FISHing for mechanisms of cytogenetically defined terminal deletions using chromosome-specific subtelomeric probes

Abstract

Cytogenetically defined terminal deletions are thought to be a major, yet underappreciated, cause of mental retardation and multiple congenital anomalies. The mechanisms by which terminal deletions arise and are stabilized are not completely understood; although all ends of human chromosomes must have a telomeric cap to be stable. At least three mechanisms exist to maintain chromosome ends with cytogenetically defined terminal deletions: stabilization of terminal deletions through a process of telomere regeneration (termed 'telomere healing'), retention of the original telomere producing interstitial deletions, and formation of derivative chromosomes by obtaining a different telomeric sequence through cytogenetic rearrangement (termed 'telomere capture'). We used chromosome-specific subtelomeric probes and FISH to characterize cytogenetically defined terminal deletions in patients with 1p36 monosomy. Based on the current resolution of these subtelomeric probes, our results indicate that cytogenetically defined terminal deletions of 1p36 are likely to occur through all three mechanisms, although we speculate that the majority of cases were stabilized through telomere regeneration. These results demonstrate the use of chromosome-specific subtelomeric probes as an efficient first step toward uncovering the mechanisms that result in the stabilization of cytogenetically defined terminal deletions.