That such "minor mutations" can cause unexpected effects stems largely from recent findings in cystic fibrosis (CF).

Writing in the July issue of Clinical Chemistry, Dr. Lawrence M. Silverman, professor of pathology and laboratory medicine at UNC-CH School of Medicine and Dr. Kenneth J. Friedman, a postdoctoral research associate, note that mutations in CFTR - the CF gene - can cause several distinct conditions having clinical similarities to CF. "And when we look at people with ICP and CBAVD, we find mutations in the same gene - the CF gene. So it's the type of mutation within the gene itself that causes the specific disease manifestations," he states.

Silverman and Friedman argue that atypical disease manifestations caused by minor mutations in the CF gene may have important implications for genetic screening and the field of molecular diagnostics in general.

At the annual meeting of the American Association for Clinical Chemistry in New Orleans, Wednesday, July 28, Silverman will discuss these implications when he speaks on national efforts to standardize genetic testing.

"Advanced molecular techniques provide a double-edged sword because they often detect sequence changes [mutations in genes] whose deleterious effects are by no means established," they write.

"When we start sequencing human genes, we may find some things that are not what we expected with that gene," Silverman says. "We have to appreciate that genes can operate at different levels. In CF, according to this new concept, certain mutations that are very severe can result in the typical disease phenotype. If other mutations are milder, more tissue-specific, you can have ICP or CBAVD. And there are still other mutations that will just create lesser sinus-related and pulmonary manifestations."

The situation also may extend beyond possible tissue-specific mutations. Mutations may be "developmentally specific." The consequences of the protein produced by a mutated gene would depend specifically on when that protein is active during the individual's development, Silverman says.

"But then it also might be mutation specific," he adds. With certain mutations we know how the protein is altered. But what if mutations create new functions for the protein, functions that may be deleterious?"

Thus, some mutations would not simply make the gene's protein function less effectively. The mutation would change the protein's function. "And that means the protein being produced has a new negative function," Silverman explains.

"We're arguing that mutations found with the powerful techniques for genotyping, will not always predict the classic disease phenotype, but a variant of it - as in the case of CF, with only a portion of the phenotype," he says.

Thus, several questions arise from this genotype-phenotype argument. In people with disorders having clinical similarities to a larger genetic disease, such as CF, do these disorders actually represent milder versions of that disease? Should such patients be examined clinically for subtle abnormalities of the disease that might otherwise escape detection? And should they be genetically screened for possible disease-related mutations?

"We see patients who come in for chronic pancreatitis whom we now test for CF mutations," the researcher says.

For Silverman and Friedman, the genotype-phenotype argument raises another question: "As the human genome project nears completion in 2003, what other genetic disorders will follow a similar paradigm?"

Note: If no author is given, the source is cited instead.

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