LONDON - Subtle rearrangements of the telomeres, the sequences present at the ends of the chromosomes, have been found to account for many cases of mental retardation. The finding means families with a child who has learning difficulties might be able to find out the reason for the child's disability, and could opt for prenatal testing during subsequent pregnancies.

Samantha Knight, a molecular biologist at the Institute of Molecular Medicine at the John Radcliffe Hospital in Oxford, UK, told BioWorld International: "This is a significant finding because standard diagnostic tests have been unable to pick up genetic rearrangements at this level of resolution before. It is important for families because it gives them a diagnosis, and it is significant because it places subtelomeric rearrangements as the most common cause of mental handicap after Down's syndrome."

Knight, working with Jonathan Flint and other colleagues at the institute, and with researchers based in London and Cambridge, has reported the work in a paper in the Nov. 13 Lancet titled: "Subtle chromosomal rearrangements in children with unexplained mental retardation."

Mental retardation is classified as mild if the person's IQ score is between 50 and 70, and moderate to severe if the IQ score is less than 50. Moderate to severe mental retardation has a prevalence of between 30 and 55 per 10,000 population, and the cause is unknown in up to 40 percent of cases. Mild mental retardation has a much higher prevalence, at two per 100 population, and the cause is unknown in as many as 70 percent of cases.

Knight said, "This is the reason we were interested in mental retardation, because it is such a common disorder which imposes a large medical, psychological and social burden."

The team thought it was likely there was a genetic cause for many of the cases of mental retardation, partly because some families have several members affected and partly because the retardation is often associated with an abnormal facial appearance, or other physical abnormalities.

"This suggests," Knight said, "that there may be something happening at the genetic level. So we set out to find out what those genetic causes might be, and we decided to concentrate first on the telomeres."

Several factors encouraged the team to point the research in this direction. First, the telomeres have both a higher frequency of recombination than the rest of the genome during meiotic division, and they are more richly populated with genes than the remaining portions of the chromosomes. Any mistakes made during replication of DNA in the telomeres would therefore be more likely to affect gene sequences and have consequences for the individual9s phenotype. Secondly, several recognized genetic syndromes involving mental retardation had already been shown to be due to genetic rearrangements of the telomeres.

A pilot study carried out by Flint suggested about six percent of cases of unexplained mental retardation might be due to such telomeric rearrangements. However, this study had used DNA probes that detect hypervariable polymorphisms, a technique that could not be readily scaled up for a study that would need to examine the telomeres of every chromosome, in each patient and both parents.

Flint, Knight and their colleagues therefore decided to use the technique known as fluorescence in situ hybridization (FISH), having first identified probes that were unique for each telomere.

When they used this technique to examine the telomeres of 284 children with unexplained moderate to severe retardation and 182 with unexplained mild retardation, they found that the frequency of subtle chromosomal abnormalities was 7.4 percent in the first group, and 0.5 percent in the second group. The estimated prevalence of these abnormalities was 2.1 per 10,000 population, and about half of the cases were familial.

Writing in the Lancet, the team concluded: "Owing to the high prevalence of familial cases, screening for subtle chromosomal rearrangements is warranted in children with unexplained moderate to severe mental retardation."

Cytocell Ltd., of Adderbury, UK, is now marketing telomere probes as part of a special Multiprobetelomere kit, but Knight said the probes are available from the American Type Culture Collection at a cost of $254 per set to all research laboratories that request them.

Knight, Flint and colleagues are now focusing on identifying which genes are present in the portions of the telomeres that are rearranged or missing in some cases of mental retardation.

Knight added, "In addition, there are still an enormous number of children with unexplained mental retardation that we have not been able to diagnose using this test. We now want to embark on the enormous task of looking at everything that lies between the telomeres for deletions and rearrangements."

She expects some kind of DNA chip technology will be required for such a huge undertaking. This technology is likely to involve arraying thousands of DNA sequences from across the genome onto a glass support, co-hybridizing equal amounts of differentially labeled DNA (from patients and controls) to that support, and then looking for differences between the two hybridization patterns. This method should make it possible to detect DNA sequences that are missing or duplicated in people with mental retardation.