A quilt is raised up for bidders to see at the auction to benefit the Clinic for Special Children in July.

At a medical clinic in rural Pennsylvania, people come to have their genes analyzed by some of the most sophisticated technology in the world, and they arrive in horse and buggy. It may seem an unlikely place for genomics to thrive, given that most Amish don’t have electricity or telephones in their homes. But Amish parents are as eager as any parent for their children to benefit from new technology, and their willingness to participate in research has paid off. In a study announced this week, scientists have pinpointed a genetic mutation that causes an inherited form of sudden infant death syndrome, or SIDS, in which infants die from cardiac or respiratory arrest before their first birthday. The disease has taken the lives of more than twenty Amish infants over the past two decades. The scientists used cutting-edge genomic technology to identify the gene responsible for the fatal disease. Now, newborns are screened for the mutant gene in the clinic at a cost of about $20. The Clinic for Special Children At the center of the research is Dr. D. Holmes Morton, a Harvard-trained pediatrician who has spearheaded research to diagnose and treat diseases among the Amish for more than twenty years. For decades, the Amish have been the focus of research on genetic disorders, in part because they have a small gene pool and certain genetic diseases appear more often than in genetically diverse populations. Morton’s interest in the Amish began when he was a physician at Children’s Hospital in Philadelphia in the 1980s and treated Amish children with rare, metabolic diseases. The patients often traveled long distances with their families from rural Pennsylvania to seek treatment at city hospitals. Wanting to do more, Morton hoped to start a local clinic and laboratory that would help diagnose disease early-on so that patients would have a better chance of survival. In 1989, he and his wife, Caroline, packed up their belongings and moved to Strasburg, Pennsylvania, to found the Clinic for Special Children, a community hospital that provides affordable care, counseling, and genetic testing for disorders unique to the Amish and Mennonite populations. The clinic is home grown. The Mortons bought un-tillable land for the clinic from an Amish farmer and had a barn-raising to erect the structure. Local craftsman helped finish the inside. “We wanted a building that fit the landscape and that looked like it belonged to the community,” says Caroline Morton, who is executive director of the clinic. Dr. Morton initially did most of his own genetic testing and lab work at the clinic, but after several years he began sending DNA samples out for screening for more than 30 disorders. Today, in addition to these off-site tests, Morton and his team at the clinic screen for more than 25 extremely rare disorders. Affymetrix GeneChip.

An Unexpected Partnership A little more than a year ago, a neurobiologist named Dietrich Stephan and Robert Wells, an executive for California-based biotech company Affymetrix, took an autumn drive to the Mortons’ clinic in Lancaster County, Pennsylvania. They heard about the clinic from a mutual friend, Terry Sharrer, a science curator at the Smithsonian Institutions. They also heard that nine families in the Old Order Amish community had lost 21 infants to sudden respiratory or cardiac arrest. Despite extensive testing at hospitals in Pennsylvania, doctors had not been able to determine the cause of disease. Baby girls with the disease appear normal, but baby boys have undeveloped testes. Parents told the doctors they could recognize a sick infant by the sound of his or her cry, which sounded like a goat’s cry. After the drive to Lancaster County, Stephan and Morton, with the help of Affymetrix, decided to try to solve the SIDS mystery. Stephan had recently joined a new genomics research institute in Phoenix, Arizona, called the Translational Genomics Research Institute (TGEN), and offered its resources. When Affymetrix agreed to donate $40,000 worth of specialized microarrays, which are used to analyze variations in the genome, a coast-to-coast collaboration was born. A Gene Candidate To start, Morton and his colleagues at the Clinic for Special Children collected blood from four sick infants and their family members. They isolated DNA from the blood and shipped it to Stephan at TGEN. Within a few days, the Arizona scientists had used the specialized microarrays, known as “SNP chips,” to isolate a stretch of DNA on chromosome 6 that appeared to contain the gene that caused the disease. “They were able to do in a matter of weeks what Morton had been trying to do for several years,” says Robert Wells of Affymetrix. Next, the scientists used online databases to learn about genes in the region and pinpointed a gene that might be responsible for the type of SIDS that afflicted the Amish infants. Their hunch was supported by DNA analysis: All of the sick infants had two mutant copies of the gene, and all of their parents were carriers of the mutant gene. The Clinic for Special Children in Strasburg, Pennsylvania.

The gene, called TSPYL, is turned on in both the brain and the testes during development. The gene acts like a light switch, turning on and off other groups of genes that are important to development of the brain and reproductive system in babies, the scientists say. When the gene does not work properly, as in the Amish children, there can be fatal heart and respiratory problems. All of the sick children who were alive when the study began have since died. Now, infants that come to the Clinic for Special Children are tested for the disorder with a simple gene test. In the year since the test has been available, no child has been diagnosed with this form of SIDS, which the researchers call sudden infant death with dysgenesis of the testes (SIDDT). “The most direct result of this study is that we have a genetic test to detect a disease that has been hard to diagnose,” says Morton. The results of the research appear this week in Proceedings of the National Academies of Sciences. Despite this progress, there is no treatment for the disorder. But Morton and others are studying the gene in the hopes of understanding how it might cause disease and ultimately of developing treatments. Sudden Infant Death Syndrome Sudden infant death syndrome is a catch-all phrase used to describe any infant death of unknown causes before the age of one. The death could be accidental or medical in nature, and there are a number of genetic disorders known to cause sudden cardiac arrest in infants. Morton and his colleagues suspect that the gene mutation they have found in the Amish population may occur in the general population. They are investigating whether other mutations in the gene may cause sudden infant death and developmental problems in children. “We don’t know how prevalent this is in the general population,” says Stephan. “We suspect that it’s going to account for some percentage of cases, but this is obviously not the only cause of SIDS,” he says. To learn more about what the gene does in the human body, Stephan and his colleagues at TGEN are trying to develop research mice that lack the gene. A Quilt Sale for Genetic Research Every summer and fall, the Clinic for Special Children holds three benefit auctions to raise money. Amish and Mennonite families donate quilts, furniture, and baked goods for the fundraisers, which support about a third of the clinic’s annual operating costs. Before the clinic existed, many of these families had to travel to hospitals in Philadelphia and Baltimore for care. And most of the people who come to the clinic do not have health insurance. “The contrast between patients who don’t have health insurance or credit cards and the high-tech medicine they receive is startling,” says Sharrer, who has visited the clinic many times. At Affymetrix, Wells agrees. “There is no other place in the world where Affymetrix chips are being used and outside there’s a hitching post for horses,” he says. Puffenberger, E.G. et al. Mapping of sudden infant death and dysgenesis of the testes syndrome (SIDDT) by a high-density SNP genome scan and identification of TSPYL loss of function. Published online in Proceedings of the National Academy of Sciences July 19, 2004.

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