A Modern Miracle in the Most Traditional of Communities
October, 2004
This story about a modern genetic breakthrough takes place in one of the most unlikely venues for genetics: Amish Country in Lancaster County, Pennsylvania, where a group of Old Order Amish - about 18,000 people - currently live.
While it is unusual for a community such as the Amish to embrace a technology as modern as genetics, ironically this particular community will now be known for a landmark genetic study. This July, researchers at the Clinic for Special Children and the Translational Genomics Research Institute (TGEN) hunted down the gene responsible for a new form of SIDS (SIDDT) that was responsible for the deaths of 21 Amish babies. They used GeneChip® Mapping 10K Arrays donated by Affymetrix.
The Amish are descendents of Anabaptists who lived in Switzerland, eastern France, and southern Germany. The Anabaptists - which included the Mennonites - emerged from the Protestant Reformation in the early 1500s. In 1694, followers of Jacob Ammann - now called "Amish" - split from the Anabaptists to start their own church. After many were killed as heretics in the early 1700s, a small group of approximately 200 survivors migrated to the eastern United States, where they continue to live today in much the same fashion as they did in the eighteenth century. The Amish eschew modern technology, use horse drawn buggies, and work their fields by hand.
Because their religious doctrine prevents marrying outside of the faith, the current Amish population in Lancaster County consists of about 18,000 descendants from the original 200. And because of intermarriage, genetic drift, and large family size, many autosomal recessive diseases that are rare in the broader population occur with a higher frequency in this population. One such disease was a form of Sudden Infant Death Syndrome (SIDS) - the catchall term for a syndrome that leads to approximately 3000 infant deaths per year in the U.S.
Dr. Holmes Morton, a pediatrician, founder, and Director of the Clinic for Special Children in Strasburg first became aware of the SIDS epidemic among the Amish from two pediatricians practicing in Huntingdon, Pennsylvania. Over two generations, nine families from this community lost twenty-one infants to this sudden death syndrome, which suggested a recessive inheritance pattern. All infants with SIDS died before 12 months of age of abrupt cardiac and respiratory arrest.
After extensive testing at several major medical centers failed to identify the cause of the disorder, Dr. Morton and his colleagues Dr. Kevin Strauss and Dr. Erik Puffenberger - renowned geneticist and Laboratory Director at the Clinic for Special Children - decided to do something to help the Amish and gain a better understanding of the genetics behind this form of SIDS.
A diary kept by a fourteen-year-old sister of an affected infant and family genealogies dating back to the early 1700s - and often recorded in family bibles - were made available to the researchers due to their trust in Dr. Morton and his clinic. Because the Amish do not usually take part in traditional insurance programs and pay cash for medical care of all forms, Dr. Morton and his wife established the Clinic for Special Children in 1989 as a non-profit organization. The Clinic is supported in large part by donations and fundraising benefit auctions. From the start, the Clinic included a high-complexity CLIA-certified lab used to diagnose and monitor biochemical genetic disorders and established routine newborn screening for many conditions treated at the Clinic.
Dr. Morton and Dr. Strauss worked closely with the Amish community to learn more about this particular subclass of SIDS. They discovered that the children's caretakers noticed a particular cry among children afflicted by SIDS, which was similar to the sound of a goat. The afflicted males had ambiguous genitals and were sometimes mistaken for females at birth. All of the infants died from cardiorespiratory arrest before the age of twelve months.
While many of these infants underwent testing at major medical centers, no abnormalities were found, although males with this particular form of SIDS may also have had underdeveloped testes. Females appeared to be normal and had normal female hormones in blood and urine. Despite these differences, male and female infants with this form of SIDS died suddenly at the same age.
