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Invest Ophthalmol Vis Sci 2007;48: E-Abstract 5598.
© 2007 ARVO


Progress Determining the Mechanism of Segmental Duplication and Deletion in Axenfeld Rieger Phenotypes

B. Chanda1A, M. Asai-Coakwell1A, M. Ye1A, J. C. Sowden2, M. A. Walter1A,1B and O. J. Lehmann1A,1B

AOphthalmology, BMedical Genetics, 1University of Alberta, Edmonton, Alberta, Canada
2Developmental Biology Unit, Institute of Child Health, London, United Kingdom

Commerical Relationships: B. Chanda, None; M. Asai-Coakwell, None; M. Ye, None; J.C. Sowden, None; M.A. Walter, None; O.J. Lehmann, None.

Support: Canada Research Chair Program, AHFMR, CIHR


Purpose:To identify the cause(s) of chromosome 6p25 segmental duplication and deletion, which result in a spectrum of Axenfeld Rieger phenotypes.

Methods:Array Comparative Genome Hybridization (CGH) was undertaken to refine the location of breakpoints in segmental deletion (n=1) and duplication (n=5) pedigrees. Subsequently, long range PCR was performed to amplify breakpoint-spanning junctional fragments with sequencing and in silico analysis used to determine the genomic architecture of the junctional fragment and the region flanking the breakpoints.

Results:CGH accurately defined the extent of 6p25 segmental anomalies [deletion 1216 kb; duplications 474, 477.5 and 492kb]. A 1.2kb junctional fragment amplified in the deletion pedigree (n=5 affected) segregated with the clinical phenotype. The breakpoints lie within simple repeats with 368bp of novel sequence, comprising two 100% homologous motifs in head to tail orientation, inserted between them separated by a 13bp insert. Analyses of the segmental duplications are commencing.

Conclusions:Array CGH represents a powerful technique to define the extent of chromosomal anomalies and facilitate analysis of the mechanism(s) that cause glaucoma-associated segmental duplications and deletions. The segmental deletion exhibits features of both homologous recombination and non-homologous end joining with an unusually large insert of DNA at the breakpoint. The variation in segmental duplication size indicates existence of a common causative mechanism and elucidation of this will clarify the etiology of a proportion of Axenfeld Rieger syndrome cases.

Keywords: genetics • development

© 2007, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Permission to republish any abstract or part of an abstract in any form must be obtained in writing from the ARVO Office prior to publication.