Conclusion

The discovery that subtelomeric rearrangements are a significant cause of unexplained MR has led to a vast number of studies aimed at providing diagnoses in this group. Results from over 3000 patients show that rearrangements involving the ends of chromosomes can be detected in about 5% of unselected cases, that the prevalence of subtelomeric anomalies is higher in patients with moderate to severe MR (about 7%), and that in about half of those with subtelomeric anomalies, the rearrangements appear to have arisen de novo whereas in half they are familial, unbalanced rearrangements arising from balanced translocations in a parent. Efforts are in progress to refine our current knowledge and to identify more specific subsets of MR individuals by defining those phenotypes more likely to be associated with subtelomeric rearrangements. Some progress has been made based on reported cases, but many more cases need to be categorized before the phenotypes of particular deletions or duplications become clear.

Although originally developed for the study of idiopathic MR, subtelomeric testing is also proving useful for other clinical applications, including the full characterization of partially defined chromosomal abnormalities, the study of spontaneous recurrent miscarriages, infertility, and hematological malignancies, and for preimplan-tation diagnosis (in selected cases). Whatever the application, one diagnostically important issue will be to resolve how much monosomy or trisomy at each of the telomeric regions can be tolerated without phenotypic effect. This is being addressed by establishing a set of markers and clones to measure the size of monosomic/ trisomic regions, thereby providing the foundations for future studies designed to determine whether a given subtelomeric rearrangement would be expected to be benign or pathogenic.[29]

The identification of subtelomeric rearrangements represents an important step toward understanding the genetic causes of unexplained MR. The findings thus far have been particularly relevant for providing clinical diagnoses and more accurate genetic counseling, but ultimately will be important for understanding cognitive development as a whole and for developing new therapeutic avenues. In this respect, subtelomeric studies have already opened important avenues for future research. For example, one crucial question is whether small rearrangements occurring elsewhere in the genome might also be responsible for a significant proportion of unexplained MR cases. Indeed, there are already indications that whole-genome screening for copy number changes would be worthwhile.[15,30] One emerging technology that might prove suitable for this is CGH to microarrays as a single array-CGH experiment has the potential to identify copy number changes anywhere in the test genome at a resolution of 1 Mb or less. Using such approaches will undoubtedly lead to further advanced diagnostic, counseling, and therapeutic capabilities together with a greater scientific understanding of unexplained MR and will also find application in a wide range of other human conditions with genetic origins.

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