The clinical utility of enhanced subtelomeric coverage in array CGH

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Abstract
Telomeric chromosome abnormalities are a substantial cause of mental retardation and birth defects. Although subtelomeric fluorescence in situ hybridization (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 detection method. Due to the clinical relevance of telomeric abnormalities, it has been proposed that array CGH using panels of BAC clones that map to regularly spaced intervals along the length of each telomere could be used to characterize subtelomeric aberrations more precisely in a single experiment. We have added 1,120 FISH‐mapped BAC clones to our microarray to enhance the coverage of the 41 unique human subtelomeric regions. Contigs of clones were selected in increments of ∼0.5 Mb beginning with the most distal unique sequence for each subtelomere and extending on average ∼5.7 Mb toward the centromere. We have used this microarray to characterize 169 clinically significant subtelomeric abnormalities identified out of nearly 7,000 consecutive clinical cases analyzed by array CGH in our diagnostic laboratory. The expanded telomere coverage was sufficient to define the breakpoints of over half (56%) of the chromosome abnormalities. However, 44% of the subtelomeric aberrations extended beyond the size of this expanded coverage suggesting that many subtelomeric abnormalities are >5 Mb in size and that greater representation may be of even more value. In addition to identifying 6 cases of complex rearrangements, we have identified 42 cases of interstitial deletions that would have been missed by subtelomere FISH panels that use a single clone to the most distal unique sequence for each region. Microarrays designed to investigate regions known to be involved in chromosome abnormalities will enhance the detection of cytogenetic abnormalities at unprecedented resolution and frequency.