Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 4, 916-926, 28 March 2008
doi:10.1016/j.ajhg.2008.02.007
Article
FISH Mapping of De Novo Apparently Balanced Chromosome Rearrangements Identifies Characteristics Associated with Phenotypic Abnormality
J.A. Fantes1, 9, E. Boland2, 9, J. Ramsay1, D. Donnai2, M. Splitt3, J.A. Goodship3, H. Stewart4, M. Whiteford5, P. Gautier1, L. Harewood1, 6, S. Holloway7, F. Sharkey1, 8, E. Maher8, V. van Heyningen1, J. Clayton-Smith2, D.R. Fitzpatrick1, 
, 
and G.C.M. Black2
1 Medical and Developmental Genetics Section, Medical Research Council (MRC) Human Genetics Unit, Edinburgh EH4 2XU, Scotland, UK
2 Department of Clinical Genetics, Central Manchester and Manchester Children's University Hospitals NHS Trust, St. Mary's Hospital, Manchester M13 0JH, UK
3 Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
4 Department of Medical Genetics, Churchill Hospital, Old Road, Headington, Oxford, UK
5 Clinical Genetics Department, Yorkhill Hospital, Glasgow G3 8SJ, Scotland, UK
6 Université de Lausanne, Centre Intégratif de Génomique (CIG), CH-1015 Lausanne, Switzerland
7 South East Scotland Clinical Genetics Services, Western General Hospital, Edinburgh EH4 2XU, Scotland, UK
8 Regional Cytogenetics Laboratory, Western General Hospital, Edinburgh EH4 2XU, Scotland, UK
Corresponding author9 These authors contributed equally to this work.
Abstract
We report fluorescence in situ hybridization (FISH) mapping of 152, mostly de novo, apparently balanced chromosomal rearrangement (ABCR) breakpoints in 76 individuals, 30 of whom had no obvious phenotypic abnormality (control group) and 46 of whom had an associated disease (case group). The aim of this study was to identify breakpoint characteristics that could discriminate between these groups and which might be of predictive value in de novo ABCR (DN-ABCR) cases detected antenatally. We found no difference in the proportion of breakpoints that interrupted a gene, although in three cases, direct interruption or deletion of known autosomal-dominant or X-linked recessive Mendelian disease genes was diagnostic. The only significant predictor of phenotypic abnormality in the group as a whole was the localization of one or both breakpoints to an R-positive (G-negative) band with estimated predictive values of 0.69 (95% CL 0.54–0.81) and 0.90 (95% CL 0.60–0.98), respectively. R-positive bands are known to contain more genes and have a higher guanine-cytosine (GC) content than do G-positive (R-negative) bands; however, whether a gene was interrupted by the breakpoint or the GC content in the 200kB around the breakpoint had no discriminant ability. Our results suggest that the large-scale genomic context of the breakpoint has prognostic utility and that the pathological mechanism of mapping to an R-band cannot be accounted for by direct gene inactivation.
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