Subtelomeric rearrangements detected by FISH in three of 33 families with idiopathic mental retardation and minor physical anomalies.

Mental retardation (MR), defined as an intelligence quotient (IQ) of less than 70, affects 2-3% of the population and its aetiology and pathogenesis are still poorly understood. The aetiology can be established in only ~64% of cases with moderate to profound MR and in ~24% of cases with mild MR. Available data indicate that chromosome aberrations are found in 4-28% of affected subjects. However, the yield of these abnormalities is increased when the severity of mental retardation and the presence of congenital anomalies are taken into account. In the past decade, molecular-cytogenetic methods have documented a number of submicroscopic chromosomal rearrangements involving telomeric regions of chromosomes. They have been implicated in α thalassaemia with MR, Wolf-Hirschhorn syndrome,, cri du chat syndrome, 9 10 and Miller-Dieker syndrome. 11 Their presence has also been reported in patients with 18p−, 18q−, 22q−, and 1p− deletion syndromes. These observations suggest that the telomeric regions of chromosomes might be more prone to cryptic rearrangements and thus might be responsible for mental retardation. As telomeric regions of chromosomes have the highest gene concentration in the human genome, rearrangements involving these regions may have severe phenotypic consequences. Moreover, the molecular structure of telomeric regions and high frequency of recombination are predisposing factors to the occurrence of such rearrangements. 27 At present, there is still no single, useful cytogenetic method for screening the entire genome, regardless of the size of suspected chromosomal abnormality. Classical cytogenetic analysis, even with the use of high resolution banding, enables the detection of abnormalities >3-10 Mb in size. Thus, the resolution of the method is not sensitive enough to identify subtle submicroscopic rearrangements. They are not detected by G banding not only because of their small size but also because of their localisation at the terminal light G bands, which are similar for most chromosomes and less readily distinguishable. In the first studies of telomeric regions in patients with mental retardation, Flint et al used highly polymorphic markers to search for cryptic rearrangements. However, DNA polymorphism analysis requires DNA samples from both patient and parents and its use is limited by the informativeness of DNA markers. This analysis enables detection of deletion, duplication, and uniparental disomy cases but does not distinguish a normal person from a carrier of a balanced translocation. 29 Recently, primers used in microsatellite analysis were labelled with fluorochromes, which allowed the detection of the PCR amplification products on an automatic sequencer. This innovation enabled the automated fluorescence analysis of subtelomeric regions. Another strategy applied FISH with probes specific for subtelomeric regions of 22 autosomes and sex chromosomes. The method was adapted for simultaneous analysis of the subtelomeric regions of every chromosome in one hybridisation test. The pair of probes for each chromosome was labelled with dual colours, allowing distinction between the telomeres of the p and q arms. This method, in contrast to the first one,