Genetic Screening : Clues in DNA, Genetic Markers

by Food and Drug Administration (FDA)

(Page 2 of 4)

Clues in DNA

The sequence of a gene's building blocks (called bases) instructs the cell to string together amino acids to build a particular protein. Screens for PKU, sickle cell disease, and Tay Sachs disease were possible because the abnormal proteins causing the symptoms were known.

But knowing which protein lurks behind a genetic disease is rare. Still, with much work and luck, researchers can pinpoint the stretch of DNA that causes a disease, even if its corresponding protein is not known. Zeroing in on the few thousand DNA bases whose activity causes a disease, among the 3 billion bases wound into every human cell, is a needle-in-a-haystack quest of daunting proportions. Even narrowing the gene search down to a specific chromosome is a tall order. (Chromosomes are rod-shaped bodies that carry the genes.) Often, this search can be expedited by very special patients.

In the 1970s, for example, a few young people with Duchenne's muscular dystrophy (DMD) and similarly broken X chromosomes (the X chromosome and Y chromosome determine sex; females are XX, and males are XY) led researchers to the precise location of the DMD gene?the site of the chromosome break

Then, in 1985, a boy was found who not only had DMD, but two other diseases linked to his X chromosome. In addition, his X chromosome had a tiny gap in it. The gap corresponded to the region of the break in the already-known unusual chromosomes.

It wasn't long before Louis Kunkel, Ph.D., at Harvard Medical School used a technique called "chromosome walking" to find that these patients' X chromosomes were missing a huge gene. That gene normally encodes a protein called dystrophin, which is present, sparingly, just beneath the surfaces of muscle cells and is essential for their activity. Because boys inheriting DMD from carrier mothers lack dystrophin, they become wheelchair bound by puberty, and die by their 20s. Thanks to the discovery of dystrophin's role, cell transplants are now being tested to treat DMD (see accompanying article, "Treating the Fetus and Child").

Patients with unusual chromosomes have also helped to unravel the genes behind Wilms' tumor (a childhood kidney cancer) and neurofibromatosis (also known, erroneously, as Elephant Man disease), which causes benign tumors to grow beneath the skin.

Genetic Markers

Even without unusual chromosomes as clues, some genes can be tracked by studying the DNA neighboring them?a little like judging a party by surveying the guests, even if the host is not in sight. The neighboring DNA is called a genetic marker, and it provides an indirect glimpse of a gene.

A genetic marker is an unusual sequence of DNA located near an unknown disease-causing gene. In certain families, a marker is found in every person who has the disease, but not in healthy relatives. Finding a marker is a laborious process, involving cutting DNA from many family members and meticulously searching for a piece of an unusual size found only among the ill.

A genetic marker allows detection of a disease-causing gene before symptoms arise. It can be tracked in a person of any age, as well as a fetus, because all genes are present from conception. For "marked" genes whose associated diseases are currently untreatable, such as those that cause the uncontrollable movements and personality changes of Huntington disease and the mental deterioration of inherited Alzheimer's disease, the value of predicting future ills may be questionable. Some healthy individuals, told they have such genetic diseases in their futures, may become suicidal. Others, however, may want to know the prognosis so they can plan their lives.

The promise of a genetic marker, though, is that it tells investigators where to hunt for the disease-causing gene. Once that is known, the gene's protein can be deduced from the gene's sequence and the biochemical basis of the symptoms revealed. Treatment may follow.

For example, in 1988 a marker for neurofibromatosis was found, and the gene was identified in July 1990. In August 1990, a University of Utah team led by Ray White, Ph.D., deciphered the gene's product. It is a protein that normally suppresses certain cancer-causing genes (oncogenes). White says that "future experiments . . . may suggest new means of therapy. It may become possible, for example, to develop a blocking agent to halt the stimulation of cell growth in a developing neurofibroma [tumor]. Or, it might also be possible to deliver the gene product locally, likewise inhibiting development of neurofibromas."

Cystic Fibrosis and Beyond

Soon, mass population screening may begin for cystic fibrosis, the most common inherited disease of whites. In cystic fibrosis, glands in the lungs and pancreas secrete abnormally thick mucus that obstructs these structures. Also, sweat is very salty. The protein behind cystic fibrosis normally forms a channel in certain cells that controls passage of salts.

A marker for cystic fibrosis was found in 1985, but, like all marker tests, it requires that several family members participate so that the unusual sequence of DNA that travels with the disease-causing gene in that family can be traced. A marker test cannot be used on people who have no relatives with the disorder. For a population-based test (one on people who do not have cystic fibrosis in the family), the gene itself must be in hand. This was indeed accomplished in 1989 by Francis Collins, Ph.D., M.D., at the University of Michigan at Ann Arbor and Lap-Chee Tsui, Ph.D., M.D., at the Hospital for Sick Children in Toronto.

But carrier screening for cystic fibrosis is complicated, because the specific alteration, or mutation, in the gene that led to its identification causes the disorder in only 75 percent of whites of Anglo-Saxon origin?and in less than 40 percent of Jews, blacks, Asians, Italians, and other population groups. This means that a carrier test based only on this one mutation will give many false negatives?people who have a genetic glitch slightly different from the first, who will erroneously be told that they are not carriers.

Scientists are finding dozens of other mutations that cause cystic fibrosis, and additional screening tests for carriers are being developed. With these tests, more carriers can be identified. "Testing for [the four most common mutations] will still detect only 80 to 85 percent of carriers in the United States. It is not yet time for population screening, but it is the time for pilot projects," says Collins.

For now, carrier testing is recommended only for people with cystic fibrosis in the family, says Tom Tsakeris, director of FDA's division of clinical laboratory devices. In these cases, markers can be used along with identifying the mutation, increasing accuracy to close to 100 percent. Demand for population-based carrier testing is likely to be great, because 1 in 25 of all whites 8 million to 12 million people carries the gene.

About the Author

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