Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 1, 181-187, 10 January 2008
doi:10.1016/j.ajhg.2007.08.001
Report
Autosomal-Dominant Microtia Linked to Five Tandem Copies of a Copy-Number-Variable Region at Chromosome 4p16
Irina Balikova1, Kevin Martens1, Cindy Melotte1, Mustapha Amyere2, Steven Van Vooren3, Yves Moreau3, David Vetrie4, Heike Fiegler4, Nigel P. Carter4, Thomas Liehr5, Miikka Vikkula2, Gert Matthijs1, Jean-Pierre Fryns1, Ingele Casteels6, Koen Devriendt1 and Joris Robert Vermeesch1, 
, 
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
Corresponding authorAbstract
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.
Article Information
PubMed
Related Articles
- The Fine-Scale and Complex Architecture of Human Copy-Number...The Fine-Scale and Complex Architecture of Human Copy-Number Variation
The American Journal of Human Genetics, Volume 82, Issue 3, 3 March 2008, Pages 685-695
George H. Perry, Amir Ben-Dor, Anya Tsalenko, Nick Sampas, Laia Rodriguez-Revenga, Charles W. Tran, Alicia Scheffer, Israel Steinfeld, Peter Tsang, N. Alice Yamada, Han Soo Park, Jong-Il Kim, Jeong-Sun Seo, Zohar Yakhini, Stephen Laderman, Laurakay Bruhn and Charles Lee
AbstractDespite considerable excitement over the potential functional significance of copy-number variants (CNVs), we still lack knowledge of the fine-scale architecture of the large majority of CNV regions in the human genome. In this study, we used a high-resolution array-based comparative genomic hybridization (aCGH) platform that targeted known CNV regions of the human genome at approximately 1 kb resolution to interrogate the genomic DNAs of 30 individuals from four HapMap populations. Our results revealed that 1020 of 1153 CNV loci (88%) were actually smaller in size than what is recorded in the Database of Genomic Variants based on previously published studies. A reduction in size of more than 50% was observed for 876 CNV regions (76%). We conclude that the total genomic content of currently known common human CNVs is likely smaller than previously thought. In addition, approximately 8% of the CNV regions observed in multiple individuals exhibited genomic architectural complexity in the form of smaller CNVs within larger ones and CNVs with interindividual variation in breakpoints. Future association studies that aim to capture the potential influences of CNVs on disease phenotypes will need to consider how to best ascertain this previously uncharacterized complexity.
Abstract | | - Phenotypically Concordant and Discordant Monozygotic Twins D...Phenotypically Concordant and Discordant Monozygotic Twins Display Different DNA Copy-Number-Variation Profiles
The American Journal of Human Genetics, Volume 82, Issue 3, 3 March 2008, Pages 763-771
Carl E.G. Bruder, Arkadiusz Piotrowski, Antoinet A.C.J. Gijsbers, Robin Andersson, Stephen Erickson, Teresita Diaz de Ståhl, Uwe Menzel, Johanna Sandgren, Desiree von Tell, Andrzej Poplawski, Michael Crowley, Chiquito Crasto, E. Christopher Partridge, Hemant Tiwari, David B. Allison, Jan Komorowski, Gert-Jan B. van Ommen, Dorret I. Boomsma, Nancy L. Pedersen, Johan T. den Dunnen, Karin Wirdefeldt and Jan P. Dumanski
AbstractThe exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups. These findings have an impact on our views of genotypic and phenotypic diversity in monozygotic twins and suggest that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci. Our results also imply that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics.
Abstract | | - Structural Variation of Chromosomes in Autism Spectrum Disor...Structural Variation of Chromosomes in Autism Spectrum Disorder
The American Journal of Human Genetics, Volume 82, Issue 2, 8 February 2008, Pages 477-488
Christian R. Marshall, Abdul Noor, John B. Vincent, Anath C. Lionel, Lars Feuk, Jennifer Skaug, Mary Shago, Rainald Moessner, Dalila Pinto, Yan Ren, Bhooma Thiruvahindrapduram, Andreas Fiebig, Stefan Schreiber, Jan Friedman, Cees E.J. Ketelaars, Yvonne J. Vos, Can Ficicioglu, Susan Kirkpatrick, Rob Nicolson, Leon Sloman, Anne Summers, Clare A. Gibbons, Ahmad Teebi, David Chitayat, Rosanna Weksberg, Ann Thompson, Cathy Vardy, Vicki Crosbie, Sandra Luscombe, Rebecca Baatjes, Lonnie Zwaigenbaum, Wendy Roberts, Bridget Fernandez, Peter Szatmari and Stephen W. Scherer
AbstractStructural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in ∼7% and ∼2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at ∼1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
Abstract | | - …more
