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Systematic re-examination of carriers of balanced reciprocal translocations identifies multiple candidate regions for late-onset and common disorders
I. Bache¹, K. Brondum-Nielsen², G. Bruun-Petersen³, M. Bugge¹, M. Hjorth¹, S. Holstebroe¹, P.K.A. Jensen⁴, C. Lundsteen⁵, E. Niebuhr⁶, K. Rasmussen⁷, L. Schmidt⁸, N. Tommerup¹;
¹Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Denmark, ²John F. Kennedy Institute, Glostrup, Denmark, ³Dept of Clinical Genetics, Vejle Sygehus, Denmark, ⁴Dept of Clinical Genetics, Aarhus Kommunehospital, Denmark, ⁵Dept of Clinical Genetics, Rigshospitalet, Denmark, ⁶Dept of Medical Biochemistry and Genetics, University of Copenhagen, Denmark, ⁷Dept of Clinical Genetics, Odense University Hospital, Denmark, ⁸Institute of Public Health, University of Copenhagen, Denmark.

Balanced reciprocal translocations associated with genetic disorders have facilitated the identification of genes especially for monogenic disorders with an early-onset. To assess whether chromosomal breakpoints may be associated with common and later onset disorders, we performed a systematic questionnaire-based re-examination of known reciprocal translocation carriers in Denmark. In total, questionnaires were mailed to 875 carriers of which 733 accepted to participate (compliance = 84%). The reported traits/diseases were confirmed by medical files and personal contact with the family.

We observed 27 unrelated carriers with a disease where a breakpoint involved a cytogenetic band known to harbour a corresponding locus. This included very common disorders (e.g. allergy, asthma, myopia, obesity, hypertension, coronary heart disease, Type 2 diabetes), autoimmune disorders (Type 1 diabetes, inflammatory bowel disease, hyperthyroidism), neurological / neuro-psychiatric disorders (e.g. bipolar disorder, multiple sclerosis, Parkinson's disease) and cancer. We found a significant linkage (LOD = 2.1) of dyslexia and a co-segregating translocation with a breakpoint in a confirmed locus for dyslexia, and we identified 10 other families, where the translocation co-segregated with a specific phenotype. Furthermore, we identified carriers with the same disease (e.g. cervix dysplasia, hypertension), where independent breakpoints involved the same chromosomal band.

Our study indicates that a systematic re-examination of translocation carriers promises to be a powerful way to identify loci and genes for a variety of human traits and disorders. To expand this approach to larger populations, we have initiated an international consortium to systematize the questionnaire-based re-examination and data-handling.

Presented at ESHG Conference, May 2005.