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A balanced translocation truncates Neurotrimin in a family with intracranial and thoracic aortic aneurysm
  1. Tiia M Luukkonen1,2,
  2. Minna Pöyhönen3,4,
  3. Aarno Palotie1,3,5,6,
  4. Pekka Ellonen1,
  5. Sonja Lagström1,
  6. Joseph H Lee7,
  7. Joseph D Terwilliger2,8,9,10,11,
  8. Riitta Salonen12,
  9. Teppo Varilo2,3
  1. 1Institute for Molecular Medicine Finland FIMM, Helsinki, Finland
  2. 2Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
  3. 3Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
  4. 4Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland
  5. 5Wellcome Trust Sanger Institute Hinxton, Cambridge, UK
  6. 6Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
  7. 7Sergievsky Center/Taub Institute, Columbia University, New York, New York, USA
  8. 8Department of Genetics and Development, Columbia University, New York, New York, USA
  9. 9Department of Psychiatry, Columbia University, New York, New York, USA
  10. 10Columbia Genome Center, Columbia University, New York, New York, USA
  11. 11Division of Medical Genetics, New York State Psychiatric Institute, New York, New York, USA
  12. 12Department of Medical Genetics, Väestöliitto, Helsinki, Finland
  1. Correspondence to Dr Teppo Varilo, Department of Medical Genetics, Haartman Institute, University of Helsinki, P. O. Box 63, Helsinki FIN-00014, Finland; teppo.varilo{at}helsinki.fi

Abstract

Background Balanced chromosomal rearrangements occasionally have strong phenotypic effects, which may be useful in understanding pathobiology. However, conventional strategies for characterising breakpoints are laborious and inaccurate. We present here a proband with a thoracic aortic aneurysm (TAA) and a balanced translocation t(10;11) (q23.2;q24.2). Our purpose was to sequence the chromosomal breaks in this family to reveal a novel candidate gene for aneurysm.

Methods and results Intracranial aneurysm (IA) and TAAs appear to run in the family in an autosomal dominant manner: After exploring the family history, we observed that the proband's two siblings both died from cerebral haemorrhage, and the proband's parent and parent's sibling died from aortic rupture. After application of a genome-wide paired-end DNA sequencing method for breakpoint mapping, we demonstrate that this translocation breaks intron 1 of a splicing isoform of Neurotrimin at 11q25 in a previously implicated candidate region for IAs and AAs (OMIM 612161).

Conclusions Our results demonstrate the feasibility of genome-wide paired-end sequencing for the characterisation of balanced rearrangements and identification of candidate genes in patients with potentially disease-associated chromosome rearrangements. The family samples were gathered as a part of our recently launched National Registry of Reciprocal Balanced Translocations and Inversions in Finland (n=2575), and we believe that such a registry will be a powerful resource for the localisation of chromosomal aberrations, which can bring insight into the aetiology of related phenotypes.

  • Molecular genetics
  • Cardiovascular Medicine
  • Chromosomal
  • Clinical genetics
  • Genome-wide

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