Like Southern novelists, geneticists love to chart the destinies of large, interrelated families with inherited disorders. But geneticists don't have the luxury of literary invention. They must find these kindreds in the flesh—and they will go to great lengths to do so.

Since these family groups—in obedience to religious or political beliefs, or because of geographic obstacles—have not mingled with other populations for generations, the genes of a small colony of founders are often passed on intact, and a variety of traits can be followed through parents, children, cousins, and aunts.

The lure of such families has brought geneticists to unlikely settings. It took Nancy Wexler from the National Institutes of Health in Bethesda, Maryland, to a remote shore of Lake Maracaibo in Venezuela. In search of truly large families, Raymond White moved from the University of Massachusetts in Worcester to Salt Lake City, Utah, where families with twelve children are not too rare.

Nancy Wexler's remarkable quest for the cause of Huntington's disease (HD) rapidly became a legend. HD is a genetic time bomb. In 1872 a New York physician, George Huntington, first described the inexorable course of this disease, which usually starts in middle age and slowly destroys its victims both mentally and physically. Any child of a person who has HD stands a 50-50 chance of developing the disease.

Having watched the disease erode her mother's body, mind, and spirit over the course of a decade, Wexler joined her father Milton, a Los Angeles psychoanalyst, at the Hereditary Disease Foundation, an organization he had created to do research into the disorder. At one of the foundation's research seminars, Wexler was riveted by a film of an isolated Latin American village in which dozens of people lurched about, seemingly afflicted with the very disorder that held her mother in its grip.

When federal funding for HD research finally became available in 1978, Wexler knew where to head with the money—San Luis, the Venezuelan village on Lake Maracaibo in which the film was set.

The people in the village were unaccustomed to medical attention and wary of strangers. However, Wexler had a unique bond with them because she, too, was at risk for HD. She managed to charm, wheedle, and cajole them into donating blood samples from which DNA could be extracted, while at the same time sorting out family connections.

She eventually compiled the entire pedigree—a family tree showing the presence or absence of a trait—of almost 10,000 people and collected 2,000 samples, which are immortalized in cell cultures. Harvard molecular biologist James Gusella, Indiana University's Michael Conneally, and the Massachusetts Institute of Technology's David Housman agreed to analyze the DNA samples she collected. They had probes to recognize markers on an assortment of chromosomes and hoped that one of these probes might detect a marker that traveled with the gene.

Expecting to spend years in this trial-and-error enterprise, they were elated to hit the jackpot on the third try. Their third probe bound to fragments of DNA from people with HD in a distinctive pattern that differed from that of their healthy relatives.

This marker paved the way for finding the HD gene itself in 1993 and for creating a mouse model of the disease in 1996. As a result, families that are at risk for HD can now make informed decisions during their childbearing years. And researchers hope that the mouse model will enable them to find means of preventing or curing the disease.

The Venezuelan village was a priceless source for geneticists because of its isolation. A different reason brought Raymond White to Salt Lake City: the fact that the city serves as headquarters of the Church of Jesus Christ of Latter-Day Saints, also known as the Mormon Church. The Mormon Church not only encourages its members to produce large families, but urges them to compile elaborate genealogies.

"Every family has a historian, and every historian can tell you what diseases the members have had,'' says White. Doctors also let White know about patients he might find interesting. One family referred to White had familial polyposis of the colon, a condition that predisposes people to colon cancer. Working with this large family and testing their DNA samples led him to a marker that signals a gene for susceptibility to colon cancer.

These scientists made valuable discoveries. But there is still much more geneticists need to learn from families about inherited disease risks. One way to speed up research, Nancy Wexler suggests, is for all families to follow the lead of the Amish and the Mormons and chart their own pedigrees. "Virtually everyone knows what a family tree is and how to put one together. And people know what diseases run in their families—not necessarily rare diseases but heart disease, cancer, diabetes.''

She adds that people with unusual family trees—for example, several members with early heart attacks—as well as those with rare diseases should try to link up with researchers through such groups as the National Organization for Rare Disorders, especially if their families are large.

— Beverly Merz

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In a house built on stilts over a Venezuelan lagoon, researchers gather pedigree information from families with many cases of Huntington's diseases.

Photo: ©1983 by Steve Uzzell

Nancy Wexler examines a section of the Venezuelan family's HD pedigree on a wall at NIH. The family tree now includes 10,000 persons and is over 100 feet long.

Photo: ©1986 by Steve Uzzell

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