Down's syndrome, Fragile X and similar syndromes account fornearly half of all inherited and congenital mental retardation. Nowthe other 50 percent, of no known origin, can be cut back to 47percent. An Anglo-Canadian team of psychiatrists and geneticists haspinned 3 percent to genomic abnormalities at the extreme tips ofhuman chromosomes. They're looking to double that number soon to6 percent.

A child who grows with delayed and deficient speaking ability, plusother marked impairments of intellect, i.e., an IQ below 70, butwhose chromosomes reveal no hint of known syndromes, may causeparents to wonder what inheritance they bequeathed him or her.

At Oxford University's Institute of Molecular Medicine, psychiatristJonathan Flint picked up on a slender clue: "A few cases of mentalretardation," he told BioWorld Today, "had turned up with anabnormality at the ends of their chromosomes. These cases, pickedup by chance, were discovered at the molecular level, not bystandard microscope analysis of chromosomes."

Flint asked himself whether these cases represented a generalfinding, or rarities. "In order to answer that question," he related, "Ihad to scour around other laboratories, and find pieces of DNAspecific to the ends of chromosomes." He found them in about 70percent of the telomeres he was able to examine.

The Oxford psychiatrist reasoned that for some of these seeminglycauseless instances of mental retardation waiting to be explained, anoverlooked hot spot might well reside at the extreme tips of humanchromosomes. Enlisting cases from Cambridge University inEngland and the University of Alberta in Canada, he analyzedgenetic material from 58 males and 41 females with unexplainedmental retardation.

99 Patients: No Known Cause

Flint then looked at the genomes of those affected patients, to seewhich had inherited a chromosome from both father and mother(heterozygotes) and which from one parent only. In the latter event,his testing techniques discovered chromosomal deletions markingmental retardation.

This month's issue of Nature Genetics carries an interim report of hisfindings, entitled, "The detection of subtelomeric chromosomalrearrangements in idiopathic mental retardation."

Of the 99 patients he screened for abnormal inheritance ofsubtelomeric (extreme chromosomal tips), three _ despite normalkaryotypes by routine cytogenetic screening _ showed severechromosomal anomalies in their telomeres. Flint's findings spotlighttelomeres of the human genome as a fecund hunting ground foridentifying thus far causeless cases of mental retardation.

These results, however, promise no joy to medical geneticists, whocounsel couples prenatally as to their risk of having a Down orFragile X infant. Flint's now-explainable 3 percent will not beamenable to such prenatal diagnosis.

"It's very unlikely," he said, "that the screening technology we usedwould be of any use to prenatal diagnosis, because the anomalies wefound are de novo rather than inherited." Nor do his findings shedany light on the neurophysiological mechanisms underlying thedeficient intelligence of the subjects. "That insight is a long way overthe horizon," Flint observed. "Ask me that question in five years'time, and I might give you an answer."

His just-published results derive from surveying 70 percent of thechromosomal tips in a normal human karyotype. Since reporting thisdata, Flint said, "I've been working on developing a better test forthe detection of these abnormalities, one finding polymorphicsequences of DNA in more chromosomes, as close to 100 percentspecificity as possible." He added that "It will probably take about18 months to get such a test up and running."

Case Histories Explain 3 Percent Solution

At that point, he said, "if I had a really good test, covering all thechromosomes, 100 percent sensitive, I could expect to double that 3percent figure." About 3 percent of the population in developedcountries, Flint's paper noted, are estimated to have an IQ below 70.

His case histories of the three positive patients tell the poignant taleof their abnormalities, and detection of the causes byhyperpolymorphic DNA analysis, as used in forensic science. Allthree had families with no history of mental retardation:

* A three-year-old functioned at the 18-month level by age 26months. Flint's DNA probes revealed that he had failed to inherit apaternal allele (gene variant), and has a deletion at the tip ofchromosome 13's long arm.

* A 22-year-old woman with an IQ of 20, cannot speak, but isfully mobile. She lacks a maternal allele on chromosome 22.

* A boy now 12 years old, is only mildly retarded (IQ 64). Atage 2.5, he had no speech, and spoke his first understandable wordsat age four. He too lacks a paternally inherited allele. Testing, subjectto further analysis, suggested a deletion on the long arm ofchromosome 22.

In these three cases, the missing or rearranged DNA ranged from60,000 bases to several million. But Flint cautioned,"Characterization of the rearrangements' effects on gene expressionis needed to prove that they cause mental retardation."

In more than 200 normal control families, he could find no suchdefects on the telomeres of chromosomes 13 and 22.

His paper concludes: "This study is the first demonstration thatcryptic chromosomal abnormalities make a significant contributionto idiopathic mental retardation." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.