3. Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland;4. Division of Metabolism and Molecular Pediatrics, University Children’s Hospital, Zurich, Switzerland;5. Department of Cardiological Sciences, St. George’s Hospital Medical School, London, UK;6. Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy;7. University Department of Medical Genetics and Regional Genetics Service, St. Mary’s Hospital, Manchester, UK;8. Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota;9. Department of Medical Genetics, Children’s Hospital of Oakland, Oakland, California;10. Genetique Medicale, Centre Hospitalier D’Arras, Arras, France;11. Victorian Clinical Genetics Service, Royal Children’s Hospital, Parkville, Australia;12. Departments of Clinical Genetics and Paediatrics and Child Health, Children’s Hospital at Westmead, New South Wales, Australia;13. Department of Internal Medicine, University of Texas‐Houston Medical School, Houston, TexasUniversity of Texas‐Houston Medical School, 6431 Fannin, MSB 1.614, Houston, TX 77030
Abstract:Congenital contractural arachnodactyly (CCA) is an autosomal dominant condition that shares skeletal features with Marfan syndrome (MFS), but does not have the ocular and cardiovascular complications that characterize MFS. CCA and MFS result from mutations in highly similar genes, FBN2 and FBN1, respectively. All the identified CCA mutations in FBN2 cluster in a limited region similar to where severe MFS mutations cluster in FBN1, specifically between exons 23 and 34. We screened exons 22 through 36 of FBN2 for mutations in 13 patients with classic CCA by single stranded conformational polymorphism analysis (SSCP) and then by direct sequencing. We successfully identified 10 novel mutations in this critical region of FBN2 in these patients, indicating a mutation detection rate of 75% in this limited region. Interestingly, none of these identified FBN2 mutations alter amino acids in the calcium binding consensus sequence in the EGF‐like domains, whereas many of the FBN1 mutations alter the consensus sequence. Furthermore, analysis of the clinical data of the CCA patients with characterized FBN2 mutation indicate that CCA patients have aortic root dilatation and the vast majority lack evidence of congenital heart disease. These studies have implications for our understanding of the molecular basis of CCA, along with the diagnosis and genetic counseling of CCA patients. Hum Mutat 19:39–48, 2002. © 2001 Wiley‐Liss, Inc.
Keywords:congenital contractural arachnodactyly  CCA  clinical phenotype  fibrillin 2  FBN2  fibrillin 1  FBN1  Marfan syndrome  MFS  genotype–  phenotype
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