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SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints

Julia Vogt1, Kathrin Bengesser1, Kathleen BM Claes2, Katharina Wimmer3, Victor-Felix Mautner4, Rick van Minkelen5, Eric Legius6, Hilde Brems6, Meena Upadhyaya7, Josef Högel1, Conxi Lazaro8, Thorsten Rosenbaum9, Simone Bammert1, Ludwine Messiaen10, David N Cooper7 and Hildegard Kehrer-Sawatzki1*

Author Affiliations

1 Institute of Human Genetics, University of Ulm, D-89081 Ulm, Germany

2 Centre for Medical Genetics, Ghent University Hospital, B-9000 Ghent, Belgium

3 Division of Human Genetics, Medical University Innsbruck, A-6020 Innsbruck, Austria

4 Department of Neurology, University Hospital Hamburg Eppendorf, D-20246 Hamburg, Germany

5 Department of Clinical Genetics, Erasmus MC, NL-3015 Rotterdam, The Netherlands

6 Department of Human Genetics, KU Leuven, B-3000 Leuven, Belgium

7 Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK

8 Molecular Diagnostics Unit, Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L’Hospitalet de Llobregat, E-08908 Barcelona, Spain

9 Department of Pediatrics, Duisburg General Hospital, D-47055 Duisburg, Germany

10 Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA

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Genome Biology 2014, 15:R80  doi:10.1186/gb-2014-15-6-r80

Published: 23 June 2014



Genomic disorders are caused by copy number changes that may exhibit recurrent breakpoints processed by nonallelic homologous recombination. However, region-specific disease-associated copy number changes have also been observed which exhibit non-recurrent breakpoints. The mechanisms underlying these non-recurrent copy number changes have not yet been fully elucidated.


We analyze large NF1 deletions with non-recurrent breakpoints as a model to investigate the full spectrum of causative mechanisms, and observe that they are mediated by various DNA double strand break repair mechanisms, as well as aberrant replication. Further, two of the 17 NF1 deletions with non-recurrent breakpoints, identified in unrelated patients, occur in association with the concomitant insertion of SINE/variable number of tandem repeats/Alu (SVA) retrotransposons at the deletion breakpoints. The respective breakpoints are refractory to analysis by standard breakpoint-spanning PCRs and are only identified by means of optimized PCR protocols designed to amplify across GC-rich sequences. The SVA elements are integrated within SUZ12P intron 8 in both patients, and were mediated by target-primed reverse transcription of SVA mRNA intermediates derived from retrotranspositionally active source elements. Both SVA insertions occurred during early postzygotic development and are uniquely associated with large deletions of 1 Mb and 867 kb, respectively, at the insertion sites.


Since active SVA elements are abundant in the human genome and the retrotranspositional activity of many SVA source elements is high, SVA insertion-associated large genomic deletions encompassing many hundreds of kilobases could constitute a novel and as yet under-appreciated mechanism underlying large-scale copy number changes in the human genome.