Characterization of terminal chromosome anomalies using multisubtelomere FISH

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Abstract
Telomeric repeat sequences (TTAGGG) are known to cap the termini of every human chromosome. Proximal to these repeat sequences are chromosome‐specific repeat sequences, which in turn are distal to gene‐rich regions. Submicroscopic, subtle, or cryptic abnormalities in these regions can now be investigated using commercial probe sets for all of the chromosome‐specific subtelomeric regions of the human genome. Using this technology, previously unidentified genomic imbalance has been found in a proportion of patients with idiopathic developmental delay and learning difficulties. We have used these probe sets to investigate cases with apparently terminal anomalies detected on G‐banded chromosome analysis. As a result of such investigations, we have found that 3 (19%) of 16 apparently terminal deletion cases were the result of more complex rearrangements involving other chromosome subtelomeres. The remaining 13 cases contained no chromosome‐specific subtelomere repeats on the deleted arm, but in all 16 cases, the TTAGGG telomere repeat cap was present. A further case was investigated where extra material was found in the terminal region of the chromosome 12 short arm, found to represent a complex inversion/duplication/deletion rearrangement. Investigation of all cases with terminal anomalies, including apparently terminal deletions, is likely to uncover further cases involving complex rearrangements and should lead to a greater understanding of the mechanisms by which these abnormalities arise.