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Autosomal-dominant microtia linked to five tandem copies of a copy-number-variable region at chromosome 4p16 |
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| Authors: | Balikova Irina Martens Kevin Melotte Cindy Amyere Mustapha Van Vooren Steven Moreau Yves Vetrie David Fiegler Heike Carter Nigel P Liehr Thomas Vikkula Miikka Matthijs Gert Fryns Jean-Pierre Casteels Ingele Devriendt Koen Vermeesch Joris Robert |
| Affiliation: | 1 Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium 2 Laboratory of Human Molecular Genetics, Université Catholique de Louvain, B-1200 Brussels, Belgium 3 Department of Electrical Engineering, University of Leuven, 3000 Leuven, Belgium 4 The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom 5 Institute of Human Genetics and Anthropology, Friedrich-Schiller-Universität, D-07740 Jena, Germany 6 Department of Ophthalmology, University of Leuven, 3000 Leuven, Belgium |
| Abstract: | Recently, large-scale benign copy-number variations (CNVs)—encompassing over 12% of the genome and containing genes considered to be dosage tolerant for human development—were uncovered in the human population. Here we present a family with a novel autosomal-dominantly inherited syndrome characterized by microtia, eye coloboma, and imperforation of the nasolacrimal duct. This phenotype is linked to a cytogenetically visible alteration at 4pter consisting of five copies of a copy-number-variable region, encompassing a low-copy repeat (LCR)-rich sequence. We demonstrate that the ~750 kb amplicon occurs in exact tandem copies. This is the first example of an amplified CNV associated with a Mendelian disorder, a discovery that implies that genome screens for genetic disorders should include the analysis of so-called benign CNVs and LCRs. |
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