The clinical utility of enhanced subtelomere coverage in array CGH. B.C. Ballif, S.G. Sulpizio, R.M. Lloyd, S. Gaskin, S.L. Minier, K. Sundin, M. Lincicum, E.A. Rorem, C.D. Kashork, B.A. Bejjani, L.G. Shaffer. Signature Genomic Laboratories, Spokane, WA.
   Telomeric chromosome abnormalities are a substantial cause of mental retardation and birth defects. Although subtelomeric FISH probes have been widely used to identify submicroscopic telomeric rearrangements, array-based comparative genomic hybridization (array CGH) has emerged as a more efficient and comprehensive approach to the identification of chromosomal aberrations. Due to the clinical relevance of telomeric abnormalities, it has been proposed that array CGH using panels of BAC clones which map to regularly spaced intervals along the length of each telomere could be used to more precisely characterize subtelomeric aberrations in a single experiment. We have constructed a CGH microarray that includes expanded coverage for 41 subtelomeric regions using 1120 FISH-mapped BAC clones. Contigs of clones were selected in increments of ~0.5 Mb, beginning with the most distal unique sequence for each telomere and extending on average 5.7 Mb. We have used this microarray to analyze 62 cases with known subtelomeric aberrations previously characterized using an array with only a single contig of 3-6 clones at each telomere. The expanded telomere coverage was sufficient to define the breakpoint regions of over half (55%) of the chromosome abnormalities. However, 45% of the subtelomeric aberrations extended beyond the size of our expanded coverage suggesting that many subtelomeric abnormalities are 5 Mb in size and that representation extending to 10 Mb may be of even greater value. The enhanced coverage not only clarified the size of the telomeric rearrangements, it also identified at least one case with a more complex subtelomeric rearrangement which may shed light on its mechanism of formation. In addition, we have identified 6 cases of interstitial deletions that would have been missed by both subtelomere FISH and limited array CGH using clones only to the most distal unique sequences. These data suggest that increased coverage at the subtelomeres improves the diagnostic usefulness of array CGH and detects unsuspected complexity of these clinically significant regions.