AUTOSOMAL DOMINANT MICROTIA LINKED TO FIVE TANDEM COPIES OF A COPY NUMBER VARIABLE REGION AT CHROMOSOME 4pTER
Irina Balikova1, Kevin Martens1, Cindy Melotte1, Steven Van Vooren4, Yves Moreau4, David Vetrie3, Heike Fiegler3, Nigel Carter3, Thomas Liehr2, Gert Matthijs1, Jean-Pierre Fryns1, Ingele Casteels1 , Koen Devriendt1 and Joris Robert Vermeesch1
1
Center for Human Genetics and Department of Ophthalmology (IC) University of Leuven, Belgium. 2
Institute of Human Genetics and Anthropology, Jena, Germany 3
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambs., UK 4
ESAT-SISTA K.U. Leuven, Belgium
Recently, large scale benign copy number variations ( CNV’s) were uncovered in the human population, encompassing over 12% of our genome. Deletions and duplications of these regions present in normal individuals contain genes considered to be dosage tolerant for human development. We present a family with a novel autosomal dominant inherited syndrome characterized by microtia, eye coloboma and lacrimal duct obstruction. The phenotype is linked to a cytogenetically visible alteration at 4pter. We show that the alteration contains 5 copies of a CNV region, encompassing a low copy repeat rich region (LCR). This is the first example of an amplified CNV associated with a Mendelian disorder. We demonstrate that the ~750 kb amplicon occurs as exact tandem copies. The molecular analysis of this amplification provides a model about how copy number variability arise. In addition, the association of a copy number variation encompassing an LCR with a Mendelian trait implies that complex benign copy number variants should be included in genome wide copy number screens for genetic disorders.
