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New genetic tests diagnose unexplained cases. (Mental Retardation, Childhood Deafness).

CAMBRIDGE MASS. -- New and more accurate diagnostic testing strategies for unexplained mental retardation, DiGeorge syndrome, Prader-Willi syndrome, and the genetic causes of childhood deafness are among the advances made by genetic scientists in the past few years.

Few pediatricians are aware of the new testing methods because genetic science is evolving so rapidly, Dr. Jeff Milunsky reported at a meeting on behavioral pediatrics sponsored by Boston University.

Often what was novel and exciting 2 years ago is already outdated today A perfect example, he said, is that, "we now know human beings have 30,000-35,000 genes. Just 1 or 2 years ago, we thought that number was 100,000," said Dr. Milunsky, a clinical and molecular geneticist at the university.

The most common type of genetic testing is chromosome analysis, which has been in existence for many years. A more sensitive version of this type of test is high-resolution chromosome analysis. Fluorescence in situ hybridization (FISH) tests go one step further, allowing physicians to look at specific areas of chromosomes.

A key breakthrough in FISH testing came a few years ago when researchers found they could examine small cryptic rearrangements at the gene-rich ends of chromosomes. By using FISH testing in this manner, which is called subtelomeric FISH, Dr. Milunsky said his lab achieved a 7% increase in diagnosing children who have moderate to severe retardation but no previously detectable genetic abnormalities.

This test could be more widely used, he said, pointing out that about 40% of all mental retardation cases remain unexplained.

The FISH test also is very effective at detecting gene deletions. Two disorders now detectable using FISH are velocardiofacial syndrome and DiGeorge syndrome. Children with these syndromes and congenital heart disease have a gene deletion on chromosome 22 in 80%-90% of cases. Children born with isolated tetralogy of Fallot, truncus arteriosus, or abnormalities of the aortic arch have a 20%-30% likelihood of carrying the deletion.

In addition to FISH testing, molecular genetic analysis is progressing rapidly, Dr. Milunsky said. These tests include polymerase chain reaction mutation analysis, linkage analysis, triplet repeat analysis, and sequence analysis. They can be performed on blood samples, buccal swabs, or any skin or muscle biopsy "We do these routinely for diagnostic reasons, presymptomatic diagnosis for cancer syndromes, and for carrier detection."

For example, myotonic muscular dystrophy is an autosomal dominant disorder caused by a triplet repeat expanison on chromosome 19. The most common adultonset muscular dystrophy it has an incidence of 1 in 8,000. It causes muscular atrophy myotonia, cardiac conduction disturbances that can lead to arrhythmias, cataracts, diabetes, testicular atrophy and pregnancy complications. There is no cure but a triplet repeat analysis can diagnose the problem and provide anticipatory guidance for cardiac arrhythmias and diabetes, Dr. Milunsky said.

New molecular technology has also improved diagnosis of Prader-Willi syndrome. About 70% of these cases are caused by a deletion on the paternally derived chromosome 15, detectable using FISH testing. But 28% of these cases are caused by maternal uniparental disomy which means that both chromosome 15's have been derived from the mother, a defect that can only be ascertained with molecular testing. "Now that we have direct molecular analysis, this is how you should order Praderwilli testing," said Dr. Milunsky, noting that the test improves diagnostic accuracy from 70% to 98%.

Geneticists also are making strides in detecting inherited deafness. Researchers know that 50%-80% of non-syndromic recessive deafness and 37% of sporadic deaf ness are due to mutations in the connexin-26 gene. About 1 in 31 persons of European extraction carry a mutation of this gene, and about 1 in 28 people of Ashkenazi Jewish extraction carry a mutation. If both parents carry the abnormal gene, there is a 23% chance their child will be affected.

Dr. Milunsky pointed out that connexin-26 gene sequencing now can be ordered either as part of a cascade testing protocol, or alone. Physicians also can offer prenatal diagnosis.

"This is a very significant advance in deafness evaluation," he said. "This gene is responsible for 10% of all childhood hearing loss."
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Author:Celia, Frank
Publication:Pediatric News
Geographic Code:1USA
Date:Jun 1, 2002
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