Last year, Terry Sharrer, from the Smithsonian Institution and a friend of Dr. Morton, brought Dr. Dietrich Stephan and Thane Kreiner to the Clinic. Dr. Stephan is Director of Neurogenomics at the Translational Genomics Research Institute (TGEN) and Thane Kreiner is the Senior Vice President, Corporate Affairs at Affymetrix. This meeting resulted in a collaboration between Affymetrix, TGEN, and the Clinic for Special Children. Affymetrix donated GeneChip® Mapping 10K Arrays to the Clinic, which enabled the researchers to begin whole-genome scans of the afflicted families. The GeneChip Mapping Assay, which requires only one primer to amplify the entire genome, allowed the scientists to rapidly conduct whole-genome scans with over 10,000 SNPs and hone in on the putative genes involved in the deaths of Amish babies.
In only eight weeks - less than the time it took for researchers to write up their findings - the scientists were able to identify the genetic locus for this form of sudden infant death syndrome, which they then termed as Sudden Infant Death with Dysgenesis of Testes, or SIDDT. The researchers analyzed the DNA from four of these infants, along with their parents, siblings, and extended family members. First, the researchers narrowed the location of the disorder to a region on chromosome six. By correlating the genes known to reside in the region with their clinical understanding of the syndrome, the researchers believed a gene called TSPYL, which is expressed both in the brainstem and in testes, might be responsible for the sudden deaths in these infants. DNA sequencing of this gene in all four patients revealed a severe alteration. All affected infants were found to have two abnormal copies of the TSPYL gene and all parents were carriers of the alteration. Although several other genes are known to be associated with SIDS, this is the first gene identified which causes a primary form of SIDS.
Dr. Erik Puffenberger conducted most of the genotyping on the project and was the first author on the paper released in the July 19, 2004 online issue of the Proceeding of the National Academy of Sciences. Dr. Puffenberger is a population geneticist and molecular biologist who completed his Ph.D. with Aravenda Chakravarti. He came to the Clinic in 1998 and brought with him his experience with the Mennonite people of Pennsylvania. Dr. Puffenberger introduced routine molecular diagnostic techniques into the Clinic's CLIA Certified Lab. According to Dr. Puffenberger, "This study provides new insight into how the nervous system is regulated and highlights the benefits of close collaborations between researchers, physicians, and the patients they care for."
"The Clinic for Special Children provides medical care to children for more than 60 genetically based clinical problems," said Dr. Morton. "As a result, we have unique opportunities and responsibilities to improve the understanding of these conditions. Our partnership with Affymetrix and TGEN has - in a very short time - allowed us to gain new insights into problems that had resisted explanation for many years before the Clinic was founded."
The physicians at the Clinic for Special Children believe that SIDDT is an interesting and new disorder that immediately suggests new lines of investigation. According to Dr. Stephan, the relationship of TSPYL mutations or polymorphisms to SIDS in the general population will be studied next. Future work will examine the expression patterns of the gene in laboratory animals and the effects of this gene on the normal control of breathing and heart rate in otherwise normal, premature infants. The gene may then be used as a diagnostic test and for carrier studies within high-risk families.
While the mapping of SIDDT was a landmark study, two additional reports will be forthcoming about work in the Clinic. The first paper will describe a newly discovered autosomal recessive cause of temporal lobe seizures and mental retardation in Amish families in Lancaster and Belleville. Another will describe the use of the GeneChip® Mapping 100K Set to diagnose a previously described, but elusive, neurodegenerative condition in several Mennonite families called late-onset sialic acid storage disease. The mutation identified as the cause of this disorder is also found in children and adults in Finland.
Dr. Morton believes that the Clinic is at the beginning of efforts to investigate the molecular pathophysiology of patients with SIDDT, seizure and neurodegenerative disorders such as maple syrup disease, glutaric aciduria, and Salla disease. "We all believe the work at the Clinic with GeneChip technology will ultimately find widespread clinical applications throughout the field of medical genetics," said Dr. Morton. "But more importantly, we believe the insights gained will help us care for our patients and improve their lives and the lives of their families."
This article was written as a collaborative effort by Dr. Holmes Morton, Director of the Clinic for Special Children; Thane Kreiner Ph.D., Senior Vice President, Corporate Affairs, Affymetrix; and Pamela Hunt, Manager, Investor Relations, Affymetrix.
){kind=link}